Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][OH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Si:25]([O:15][CH2:14][C@@H:9]1[CH2:10][C@@H:11]([OH:13])[CH2:12][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-N-Boc-(2S,4R)-4-hydroxy-2-(hydroxymethyl)-pyrrolidine (500 mg) was dissolved in DMF (4.0 ml), and imidazole (164 mg) was added to the dissolution. After cooling to 0° C., tert-butylchlorodiphenylsilane (616 μl) was added to the mixture, and stirred for 1 hour. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, oily substance (655 mg). Physical properties: m/z [M+H]+ 456.2
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30](=[O:40])[CH2:31][NH:32]C(=O)OC(C)(C)C)[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.[ClH:41]>CO.O1CCCC1>[ClH:41].[ClH:41].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:25][CH2:26][N:27]([C:30](=[O:40])[CH2:31][NH2:32])[CH2:28][CH2:29]4)[N:20]=3)[CH2:17][CH2:18]2)=[O:12])=[N:2]1
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCC(=O)N1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Yield: 90.4 %

Procedure:
A solution of tert-butyl {2-[4-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperazin-1-yl]-2-oxoethyl}carbamate (70.0 mg, 0.122 mmol) and a solution of 2 N hydrogen chloride in methanol (5 ml) in tetrahydrofuran (5 ml) was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of methanol and diethyl ether to give 60.0 mg (90.4%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22](=[O:24])[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)Nc1ccccc1
Yield: 99.1 %

Procedure:
A mixture of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid (300 mg, 0.84 mmol), aniline (0.15 mL, 1.70 mmol), DMAP (60 mg, 0.50 mmol) and EDC.HCI (320 mg, 1.70 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 66 h. The reaction mixture was concentrated under vacuum and the residue was subjected to flash silica gel column chromatography eluting with methanol/CH2Cl2 (1:99, v/v) to give the desired amide 18 as a white solid (360 mg, 99% yield). 1H NMR (300 MHz, CDCl3) δ 8 1.55 (m, 4H), 2.60 (m, 2H), 3.20 (m, 2H), 4.58 (s, 2H), 4.70 (br s, 1H), 5.10 (s, 2H), 6.88 (d, 2H), 7.15. (m, 3H), 7.35 (m, 7H), 7.58 (d, 2H), 8.25 (s, 1H). m/z (ESI): 433 [C26H28N2O4 +H]+.
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:24][C:25](=[O:52])[C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:44][CH:43]=2)[CH:36]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-].C1COCC1>CO>[C:48]([C:45]1[CH:44]=[CH:43][C:42]([O:41][C:37]2[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=2)[CH2:34][NH:33][C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[C:25]([NH:24][C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[C:3]([OH:53])=[O:2])=[O:52])=[CH:47][CH:46]=1)([CH3:51])([CH3:49])[CH3:50]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C3CCCCC3)cc2)cc1)NC(=O)c1cc(Cl)ccc1NCc1cccc(Oc2ccc(C(C)(C)C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(Oc2cccc(CNc3ccc(Cl)cc3C(=O)N[C@@H](Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)C(=O)O)c2)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
The title compound was prepared following General Procedure C using (S)-2-{2-[3-(4-tert-Butyl-phenoxy)-benzylamino]-5-chloro-benzoylamino}-3-(4′-cyclohexyl-biphenyl-4-yl)-propionic acid methyl ester (135 mg, 0.19 mmol), LiOH(aq) (2.0 N, 0.22 mL, 0.44 mmol), THF (4 mL) and MeOH (1 mL). The mixture was stirred at 0° C. for 12 h. The product was obtained as off-white solid (115 mg, 0.16 mmol, 84% yield).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([O:20][CH2:21][CH3:22])=[CH:18][CH:17]=[CH:16][N:15]=1)SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([O:20][CH2:21][CH3:22])=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:4]
Reactant: CN
Reactant: CCOc1cccnc1CSCCN=C(NC#N)SC
Solvent: CCO
Product: CCOc1cccnc1CSCCN=C(NC)NC#N
Reaction time: 8 h

Procedure:
Methylamine in ethanol (33%, 10 cc) was added to a stirred suspension of N-cyano-N'-[2-((3-ethoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea (1.0 g) in ethanol (5 cc) and the mixture was left to stand overnight. Nitrogen was bubbled through the solution for one hour and the solution was concentrated and crystals which deposited were filtered off and recrystallised from ethanol/ether to give the title product (0.7 g) m.p. 126.5°-127.5°.
Reaction SMILES: [OH-].[Na+:2].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.C(O)(=O)C>CO>[Na+:2].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([O-:14])=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(O)CNc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C([O-])CNc1ccc(O)cc1
Temperature: 0 °C

