Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([OH:17])[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2].[C:25]1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)[CH:30]=CC=C[CH:26]=1.C(=O)(OCC)OCC=C>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:30]([O:17][C@H:13]1[C@H:12]2[CH2:16][C@H:15]([C@@H:10]([C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[C:1]#[N:2])=[O:9])[N:11]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)[CH:25]=[CH2:26]
Reactant: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: [Pd]
Agent: C=CCOC(=O)OCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=CCO[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)N1CCC[C@H]1C#N
Temperature: 65 °C
Reaction time: 4 h
Yield: 715.2 %

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 (510 mg) in tetrahydrofuran (5.0 mL), were added 1,4-bis(diphenylphosphino)butane (64.8 mg), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (39.3 mg) and allyl ethyl carbonate (0.4 mL). The mixture was stirred at 65° C. for 4 hrs. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (408 mg).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f48) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:27]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[O:28])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2]
Reactant: O=C(Cl)c1cccs1
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(NC(=O)c3cccs3)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
To a solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.50 g, 1.7 mmol) in tetrahydrofuran (10 mL) was added 2-thiophenecarbonyl chloride (0.36 mL, 3.4 mmol), and triethylamine (0.52 mL, 3.7 mmol) was added to the obtained mixture. The reaction mixture was stirred at room temperature for 10 min. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The residue was dissolved in conc. hydrochloric acid (5 mL) and the mixture was stirred at 40° C. for 14 hrs. The reaction mixture was neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) and crystallized from isopropyl ether-hexane to give the title compound (0.56 g, yield 82%).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:17]I>CN(C)C=O.CCOCC.[Ag]=O>[C:1]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCC(O)C1
Reactant: CI
Agent: O=[Ag]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 35.6 ml of benzylchloroformate in 200 ml of dichloromethane was added dropwise to a mixture of 10 g of (racemic)-3-pyrrolidinol, 48.3 ml of triethylamine and 725 ml of dichloromethane which was cooled to 0° C. The mixture was stirred for 48 hours at room temperature. The dichloromethane solution was extracted with 5% hydrochloric acid and 5% aqueous sodium bicarbonate. The acid and bicarbonate washes were combined, salted with sodium chloride and extracted with 2×750 ml of ethyl acetate. The combined organic extracts were dried and concentrated, giving 22.7 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol. A mixture of 2.5 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol, 2.0 ml of methyl iodide end 5.1 g of silver oxide in 50 ml of dimethylformamide was stirred at room temperature for 2 days. The mixture was diluted with ether and then filtered. The filtrate was concentrated to a small volume. The ether solution was washed with water, dried and concentrated to dryness in vacuo. The residue was purified by chromatography (silica gel) to give 2.4 g of (racemic)-N-carbobenzyloxy-3-methoxypyrrolidine as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]O)[CH2:5][CH2:4]1)[CH3:2].Cl.N1CCC(CC[CH2:21][OH:22])CC1>>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([CH2:9][CH2:10][CH2:21][OH:22])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCC(CCO)CC1
Reactant: OCCCC1CCNCC1
Agent: Cl
Product: CCN1CCC(CCCO)CC1

