Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[NH:1][CH2:2][CH2:3][CH2:4]3)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: COc1cccc(OC)c1C=O
Reactant: NCc1ccc2c(c1)CCCN2
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2c(c1)CCCN2

Procedure:
Prepared according to the described general procedure 6 (GP6) with (1,2,3,4-tetrahydroquinolin-6-yl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.53 min.; [M+H]+: 381.15 g/mol.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30](O)=[O:31]>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:31]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(Br)ccc2Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-Bromo-2-chloro-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1>O.CC#N>[CH3:1][C:2]1([CH3:13])[CH2:11][C@H:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1
Reactant: CC1(C)CC(=O)c2ccccc2O1
Solvent: O
Solvent: CC#N
Product: CC1(C)C[C@H](O)c2ccccc2O1

Procedure:
The title compound was prepared from 2,2-dimethylchroman-4-one according to the method described in Example 2B. MS (LCMS) m/z 236 (M+H2O+CH3CN)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([NH:22][CH2:21][CH2:20][C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:12]=3)[NH:16][CH:15]=2)=[O:38])=[CH:25][CH:26]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Br)cc12)c1ccc(Cc2cccc(F)c2)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(-c3ccccc3)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 16.4 %

Procedure:
A mixture of benzeneboronic acid (0.024 g; 0.195 mmol), N-(2-(5-bromo-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide (0.080 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020; 0.017 mmol) and sodium carbonate (0.038 g; 0.355 mmol) in a mixture of DME (3 mL) and water (1 mL) was irradiated in the microwave oven at 130° C. for 20 minutes. The resulting solution was partitioned between water and ethyl acetate and the organic layer was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and by preparative HPLC (method 2) to afford 0.013 g (16%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].C(N(CC)CC)C.[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23]>C(#N)C>[O:4]=[C:3]1[C@H:2]([O:1][C:15]([O:16][N:17]2[C:21](=[O:22])[CH2:20][CH2:19][C:18]2=[O:23])=[O:24])[CH2:7][CH2:6][O:5]1
Reactant: O=C1OCC[C@H]1O
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O[C@@H]1CCOC1=O)ON1C(=O)CCC1=O

Procedure:
(R)-alpha-Hydroxybutyrolactone (8 μL, 0.11 mmol) was dissolved in acetonitrile (0.5 mL) and treated with triethylamine (45 μL, 1.5 equivalents), and disuccinimidyl carbonate (42 mg, 1.5 equivalent) at 25° C. for 16 hrs. The solvents were evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and evaporated.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1.[CH3:27][N:28]=[C:29]=[O:30].C(N(CC)CC)C>C1COCC1>[CH:2]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH:15]=2)=[N:13][N:12]([C:16]2[CH:26]=[CH:25][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:29]([NH:28][CH3:27])=[O:30])[CH3:23])=[CH:18][CH:17]=2)[CH:11]=3)[CH2:4][CH2:3]1
Reactant: C[C@H](N)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)N[C@@H](C)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}-1-methylethyl]carbamate (310 mg) and 4M hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added diethyl ether, and the resultant precipitate was collected by filtration, and washed with ethyl acetate to give (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (255 mg). A mixture of (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (84 mg), methyl isocyanate (38.5 mg), triethylamine (68 mg) and THF (1 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and the mixture was washed with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (51.9 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29](=O)[CH3:30])[CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH:29]([C:25]1[CH:24]=[C:23]([CH3:22])[CH:28]=[CH:27][N:26]=1)[CH3:30])[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1CNCCCCNC(=O)OC(C)(C)C
Reactant: CC(=O)c1cc(C)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnc(C(C)N(CCCCNC(=O)OC(C)(C)C)Cc2ncccc2C)c1