Procedure:
18 g of sodium hydroxide are dissolved in 250 ml of methanol and 75 g of p-hydroxy-phenyl-glycine are added. After stirring at 60° C. for 15 minutes 2 ml of acetic acid is added to the reaction mixture which is cooled to 0° C. and the suspension is filtered. The wet p-hydroxy-phenyl-glycine sodium salt obtained is suspended in 500 ml of ethanol, 75 g of acetoacetic acid methylester and 0.5 ml of acetic acid are added and the mixture is refluxed for 90 minutes. The residue is cooled to -5° C. and the suspension obtained is filtered, the crystals are dried in vacuo at 60° C. 124.1 g of sodium-D-N-(2-methoxy-carbonyl-1-methyl-vinyl)-α-amino-(p-hydroxy-phenyl)-acetate are obtained.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:33])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Product: COc1cccc(-c2ocnc2C(=O)Nc2ccn(Cc3nc(C(C)=O)cs3)n2)c1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.83 min; [M+H]+=424.07.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH2:13]1[CH:17]2[C@H:18]3[C:23](=[O:24])[O:22][C:20](=[O:21])[C@H:19]3[CH:14]1[CH:15]=[CH:16]2.O>CC(C)=O.CN(C)C1C=CN=CC=1>[OH:6][C:5]1[C@@H:7]([C@@H:9]([OH:10])[CH2:11][O:12][C:23]([CH:18]2[CH:17]3[CH2:13][CH:14]([CH:15]=[CH:16]3)[CH:19]2[C:20]([OH:22])=[O:21])=[O:24])[O:8][C:2](=[O:1])[C:3]=1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: O=C1OC(=O)[C@H]2C3C=CC(C3)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1O[C@H]([C@@H](O)COC(=O)C2C3C=CC(C3)C2C(=O)O)C(O)=C1O
Temperature: 60 °C
Reaction time: 48 h

Procedure:
In a 50-mL one neck round bottom flask, ascorbic acid, Catalog No. A92902 from Aldrich Co. (4.80 g) was dissolved in acetone (16.42 g). In the same flask, cis-endo-5-norbornene-2,3-dicarboxylic anhydride, Catalog No. 247634 from Aldrich Co. (4.42 g), and 4-dimethylaminopyridine, Catalog No. 522821 from Aldrich Co. (0.06 g), were added. The flask was heated while stirring in a 60° C. oil bath for 48 hours. Water (15 mL) was added and the flask was heated for another 12 hours. The product was extracted in ethyl acetate (100 mL) and dry with magnesium sulfate. The product, a mixture of bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid and 3-({(2S)-2-[(2R)-3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl]-2-hydroxyethoxy}carbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid was isolated by removing ethyl acetate by rotary evaporation.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:12]2[CH:8]([O:9][CH2:10][CH2:11]2)[O:7][CH2:6]1)(=[O:3])[CH3:2].O.O.P([O-])(O)(O)=O.[Na+].C([O-])(O)=O.[Na+].ClCCl>O>[C:1]([O:4][C@@H:5]1[C@H:12]2[C@H:8]([O:9][CH2:10][CH2:11]2)[O:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1COC2OCCC12
Agent: O=C([O-])O
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 42.5 °C
Yield: 42.7 %

Procedure:
Hexahydrofuro[2,3-b]furan-3-yl acetate (124 g) to the RB flask along with buffer solution (118 g Sodium dihydrogen phosphate dihydrate dissolved in 600 ml water & pH adjusted to 6.5 with saturated NaHCO3 aqueous solution). CAL-B enzyme (19.5 g) was added to the reaction mass and stirred at 40-45° C. Reaction was monitored by Chiral-GC. Reaction was cooled to room temp., dichloromethane (1300 ml) was charged to reaction mass and filtered through hyflow bed. Dichloromethane layer was separated and washed with Sodium chloride solution (10%, 650 ml) and water (3×650 ml). Dichloromethane layer was concentrated under vacuum to get residue of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl acetate (Yield 53 g). Further, the product was purified by fractional distillation under vacuum at 98-118° C. to get main fraction 39.5 g having purity 97.98%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][OH:12])=[N:7][C:6]=2[CH:13]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][O:12][S:22]([CH3:21])(=[O:24])=[O:23])=[N:7][C:6]=2[CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1nc2cc(Br)ccc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1nc2cc(Br)ccc2s1

