Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[C:12]=3[N+:19]([O-:21])=[O:20])[CH2:7][CH2:6][C:5]=2[N:22]=1.[CH2:23](I)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[C:15]([CH3:17])[N:14]([CH2:23][CH3:24])[C:13](=[O:18])[C:12]=3[N+:19]([O-:21])=[O:20])[CH2:7][CH2:6][C:5]=2[N:22]=1
Reactant: CCI
Reactant: Cc1nc(N2CCc3nc(N)sc3CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(C)nc(N2CCc3nc(N)sc3CC2)c([N+](=O)[O-])c1=O

Procedure:
In analogy to the procedure described in example 2 the 6-(2-amino-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepin-6-yl)-2-methyl-5-nitro-3H-pyrimidin-4-one (example 3) was treated with the ethyl iodide in N,N-dimethylformamide in the presence of potassium carbonate at room temperature to yield the title compound as yellow solid; m.p.>200° C.; MS: [M+H]+=351.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:23](O)[CH3:24]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:23][CH3:24])=[O:9])=[CH:11][CH:12]=1
Reactant: CCO
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C=Cc1ccc(O)cc1

Procedure:
To a solution of 4- hydroxycinnamic acid (16.4 g) in ethanol (100 ml) was added sulfuric acid (10 ml). The mixture was refluxed with heating for 4 hours, Aqueous sodium bicarbonate solution was added to the reaction solution so as to make basic. Then, the reaction solution was extracted with chloroform. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum to yield a raw product of ethyl 4-hydroxycinnamate. In a manner similar to Reference Example 1, this raw product was reacted with geranyl bromide (21.7 g) and then hydrolyzed to yield 13.9 g (46%) of 4-geranyloxycinnamic acid.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.C[O:11][C:12](=O)[CH:13](NC)[NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].[Cl-].[NH4+].O>O1CCCC1>[Cl:8][C:7]1[C:2]([C:12](=[O:11])[CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:23])([F:25])[F:24])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Br)c(Cl)c1
Reactant: CNC(NC(=O)c1ccccc1C(F)(F)F)C(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Temperature: -20 °C
Yield: 23.1 %

Procedure:
To 17.6 g of 2-bromo-3,5-dichloropyridin in 5 ml of tetrahydrofuran, 58.3 ml of a 1.3M tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride complex was added dropwise with stirring at −20° C., and after the addition, the mixture was stirred at the same temperature for 30 minutes. Then, to the reaction mixture, 10.0 g of N-[2-methoxy(methyl)amino-2-oxoethyl]-2-(trifluoromethyl)benzamide in 57.4 ml of tetrahydrofuran was added dropwise, and after the addition, the mixture was stirred at room temperature for another 3 hours. After completion of the reaction, the reaction mixture was mixed with 100 ml of saturated aqueous ammonium chloride and 100 ml of water and extracted with ethyl acetate (150 ml×2), the resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 3.0 g of the desired product as pale yellow crystals.
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[C:23]([NH:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])(=[O:27])[CH:24]([CH3:26])[CH3:25].N12CCCN=C1CCCCC2>CN(C)C=O>[C:23]([NH:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)=[O:33])(=[O:27])[CH:24]([CH3:26])[CH3:25]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(C)C(=O)NCCCC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)C(=O)NCCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 39.3 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 4-isobutyrylaminobutyric acid (5.2 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g). The residue obtained is recrystallized in acetonitrile and then purified by chromatography on silica (0.063-0.2 mm; 130 g) contained in a column 3 cm in diameter [eluant: methylene chloride/methanol (98:2 by volume) mixture] collecting 25-cc fractions. Fractions 79 to 85 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized by stirring in isopropyl ether. 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-isobutyrylaminobutyrate (5.5 g), m.p. 208° C., is thereby obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]2[N:21]=[N:22][NH:23][N:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O[CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:43]=[CH:44][CH:45]=1)[O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:25]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]2[N:21]=[N:22][N:23]([CH2:32][CH2:33][C:34]3[CH:35]=[C:36]([CH:43]=[CH:44][CH:45]=3)[O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[N:24]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)COc1cccc(CCO)c1
Reactant: c1ccc(C(c2ccccc2)c2nn[nH]n2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)COc1cccc(CCn2nnc(C(c3ccccc3)c3ccccc3)n2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Diethyl azodicarboxylate (0.96 g, 5.5 mmol) was added to a stirred solution of 5-(diphenylmethyl)-2H-tetrazole (1.00 g, 4.2 mmol), methyl [3-(2-hydroxyethyl)phenoxy]acetate (0.98 g, 4.6 mmol) and triphenylphosphine (1.44 g, 5.5 mmol) in dry THF (17 mL) cooled to 0° C. in an ice bath. The ice bath was removed and the mixture stirred at room temperature for 1 hour before the solvent was evaporated. The residue was chromatographed on a column of silica gel using a mixture of hexanes and ethyl acetate (3:1) to give methyl [3-[2-[5-(diphenylmethyl)-2H-tetrazol-2-yl]ethyl]phenoxy]acetate (1.06 g, 58%) as a colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[O:12])[C:4](=[O:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)=[CH:37][CH:36]=2)O1>>[CH3:25][C:10]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:9][CH2:8][N:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=3)=[CH:39][CH:40]=2)=[CH:3][C:4]1=[O:26])[C:11]([NH:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)=[O:12]
Reactant: CC1(C)OB(c2ccc(-c3ccncc3)cc2)OC1(C)C
Reactant: CC(CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Product: CC(CCn1ccc(-c2ccc(-c3ccncc3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O