Procedure:
Using General Procedure B, reaction of {4-[(3-Methyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester, 1-(4-methylpyridin-2-yl)-ethanone and NaBH(OAc)3 in CH2Cl2 gave {4-[[1-(4-methyl-pyridin-2-yl)-ethyl]-(3-methylpyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a pale yellow oil. Conversion to the HBr salt using General Procedure D gave COMPOUND 244 as a white solid. 1H NMR (D2O) δ 1.47 (br, 4H), 1.54 (d, 3H, J=6.0 Hz), 2.45 (s, 3H), 2.60 (m, 1H), 2.63 (s, 3H), 2.71 (m, 1H), 2.85 (br, 2H), 4.27 (s, 2H), 4.49 (q, 1H, J=6.0 Hz), 7.78 (d, 1H, J=6.3 Hz), 7.83 (t, 1H, J=7.2 Hz), 7.95 (s, 1H), 8.33 (d, 1H, J=7.8 Hz), 8.56 (m, 2H). 13C NMR (D2O) δ 15.08, 17.10, 22.38, 24.01, 25.03, 39.57, 51.07, 52.81, 59.73, 125.84, 127.25, 127.40, 137.08, 138.22, 140.83, 148.27, 152.41, 154.85, 162.82. ES-MS m/z 313 (M+H). Anal. Calcd. for C19H28N4.4.3HBr.3.5H2O: C, 31.55; H, 5.48; N, 7.74; Br, 47.49. Found: C, 31.64; H, 5.63; N, 7.43; Br, 47.61.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[Cl-].[CH:32]12[CH2:46][CH:36]([N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38]1)[CH2:35][NH:34][CH2:33]2>>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:32]2[CH2:46][CH:36]1[CH2:35][N:34]([C:20]([C:19]1[CH:18]=[N:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:10]=4[N:11]=3)=[CH:24][CH:23]=1)=[O:22])[CH2:33]2)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC1C2
Agent: [Cl-]
Agent: [Li+]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CC(C4)N(C(=O)OC(C)(C)C)C5)cn3)nc2n1C1CCCC1
Yield: 80 %

Procedure:
Following general amide formation method 1, 6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (in a salt form with 5 eq. of LiCl) (571 mg, 0.942 mmol) was combined with tert-butyl 3,6-diazabicyclo[3.2.1]octane-6-carboxylate (200 mg, 0.942 mmol) to give 446 mg of 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,6-diaza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester in 80% yield. MS (ESI) m/e (M+H+): 588.9.
Reaction SMILES: [CH3:1][N:2]([CH3:54])[C:3](=[O:53])[CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])=[CH:35][C:34]=3[O:48][CH3:49])=[CH:29][CH:28]=2)=[O:26])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:50]([O-:52])=[O:51])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)(C(F)(F)F)=O.ClCCl>[CH3:54][N:2]([CH3:1])[C:3](=[O:53])[CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:35][C:34]=3[O:48][CH3:49])=[CH:29][CH:28]=2)=[O:26])(=[O:22])=[O:23])=[CH:17][C:16]=1[N+:50]([O-:52])=[O:51])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc(CCC(=O)OC(C)(C)C)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@@H](CSc3ccccc3)CC(=O)N(C)C)c([N+](=O)[O-])c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CCC(=O)O)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@@H](CSc3ccccc3)CC(=O)N(C)C)c([N+](=O)[O-])c2)cc1