Procedure:
Prepared similarly to Intermediate 20 from 3-(4-piperidinyl)-1-propanol hydrochloride.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]#[N:7])[CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[CH3:16][O:17][CH2:18]Cl>O1CCCC1>[CH3:16][O:17][CH2:18][C:4]1([C:6]#[N:7])[CH2:5][C:2](=[CH2:1])[CH2:3]1
Reactant: C=C1CC(C#N)C1
Reactant: COCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1CC(C#N)(COC)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-methylenecyclobutanecarbonitrile (1.00 g, 0.0107 mol) in tetrahydrofuran (40 mL, 0.5 mol) was added 2.00 M of lithium diisopropylamide in tetrahydrofuran (6.44 mL) at −78° C. After stirred at −78° C. for 30 min, to the resulting mixture was added chloromethyl methyl ether (1.02 mL, 0.0134 mol). The reaction was stirred at −78° C. for 30 min, then allowed to warm up to rt, quenched with ammonium chloride, then extracted with ether. The combined organic layers were washed with water, brine, dried, and evaporated to dryness. The crude residue was used directly in next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.CN(C)[CH:18]=[O:19].Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([CH:3]=1)[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: CCc1ccc(Br)cc1I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCc1ccc(Br)cc1C=O
Temperature: -20 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a solution of 4-bromo-1-ethyl-2-iodobenzene (31.8 g, 103 mmol) (described in WO 2008/071405) in anhydrous tetrahydrofuran (250 ml) at −20° C. is added isopropyl magnesium chloride (55 ml, 110 mmol, 2M solution in tetrahydrofuran) dropwise over 10 minutes. Once the addition is complete the reaction mixture is stirred at −20° C. for 3 hours, followed by dropwise addition of anhydrous N,N-dimethylformamide (16.0 ml, 200 mmol). The reaction mixture is stirred at room temperature for a further 2.5 hours, then left to stand overnight. 2M hydrochloric acid (90 ml) is added and the crude product is extracted into dichloromethane. Organics are combined, dried over magnesium sulfate then filtered and the filtrate evaporated under reduced pressure to afford 5-bromo-2-ethyl-benzaldehyde (21.20 g) as an orange liquid.
Reaction SMILES: [F:1][C:2]([F:22])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([CH3:5])=[CH2:4].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:4][C:3]([C:2]([F:22])([F:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH2:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)C(F)(F)CCCCCCCCCCCCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CBr)C(F)(F)CCCCCCCCCCCCCCCC

Procedure:
A slurry of 140 mg of 3,3-difluoro-2-methyl-1-nonadecene in 2 ml of carbon tetrachloride containing 43 mg of N-bromosuccinimide and a catalytic amount of azobisisobutryonitrile is stirred at ambient temperature for 30 minutes. The mixture is filtered through a short pad of silica gel which is repeatedly washed with hexane. The combined filtrates are evaporated and the residue is purified on silica gel using hexanes to give 38 mg of the desired product as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].Cl[CH2:14][C:15]#[N:16]>[OH-].[Na+].CN(C)C=O>[C:15]([CH2:14][N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)#[N:16]
Reactant: N#CCCl
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2CC#N

Procedure:
35.0 g (0.25 mole) of 3-methyl-xanthine (Chem. Ber. 83, 209 1950) are dissolved in 81.4 ml (0.25 mole) of a 10% sodium hydroxide solution under shaking; crystallization takes place within some minutes. Water is distilled off in vacuo and the traces of water are removed by azeotropic distillation with toluene. The residue is suspended in 35 ml of dimethyl formamide, whereupon a solution of 18.9 g (0.25 mole) of chloroacetonitrile in 80 ml of dimethyl formamide is added dropwise at 100° C. within 30 minutes. The reaction mixture is stirred at 100° C. for a further hour, filtered until hot, the precipitate (sodium chloride) is washed with hot dimethyl formamide and the united solutions are evaporated to dryness under reduced pressure. The residue is treated with 100 ml of acetone, the crystals are filtered by suction and throughly washed with acetone. The 7-cyanomethyl-3-methyl-xanthine (m.p.: 285°-287° C.) thus obtained can be used in further reactions.
Reaction SMILES: [CH3:1][C@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[OH:15])[CH2:3][OH:4].[C:16](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][C@H:2]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[CH2:3][OH:4]
Reactant: COc1cccc(SC[C@@H](C)CO)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc(SC[C@@H](C)CO)c1OC
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
0.43 g (0.0019 mol) of 2-(S)-methyl-3-(2-hydroxy-3-methoxyphenylthio)propan-1-ol (XXg), 10 ml of acetone and 0.26 g (0.0019 mol) of potassium carbonate are introduced into a round-bottomed flask kept under an inert atmosphere. After 15 minutes, 0.12 ml (0.0019 mol) of methyl iodide is introduced and the mixture is heated at 60° C. for 8 hours. The mixture is concentrated under reduced pressure. The residue is taken up in water and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated. The residue obtained is used without additional purification in the following stage.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.[I:23]N1C(=O)CCC1=O>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([I:23])=[C:7]([O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2I)CC1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-Bromo-6-(trans-4-tert-butyl-cyclohexyloxy)-naphthalene (500 mg, 0.001 mol) in Methylene chloride (2 mL, 0.03 mol), N-iodosuccinimide (600 mg, 0.003 mol) was added, followed by zirconium tetrachloride (60 mg, 0.0003 mol) at 23° C. The reaction mixture was then sonicated and stirred for 5 minutes at 23° C. Reaction was then diluted with DCM and the solids were removed via filtration through a 4 micron filter. 1 g of SiO2 was added directly to the solution and the solvent was then removed under reduced pressure. The SiO2 was then loaded onto a column (SiO2, 24 g, 0-10% ethyl acetate/hexanes (ran neat hexanes for first 9 minutes of a 30 min gradient)) to give the DP as a tan amorphous solid with 20% impurity (SM) by HNMR. Material was then triturated with methanol, filtered, and dried on filter to give 386 mg of the desired product as a white solid in (60%). ESI-MS: 488 (M+H)+.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:33]1[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:34]=1>>[C:43]([C:35]1[CH:34]=[C:33](/[C:27](/[Si:28]([CH3:29])([CH3:30])[CH3:31])=[CH:26]/[C:23]2[CH:22]=[CH:21][C:20]([CH2:19][OH:18])=[CH:25][CH:24]=2)[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:36]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)cc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)c1cc(/C(=C/c2ccc(CO)cc2)[Si](C)(C)C)cc(C(C)(C)C)c1