Procedure:
To a mixture of 2-(5-bromo-benzothiazol-2-yl)-ethanol (0.94 g, 3.6 mmol) in 10 mL CH2Cl2, Et3N (0.99 g, 9.8 mmol), was added methanesulfonyl chloride (0.46 g, 4.0 mmol) dropwise at room temperature. The reaction was worked up by concentrating under vacuum and then used in the next step, Example 1C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[O:32])=[C:26]([F:41])[CH:25]=1)#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([OH:21])[CH2:22][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)=[O:32])=[C:26]([F:41])[CH:25]=1)#[N:7]
Reactant: CCNCC
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC1CO1
Solvent: C1CCOC1
Product: CCN(CC)CC(O)COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C#N
Temperature: 50 °C

Procedure:
After adding tetrahydrofuran (1 ml) and diethylamine (0.1 ml) to N-[4-(6-cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)urea (100 mg), the mixture was heated at 50° C. for 30 minutes. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (32 mg) as light yellow crystals.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])=[O:4])[CH3:2]>C(O)C.O=[Pt]=O>[CH2:1]([S:3]([NH:6][C@@H:7]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: O=[Pt]=O
Solvent: CCO
Product: CCS(=O)(=O)N[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 80.3 %

Procedure:
To a solution of EtSO2-D-Phe-Pro-OH (10 g, 28 mmol) in ethanol (300 mL) was added PtO2 (5 g). The mixture was hydrogenated using a high pressure apparatus at 4.1 bar and 20° C. for 20 h. The solution was then filtered through diatomaceous earth, and concentrated to give 8.1 g (80%) of thick oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].Cl.[CH:15]([N:18]([CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]Cl)([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:20][CH2:19][N:18]([CH:22]([CH3:24])[CH3:23])[CH:15]([CH3:17])[CH3:16])[C:8](=[O:11])[C:7]2=[O:12]
Reactant: Cc1cc(Br)c2c(c1)C(=O)C(=O)N2
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Product: Cc1cc(Br)c2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Yield: 13.1 %

Procedure:
By using the 7-bromo-5-methylisatin and 2-diisopropylaminoethyl chloride hydrochloride, a method analogous to that described in Reference Example 1 was carried out to obtain 7-bromo-1-(2-diisopropylaminoethyl)-5-methylisatin having a melting point of 94°-97° C. (yield: 13.1%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C[Si]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](O[Si](C(C)(C)C)(C)C)[C:31]=1[CH:44]1[CH2:49][CH2:48][C:47](=[CH2:50])[CH2:46][CH2:45]1)(C(C)C)C)(C)(C)C.[O:51]1CCCC1>>[CH2:50]=[C:47]1[CH2:48][CH2:49][CH:44]([C:31]2[CH:32]=[CH:33][C:34]([OH:51])=[CH:35][C:30]=2[OH:29])[CH2:45][CH2:46]1
Reactant: C=C1CCC(c2c(O[Si](C)(CC(C)(C)C)C(C)C)cccc2O[Si](C)(C)C(C)(C)C)CC1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C=C1CCC(c2ccc(O)cc2O)CC1
Reaction time: 24 h
Yield: 90 %

Procedure:
Tetrabutylammonium fluoride (230 μl) was added to a stirred solution of tert-butyl-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-methylenecyclohexyl)phenoxy](isopropyl)dimethylsilane (40 mg) in tetrahydrofuran (2 ml) at room temperature. After 24 hr, further tetrabutylammonium fluoride (50 μl) was added, and after 2 hr the solvent was removed under reduced pressure. The residue was partitioned between water (20 ml) and ethyl acetate (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 2:3 v/v) to give the title compound as a white solid (17 mg, 90%). δH (CD3OD) 1.25-1.40 (2H, m), 1.75-1.82 (2H, m), 2.04-2.15 (2H, m), 2.22-2.30 (2H, m), 2.86 (1H, tt), 3.20 (1H, m), 4.50 (2H, s), 6.10-6.16 (2H, m), 6.72 (1H, d); m/z (ES+) 205 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=O.[NH:11]([CH2:13][CH2:14][OH:15])[NH2:12]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1/[CH:8]=[N:12]/[NH:11][CH2:13][CH2:14][OH:15]
Reactant: O=Cc1c(Br)cncc1Br
Reactant: NNCCO
Product: OCCN/N=C/c1c(Br)cncc1Br
Temperature: 120 °C
Yield: 92.8 %