Procedure:
(+/−)-4-(4-Iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be prepared as in Preparation 2A and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine were converted to the title product following the general procedure outlined for (+/−)-4-[4-(1-benzofuran-2-yl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide in Example 33, Step A. The title compound was obtained as a white solid (161 mg, 61%) LC-MS m/z 526.7 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:31]=[C:32]([C:34]3([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:33]=2)[C:26]([O:28]CC)=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:31]=[C:32]([C:34]3([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:33]=2)[C:26]([OH:28])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(C2(C#N)CCCC2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)c1nnc(-c2cc(C(=O)O)cc(C3(C#N)CCCC3)c2)o1

Procedure:
A solution of ethyl 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)benzoate (0.17 g, 0.31 mmol) and LiOH.H2O (65 mg, 1.55 mmol) in 8.1 mL THF and 3.1 mL H2O was stirred at rt overnight. The reaction was concentrated, diluted with H2O, made acidic with 10% citric acid solution and extracted with EtOAc. The combined organic layers were washed with brine. Drying and solvent evaporation gave 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)benzoic acid. 1H NMR (400 MHz, CDCl3) δ 8.62 (bs, 1H), 8.36 (d, J=1.4 Hz, 2H), 7.28 (m, 3H), 7.09 (d, J=5.7 Hz, 2H), 5.22 (bs, 1H), 3.61 (d, J=13.4 Hz, 1H), 3.43 (m, 1H), 2.60 (m, 2H), 2.20-2.01 (m, 6H), 1.75 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[CH2:46]([NH2:54])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].Cl>C(Cl)Cl.C(Cl)CCl>[CH2:1]([O:3][C:4](=[O:35])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:54][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: CCCCCCCCN
Reactant: CCOC(=O)C(=O)N(Cc1ccc(-c2ccc(C(=O)O)cc2)cc1)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCCCNC(=O)c1ccc(-c2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc2)cc1
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of 4′-({[ethoxy(oxo)acetyl][4-(trifluoromethyl)benzyl]amino}methyl)-1,1′-biphenyl-4-carboxylic acid (100 mg), EDC (47 mg) and HOBt (28 mg) in DCM (4 mL) was added octylamine (0.041 mL). The resulting reaction mixture was stirred for 3 h. DCM (15 mL) and an aqueous solution of HCl (1N, 10 mL) was added. The aqueous layer was extracted with DCM (3×15 mL). The combined organic layers were washed with a saturated solution of NaHCO3 (15 mL) and dried over MgSO4. Evaporation of the solvents gave an oil which was purified by flash chromatography over silica gel (c-Hex/AcOEt 2/1) to give the title compound as a colorless oil (41 mg, 33%). M+(LC/MS(ESI)): 597.8; M−(LC/MS(ESI)): 595.0. HPLC (Condition A), Rt: 6.61 min (HPLC purity: 99.87%)
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([O:12][CH:13]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)[CH2:30][CH3:31]>>[C:33]1([C:29]([CH2:30][CH3:31])=[C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:28][CH:27]=2)[C:8]2[CH:9]=[CH:10][C:11]([O:12][CH:13]3[CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:25][CH:26]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)c3ccc(O)cc3)cc2)C1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OC2CCNC2)cc1)c1ccccc1
Yield: 85.6 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, tert-butyl 3-(4-(4-hydroxybenzoyl)phenoxy)pyrrolidine-1-carboxylate (395 mg, 1.03 mmol) was reacted with propiophenone (276 mg, 2.06 mmol) to give 340 mg desired product (86% yield, Z/E=1/1) as a light yellow solid. m/z=386[M+1]+.
Reaction SMILES: [Si]([O:18][C:19]1[CH:64]=[CH:63][C:22]([O:23][CH2:24][C@@H:25]([OH:62])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:61]=[CH:60][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([S:41]([C:44]4[CH:49]=[CH:48][C:47]([NH:50][C:51]([NH:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:52])=[CH:46][CH:45]=4)(=[O:43])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:54]([NH:53][C:51]([NH:50][C:47]1[CH:48]=[CH:49][C:44]([S:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:60]=[CH:61][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:62])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:64][CH:63]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)(=[O:43])=[O:42])=[CH:45][CH:46]=1)=[O:52])[CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1