Procedure:
Following General Procedure A, 4-[(trimethylsilyl)ethynyl]benzyl tert-butyldiphenylsilyl ether and 1-bromo-3,5-Di-tert-butylbenzene (which can be prepared by the procedure described in Komen and Bickel Synth. Commun, 1996, 26, 1693-1698) were coupled to give the title compound (Compound 32). PNMR (300 MHz, CDCl3) δ 7.40 (s, 4H), 7.33 (s, 2H), 7.08 (s, 1H), 7.07 (s, 1H), 4.78 (d, J=5.9 Hz, 1H), 1.41 (s, 18H), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[OH:36][CH2:35][C:34]([NH:33][S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]([F:16])[F:15])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31])([CH3:38])[CH3:37]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.3) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Light yellow solid. MS (ISP) 550.1 [(M+H+]; mp 229° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][C:7]=2[N:15]2[C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:22][C:23]([CH3:31])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[C:18]3([CH2:19][O:20][CH2:21]3)[CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:11]=1)=[O:13])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[CH3:31]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(N3CCC34COC4)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(cyclopropylmethoxy)-5-(6-oxa-1-azaspiro[3.3]heptan-1-yl)picolinic acid (Example 234 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials. MS (EI): m/e=414.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4].[NH:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:35]1([CH2:2][C:3]([NH:5][CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([C:17](=[O:34])[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[CH:20][CH:19]=3)[CH2:9][CH2:8][CH2:7]2)=[O:4])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)CCl)c3ccccc32)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)Cn3ccnc3)c3ccccc32)cc1
Yield: 23.4 %