Procedure:
In analogy to GP1, 468 mg of 3,5-dibromo-pyridine-4-carbaldehyde (1.77 mmol, 1 eq; commercially available or prepared as described in U.S. Pat. No. 6,232,320 or WO2005110410) were dissolved in 8 mL 1-propyl alkohol, treated with 0.36 mL 2-hydrazino-ethanol (5.3 mmol, 3 eq.) and heated to 120° C. for 30 min (employing a Biotage Initiator® microwave oven). The reaction mixture was concentrated, the residue partitioned between water and ethyl acetate, the aqueous layer reextracted with ethyl acetate, the combined organic layers dried and concentrated in vacuo to yield 530 mg of the desired product (1.64 mmol, 93% yield), which was used in the subsequent cyclization without further purification steps.
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1.[CH3:10][NH:11][CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CCOC(C)=O>[CH3:10][N:11]([CH3:12])[CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1
Reactant: CNC
Reactant: COC(=O)C1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(N(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A solution of methyl 3-oxocyclobutanecarboxylate (0.5 g, 3.90 mmol) in EtOAc (10 mL) was treated with dimethylamine (1M in THF, 11.71 mL, 11.71 mmol), stirred at RT for 1 h, treated portion-wise with sodium triacetoxyborohydride (1.158 g, 5.46 mmol) and stirred at RT overnight. The mixture was treated with 1N NaOH, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford methyl 3-(dimethylamino)cyclobutanecarboxylate (596 mg, 97%). 1H NMR (400 MHz, DMSO-d6): δ 3.57 (s, 3H), 3.33-3.26 (m, 1H), 2.75-2.74 (m, 1H), 2.19-2.18 (m, 2H), 1.97 (s, 6H), 1.88-1.85 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[N+:20]([C:9]1[CH:10]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]=1[C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:33][CH:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)[CH3:32])[CH:7]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(Nc1cc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])ncn1)c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 54.7 %

Procedure:
Into a 100 mL round bottom flask, was placed a solution of 4-chloro-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidine (100 mg, 0.31 mmol, 1.00 equiv) in toluene (10 mL), 1-(3-(trifluoromethyl)phenyl)ethanamine (71 mg, 0.38 mmol, 1.20 equiv), BINAP (9 mg, 0.01 mmol, 0.05 equiv), Cs2CO3 (144 mg, 0.44 mmol, 1.40 equiv), and Pd(dba)3CHCl3 (6.5 mg, 0.01 mmol, 0.02 equiv). The resulting solution was stirred for 3 h at 120° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). The product was obtained as 80 mg (54%) of a yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:17])[CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=2)=[N:4][CH2:3]1
Reactant: CC(C)(CNC(=O)c1ccc(C(F)(F)F)cc1)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CN=C(c2ccc(C(F)(F)F)cc2)c2ccccc21
Temperature: 110 °C

Procedure:
A 100-mL round-bottomed flask was charged with N-(2-methyl-2-phenylpropyl)-4-(trifluoromethyl)benzamide (2.69 g, 8.39 mmol), phosphorus pentaoxide (1.88 g, 16.8 mmol), toluene (40 mL) and phosphorous oxychloride (6.3 mL, 67.1 mmol). The reaction mixture was heated at 110° C. for 16 h and allowed to cool down to RT. Then it was poured over ice-water and neutralized with NaOH (10%). The organic phase was taken and the aqueous phase was extracted several times with EtOAc. The combined organic layers were washed with sat NaHCO3, water, brine and dried over Na2SO4. The solvent was removed under vacuum and the product used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[N:13]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[C:12]([CH3:27])([CH3:26])[CH2:11][CH2:10]1.[Cl-].[NH4+:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[N:13]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([NH2:29])=[O:25])=[C:16]3[N:15]=2)[C:12]([CH3:27])([CH3:26])[CH2:11][CH2:10]1
Reactant: CC1(C)CC[C@H](c2cc(F)ccc2F)N1c1ccn2ncc(C(=O)O)c2n1
Reactant: [NH4+]
Agent: [Cl-]
Product: CC1(C)CC[C@H](c2cc(F)ccc2F)N1c1ccn2ncc(C(N)=O)c2n1
Yield: 33 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and ammonium chloride. The crude material was purified by reverse phase HPLC (0-70% acetonitrile/water) to provide the title compound (8.5 mg, 33% yield). MS (apci) m/z=372.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[N+:12]([O-])(O)=O>>[NH2:12][C:3]1[C:2]([F:1])=[CH:11][C:6]2[NH:7][C:8](=[O:10])[O:9][C:5]=2[CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2cc(F)ccc2o1
Product: Nc1cc2oc(=O)[nH]c2cc1F
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 300 ml concentrated nitric acid, at room temperature, was added portionwise 73.2 g (0.48 mole) of 5-fluoro-2(3H)-benzoxazolone. The reaction mixture was warmed to 50° C., and was stirred for 4 hours. After cooling, the reaction mixture was poured onto ice. The precipitate which formed was collected, washed with water, and dried to give 72.8 g of the title compound as a brown powder: m.p. 207°-209° C.