Procedure:
N-[4-({4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}sulfonyl)phenyl]-N′-hexylurea (0.18 g, 0.199 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound as the hydrochloride salt (0.1 g, 0.142 mmol).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.Cl>O.CO>[C:23]([O:22][C:20]([NH:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(CN2CCC(C(=O)O)CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(3-tert-butoxycarbonylamino-benzyl)-piperidine-4-carboxylic acid ethyl ester (7.6 g, 21.4 mmol) in a mixture of water (90 mL) and MeOH (90 mL) at RT is treated at once with LiOH mono hydrate (922 mg, 22 mmol). The mixture is stirred at RT for 18 h then HCl 1N (22 mmol, 22 mL) is added and the reaction mixture is stirred at RT for 30 min. The solvents are removed under reduce pressure and the crude acid is dried under high vacuum. The crude title compound containing LiCl is used for the next step. LC-MS A: tR=0.56 min; [M+H]+=335.26.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12][CH3:13])[CH2:6][CH2:5]1.Br[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:38]3[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=3)=[CH:18][CH:19]=2)[CH2:12][CH3:13])[CH2:6][CH2:5]1
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cn1ccc(Br)cc1=O
Product: CC[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-bromo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 59 Step 2. LC-MS Method 2 tR=1.203 min, m/z=971.4; 1H NMR (CDCl3) 0.97 (t, 3H), 1.12 (s, 3H), 1.19 (s, 3H), 1.79-2.02 (m, 2H), 2.11-2.24 (m, 4H), 2.29-2.42 (m, 1H), 2.81 (m, 1H), 3.50 (s, 3H), 5.40 (m, 1H), 6.28 (d, 1H), 6.64 (s, 1H), 7.02 (d, 2H), 7.18 (m, 3H), 7.20 (m, 2H), 7.28 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7](=O)[NH:6][C:5]=2[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.P(Cl)(Cl)([Cl:20])=O>C1COCC1>[Cl:20][C:7]1[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[C:10]2[C:2]([CH3:1])=[N:3][N:4]([CH:15]([CH3:17])[CH3:16])[C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nn(C(C)C)c2[nH]c(=O)cc(C(=O)O)c12
Solvent: C1CCOC1
Product: Cc1nn(C(C)C)c2nc(Cl)cc(C(=O)O)c12
Temperature: 105 °C
Reaction time: 24 h