Procedure:
A mixture of Example 126B in TFA (20 mL) and dichloromethane (20 mL) at room temperature was stirred for 1 hour and concentrated to provide the desired product. MS (ESI (+)) m/e 721 (M+H)+.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C@@H:20]([OH:33])[CH2:21][C@@H:22]([C:27]([CH2:31][CH3:32])([OH:30])[CH2:28][CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[O:41]1[CH2:46][CH2:45][N:44]([CH2:47][C:48]([NH:50][C@H:51](C(O)=O)[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:49])[CH2:43][CH2:42]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>>[O:41]1[CH2:42][CH2:43][N:44]([CH2:47][C:48]([NH:50][C@H:51]([C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:34][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)[C@@H:20]([OH:33])[CH2:21][C@@H:22]([C:27]([CH2:28][CH3:29])([OH:30])[CH2:31][CH3:32])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:7])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:49])[CH2:45][CH2:46]1
Reactant: O=C(CN1CCOCC1)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCC(O)(CC)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(=O)NC
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CCC(O)(CC)[C@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CN1CCOCC1)C(=O)NC
Yield: 80 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 100 mg (0.17 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-ethyl-1-hydroxypropyl)-N-methylhexanamide [prepared as described in Example 18(a)], 55 mg (0.19 mmoles) of N-morpholinoacetyl-L-phenylalanine, 0.03 ml (0.20 mmoles) of diethyl cyanophosphate, and 0.08 ml (0.57 mmoles) of triethylamine were used, to obtain 103 mg (yield 79%) of the title compound as a white amorphous substance.
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[C:11]=1[CH3:12].[N+:13]([O-])([OH:15])=[O:14]>O>[F:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[C:11]=1[CH3:12]
Reactant: Cc1c(F)ccc2oc(=O)[nH]c12
Reactant: O=[N+]([O-])O
Solvent: O
Product: Cc1c(F)c([N+](=O)[O-])cc2oc(=O)[nH]c12
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
5-Fluoro-4-methyl-2-benzoxazolone (Preparation A, 2.01 g, 12 mmoles) was treated with concentrated nitric acid (24 ml) at room temperature under stirring. The mixture was heated to 50° C. and stirring continued for 20 minutes. Ice and water were added to the mixture and the resulting solids were collected, and washed with water and then with ethanol. The crude product was dried under reduced pressure and recrystallized from ethanol to give 1.84 g (72%) of the title compound: m.p. 194°-196° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.CON(C)[C:19]([C:21]1[N:22]=[CH:23][S:24][CH:25]=1)=[O:20]>C1COCC1>[CH3:5][C:4]([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])([CH3:8])[C:6]#[C:7][C:19]([C:21]1[N:22]=[CH:23][S:24][CH:25]=1)=[O:20]
Reactant: CON(C)C(=O)c1cscn1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1cscn1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy)silane (0.56 g, 3.57 mmol) in dry THF (10 mL) was added n-BuLi (1.3 mL, 2.1 mmol, 1.6 M in hexane) dropwise at −78° C. under an inert atmosphere for a period of 5 min. After being stirred for 30 min at −78° C., a solution of N-methoxy-N-methylthiazole-4-carboxamide (0.25 g, 1.78 mmol) in dry THF (5 mL) was added to reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 2-4% EtOAc in Hexane to afford 4-methyl-1-(thiazol-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (0.15 g, 31.44%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[N:27]=1>>[OH:34][C:32]([CH3:35])([CH3:33])[CH2:31][N:28]1[CH:29]=[CH:30][C:26]([NH:25][C:13](=[O:15])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:2]([F:1])=[CH:23][CH:22]=[CH:21][C:20]=3[F:24])[CH:6]=[N:7]2)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:27]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CC(C)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)CC(C(=O)Nc1ccn(CC(C)(C)O)n1)n1ncc(Oc2c(F)cccc2F)cc1=O
Yield: 45 %

Procedure:
Using the method described in Example 17, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid (Intermediate 28) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a white solid (0.63 g, 45%); ES+-HRMS m/e calcd for C23H27N5O4F2 [M+H+] 476.2104 found 476.2104. 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H) 0.89 (d, J=6.6 Hz, 3H) 1.05 (s, 3H) 1.07 (s, 3H) 1.44 (br s, 1H) 1.73-1.86 (m, 1H) 2.11-2.27 (m, 1H) 3.89 (s, 2H) 4.67 (s, 1H) 5.53 (dd, J=11.2, 4.4 Hz, 1H) 6.04 (d, J=3.0 Hz, 1H) 6.40 (d, J=2.3 Hz, 1H) 7.34-7.44 (m, 2H) 7.44-7.52 (m, 1H) 7.53 (d, J=2.3 Hz, 1H) 8.28 (d, J=3.0 Hz, 1H) 10.85 (s, 1H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[O:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][N:2]1[NH:1][C:26](=[O:27])[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:29])([F:17])[F:30])=[CH:24][CH:23]=1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product from Example 11B and 2-[4-(trifluoromethyl)phenyl]acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.44 (d, J=7.1 Hz, 1H), 8.14 (td, J=7.7, 1.4 Hz, 1H), 8.01-8.10 (m, 2H), 7.70-7.76 (m, 2H), 7.60-7.63 (m, 2H), 3.86-3.87 (bs, 2H); MS (ESI) m/z 416 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([NH2:6])(=[O:5])=[O:4].N1C=CC=CC=1.Cl.[CH2:16]([NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[CH2:16]([NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([NH:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])=[O:38])=[CH:40][CH:41]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(=O)(=O)C(F)(F)F)cc1