Procedure:
A mixed solution of 5-(2-chloroacetylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g), imidazole (0.1 g) and potassium carbonate (0.19 g) in acetonitrile (30 ml) is refluxed for 8 hours. The reaction solution is concentrated and the resulting residue is washed with water and separated by decantation. The remainder is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1→15:1), and recrystallized from ethanol/n-hexane to give 5-[2-(1-imidazolyl)acetylamino]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.15 g) as colorless needles, m.p. 250°-252° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].CO.[CH:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>C(OC(=O)C)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:16][CH:17]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Acetophenone (0.5 g) and sodium hydroxide (0.17 g) were suspended in 15 Ml of methanol pre-chilled at −10° C. p-Anisaldehyde (0.57 g) was added thereto, and stirred for 10 hr at room temperature. After neutralization with 5% hydrochloric acid solution, the product was extracted with 100 Ml of ethylacetate. The extracted organic phase was dried with anhydrous magnesium sulfate, and concentrated under vacuum evaporator. Purified compound was obtained by elution with n-hexane:ethylacetate (v/v, 1:7) through silica gel column chromatography (5×3 cm, Merk), and identified as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][N:10]2[CH2:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=1>CC#N>[Cl:8][C:6]1[N:7]=[C:2]([NH:32][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[N:3]=[C:4]([NH:9][N:10]2[CH2:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[N:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C1CN(Nc2nc(Cl)nc(Cl)n2)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CNc2nc(Cl)nc(NN3CC(=O)NC3=O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a mixture of 1-(4,6-dichloro-[1,3,5]-triazin-2-yl-amino)-imidazolidine-2,4-dione (Example 1.1, Part A) (3.84 g, 14.6 mmol) and K2CO3 (4.4 g, 31.8 mmol) in CH3CN (50 mL) was added (4-methoxyphenyl)-methanamine (2.0 g, 14.6 mmol) drop-wise at 0° C. The mixture was stirred at r.t. overnight. TLC showed the reaction was complete. The mixture was filtered and the cake was portioned between water and EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the expected compound (3.50 g, yield: 66%) as a white solid. It was used for the next step without further purification. δH (400 MHz, DMSO-d6): 11.30-11.23 (m, 1H), 10.06-9.83 (m, 1H), 8.67-8.60 (m, 1H), 7.24-7.13 (m, 2H), 6.90-6.83 (m, 2H), 4.40-4.35 (m, 2H), 4.26-4.05 (m, 214), 3.73 (s, 3H). Mass spectrum (ESI) m/z 364 (100%, MH+).
Reaction SMILES: C([O:3][C:4](=[O:32])/[C:5](/[O:29][CH2:30][CH3:31])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:28])C.[OH-].[Na+]>C1COCC1.CO>[CH2:30]([O:29]/[C:5](=[CH:6]\[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:28])/[C:4]([OH:32])=[O:3])[CH3:31]
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1C)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCO/C(=C\c1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of (Z)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-acrylic acid ethyl ester (6.8 g, 15.6 mmol) in THF/methanol 2/1 (102 ml) was added a 3 M aqueous NaOH solution (26 ml, 78 mmol). The reaction mixture was stirred for 3 h at ambient temperature, concentrated under reduced pressure, diluted with ice water and acidified with with 1 M aqueous HCl solution. Twofold extraction with ethyl acetate was followed by washing of the combined extracts with ice water/brine 1/1 (three times) and drying of the organic layer over sodium sulfate. The solvent was removed under reduced pressure and the crude product crystallized from dichloromethane/n-heptane to give the title compound (6.3 g, 15.5 mmol, 99%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:19])[C:5]2[N:6]=[CH:7][N:8]([C@H:11]3[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]3)[C:9]=2[N:10]=1.[OH-].[Na+].[CH2:22](Cl)[CH:23]=[CH2:24].Cl>>[CH2:24]([S:19][C:4]1[N:3]=[C:2]([NH2:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]1)[CH:23]=[CH2:22]
Reactant: Nc1nc2c(ncn2[C@@H]2C[C@H](CO)[C@@H](O)C2)c(=S)[nH]1
Reactant: C=CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCSc1nc(N)nc2c1ncn2[C@@H]1C[C@H](CO)[C@@H](O)C1

Procedure:
(+)-(1S, 2R, 4R)-4-(2-Amino-1,6-dihydro-6-thioxo-9H-purin-9-yl)-2-(hydroxymethyl)-1-cyclopentanol (351 mg, 1.25 mmol) and 1N sodium hydroxide (1.15 mL) were stirred with allyl chloride (0.15 mL) for 5 hour. The solution was neutralized with hydrochloric acid and volatiles evaporated. The residue was chromatographed on silica gel. Title compound was eluted with 12% methanol-chloroform as a white solid foam which solidified to white powder from acetonitrile (240 mg, 60%): m.p. 133°-134°; mass spectrum (cl, CH4):322 (M+1); 1H-NMR (DMSO-d6) δ: 8.07 (s, 1, H8), 6.51 (br s, 2, NH2), 6.10-5.85 (m, 1, CH=), 5.45-5.30 (m, 1, 1/2CH2 =), 5.15-5.05 (m, 1, 1/2CH2 =), 5.0-4.8 (m, 1, CHN), 4.79 (d, J=4.1 Hz, 1, OH), 4.66 (t, J=5.2 Hz, 1, CH2OH), 4.15-4.0 (m, 1, CHO), 3.98 (d, J=6.9 Hz, 2, CH2S), 3.6-3.4 (m, 2, CH2O), 2.4-1.9 (m, 4, CH+methylenes), 1,75-1.55 (m, 1, 1/2CH2); [α]20589 +9.30°, [α]20578 +9.68°, [α]20546 +11.1°, [α]20436 +18.6°, [α]20365 +25.4° (c=0.79, methanol).