Procedure:
3-Methyl-1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1.5 g, 6.38 mmol) was added to a solution of THF (15 mL) followed by addition of phosphorous oxychloride (8.9 mL, 96 mmol), and the contents heated at 105° C. overnight. After cooling to room temperature, the contents were concentrated in vacuo to remove most of the volatiles. The residual contents were slowly poured into a solution of iced water and 1N NaOH (10 mL), and the contents were stirred at room temperature for 24 h, during which time solid precipitation ensued. Additional 1N NaOH was added, upon which the solids went into solution. After stirring at room temperature for an additional 30 min., the contents were cooled in an ice bath and the mixture slowly acidified to pH=3-4 by slow addition of 6N HCl, to afford a heterogenous mixture. The mixture was filtered and a white solid set aside. The aq. layer was further extracted with EtOAc and DCM. The combined organic layers dried were dried over MgSO4, filtered and concentrated in vacuo. The resultant light brown solid was triturated in EtOAc/EtOH (1:1) and filtered to afford a first crop of white solid product, which was set aside. The filtrate was again concentrated in vacuo. The residue was diluted with EtOAc, sonicated, treated with hexanes, and filtered. The process was repeated. The isolated solid product crops were dried under vacuum (3 h) and collected as 1.33 g (80%). LCMS E-S (M+H): 254.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, 6H), 2.60 (s, 3H), 5.10 (quin, J=6.63 Hz, 1H), 7.50 (s, 1H), 14.17 (br. s., 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]=1.[CH3:17][Si](C)(C)[N-][Si](C)(C)C.[Na+].IC>C1COCC1>[CH3:17][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]=1
Reactant: c1cncc(-c2noc(-c3ccc[nH]3)n2)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cccc1-c1nc(-c2cccnc2)no1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-{5-(1H-pyrrol-2-yl)-[1,2,4]oxadiazol-3-yl}-pyridine (1 g; 0.5 mmol) in 15 ml of dry THF at −70° C. was added 0.18 g of sodium hexamethyl disilazide (1 mmol), the reaction mixture was stirred at −70° C. for 30 min. and at 0° C. for 1 hour. The reaction mixture was cooled to −70° C. and added 0.076 g of iodomethane (0.52 mmol). The reaction mixture was stirred at −70° C. for ½ hour, then at room temperature overnight. The product was isolated by column chromatography. Yield 0.04 g of yellow solid (37%). Mp. 108-109° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[F-:13].[K+].O>CC(N(C)C)=O>[F:13][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: [F-]
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(F)ccc1[N+](=O)[O-]
Yield: 71 %

Procedure:
37 g (0.2 mol) of 5-chloro-2-nitrobenzaldehyde and 23.2 g (0.4 mol) of potassium fluoride in 300 ml of dimethylacetamide are stirred for 3 hours at 150° C. The solvent is then stripped off in vacuo and the residue is stirred with 200 ml of water. The aldehyde is extracted with methylene chloride, and the organic phase is separated off, dried and evaporated down. 24 g of 5-fluoro-2-nitrobenzaldehyde with a content of 86% are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:13](=[O:15])[CH3:14])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:16][C:17](=[O:19])[CH3:18])[CH:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrN1C(=O)CCC1=O>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]([O:16][C:17](=[O:19])[CH3:18])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([O:12][C:13](=[O:15])[CH3:14])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(OC(C)=O)cc(C)cc1OC(C)=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(OC(C)=O)cc(CBr)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.6 %

Procedure:
Methyl 4-methyl-2,6-diacetoxybenzoate (14.9 grams, 56.0 mmoles) was dissolved in carbon tetrachloride (200 mL), and N-bromosuccinimide (11.1 grams, 62.2 mmoles) and benzoyl peroxide (0.2 grams, 0.8 mmoles) were added. The mixture was refluxed under nitrogen. After 3.5 hours, an additional portion (0.2 grams) of N-bromosuccinimide was added. Reflux was continued for an additional hour. The reaction mixture was cooled to room temperature and then in ice for 1 hour, and the solid removed by filtration. The filtrate was evaporated to dryness. Hexanes (250 mL) was added to the residue, and the mixture was boiled until dissolution was obtained. The hexanes solution was concentrated to about 75 mL when a solid just began to precipitate. The mixture was heated to dissolve the solid, and the solution was allowed to cool slowly to room temperature. White crystals formed slowly, and the mixture was chilled in ice for 2 hours to complete crystallization. The solid was filtered, washed with cold hexanes (100 mL), and dried in vacuo to afford 11.9 grams (62% yield) of methyl 4-bromomethyl-2,6-diacetoxy-benzoate (m.p. 93-95° C., open capillary, uncorrected). The product was contaminated with a small amount of methyl 2,6-diacetoxy-4-dibromomethylbenzoate, which did not interfere with subsequent reactions.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)C.[Br:30]N1C(=O)CCC1=O>C(O)(=O)C>[Br:30][C:10]1[S:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])=[N:7][C:6]=1[CH2:5][C:4]([OH:3])=[O:29]
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)c(Br)s2)c(C(=O)C2CCCC2)c1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a suspension of {2-[3-(2-cyclopentanecarbonyl-4-me- thyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (0.20 g, 0.52 mmol) in 10 ml of acetic acid was added N-bromosuccinimide (0.10 g, 0.57 mmol). The reaction mixture was stirred under nitrogen in a pressure bottle excluded from light overnight at 25° C. The mixture was concentrated under reduced pressure, dissolved in DMSO and purified by preparative HPLC to afford the title compound (0.137 g, 57%).