Procedure:
A solution of 1.25 g. of trifluoromethanesulfonamide in 35 ml. of pyridine was treated with 3.5 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride in methylene chloride at 10°-15° C. and then stirred under reflux for 3 hours. Evaporation afforded a gum which was stirred with 150 ml. of H2O and extracted with three 50 ml. portions of CHCl3. The extracts were combined, dried (MgsO4), and evaporated to yield a white solid. Crystallization from ether-acetone gave 2.0 g. of product, melting point 172°-174° C.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:32]=2)=[CH:18][CH:17]=1)[CH3:2].CO.[ClH:60]>ClCCl>[ClH:60].[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[CH:18][CH:17]=1)[CH3:2]
Reactant: CCOC(=O)c1cc2c(CC)nc(CC)cc2n(Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(CC)nc(CC)cc2n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Reaction time: 0.33 h

Procedure:
Ethyl 5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxylate (A) (0.42 g) was added to a mixture of methanol (5 ml), dichloromethane (1 ml) and concentrated hydrochloric acid (0.15 ml) and the mixture was stirred for 20 minutes. Volatile material was removed by evaporation and the residue was triturated with ether to give a white solid. The solid was purified by dissolution in hot ethanol and precipitation by adding ether to give ethyl 5,7-diethyl-2-oxo-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridine-3-carboxylate hydrochloride (0.186 g); NMR (d6 -DMSO): 1.25(t, 3H), 1.32(t, 3H), 1.34(t, 3H), 2.95(q, 2H), 3.35(q, 2H), 4.34(q, 2H), 5.55(s, 2H), 7.07(d, 2H), 7.21(d, 2H), 7.4-7.8(complex m, 6H), 8.7(s, 1H); mass spectrum (+ve FAB, DMSO/NBA): 509 (M+H)+ ; microanalysis, found: C, 62.5; H, 5.6; N, 14.8%; C29H28N6O3.HCl.0.14 (CH3CO2C2H5).0.5 H2O requires: C, 62.6; H, 5.5; N, 14.8%.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[C:16](=[O:18])=[O:17]>C1COCC1>[Cl:9][C:10]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: O=C=O
Reactant: Clc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Following the procedures of Guillier et al (1995) J. Org. Chem. 60(2):292-6, to a cold (−78° C.) solution of LDA (21 ml, 1.6 M in hexanes, 33.3 mmol) in anhydrous THF (70 ml) was added 4-chloropyridine (5.0 g, 33.3 mmol) under an argon atmosphere. After 1 hour at −78° C., the solution was rapidly poured onto a bed of solid CO2 contained within a 250 ml conical flask. After allowing the reaction solution to warm to ambient temperature the solution was quenched with water (30 ml). The volatile organic solvents were removed in vacuo and the remaining aqueous suspension was extracted with diethyl ether (3×100 ml). The aqueous phase was cooled to 0° C. and the adjusted to pH 4 by the addition of concentrated hydrochloric acid. The resultant precipitate was aged for 30 minutes then collected by filtration. The solid was washed with cold diethyl ether (10 ml) to afford the title compound as a white solid (3.2 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.O[NH:39][C:40]([C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[NH:47][N:46]=[CH:45]2)=[NH:41]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:39]=[C:40]([C:42]3[CH:43]=[C:44]4[C:48](=[CH:49][CH:50]=3)[NH:47][N:46]=[CH:45]4)[N:41]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3) (712 mg), EDCl.HCl (699 mg) and HOBT (493 mg) were dissolved in DMF (16.5 ml) and stirred at RT for 10 minutes. N-hydroxy-1H-indazole-5-carboximidamide (D2) (584 mg) was added and the mixture heated to 80° C. for 12 hours. The reaction mixture was then cooled to RT and left to stand for the weekend, evaporated to dryness and re-dissolved in H2O. This solution was extracted with EtOAc (×3) and the combined extracts washed with brine, evaporated and triturated with DCM twice, sonicated for 4 mins before filtering, drying and repeating once to give the title compound (407 mg) as a pink solid. δH (d6-DMSO, 400 MHz): 1.37 (6H, d), 4.89 (1H, septet), 7.46 (1H, d), 7.73 (1H, d), 8.04 (1H, d), 8.13 (1H, d), 8.20 (1H, s), 8.28 (1H, s), 8.58 (1H, s). MS (ES): C18H15ClN4O2 requires 354; found 355 (M+H).