Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28][C@@H:29]1[CH2:53][CH2:52][C@@:51]2([CH3:54])[CH:31]([CH2:32][CH2:33][C@@H:34]3[C@@H:50]2[CH2:49][CH2:48][C@@:47]2([CH3:55])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[C@H:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:30]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:28][C@@H:29]1[CH2:53][CH2:52][C@@:51]2([CH3:54])[CH:31]([CH2:32][CH2:33][C@@H:34]3[C@@H:50]2[CH2:49][CH2:48][C@@:47]2([CH3:55])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[C@H:39]([CH3:46])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:30]1)=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC(=O)[C@H](CCCCNC(=O)OCc5ccccc5)NC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
By using Nα-tert-butyloxycarbonyl-Nε-benzyloxycarbonyl-L-lysine (760 mg, 2.00 mmol) and 3α-aminocholestane (853 mg, 2.20 mmol), the title compound was obtained in the same manner as in Synthetic Example BB 1 (1.57 g, quantitative).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=O.C1(P(=[CH:33][C:34]([O:36][CH3:37])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:37][O:36][C:34](/[CH:33]=[CH:3]/[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:35]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.46 g, 36.6 mmol) was added to a solution of 4-formylbenzoic acid (5.0 g, 33.3 mmol) in toluene (200 ml) and the mixture was stirred for 2 h at room temperature. Methyl (triphenyl-phosphoranylidene)acetate (11.69 g, 35.0 mmol) was added and the mixture was heated at reflux for 20 h. Solvents were removed in vacuo and the residue was redissolved in dichloromethane and 1M NaHCO3. The layers were partitioned and the aqueous layer was acidified with 1M HCl solution then extracted with chloroform. The organic layer was dried and concentrated in vacuo to yield the title compound (3.65 g, 53%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[I:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH3:24])[CH:17]=1>>[I:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: Cc1cc(I)ccc1CO
Product: Cc1cc(I)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-iodo-2-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.33 (3H, s), 5.15 (2H, s), 5.76 (1H, d, J=1.6 Hz), 7.14 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=1.6 Hz, 5.2 Hz), 7.55-7.59 (3H, m), 8.00 (1H, s), 8.66 (1H, d, J=5.2 Hz). [M+H] Calc'd for C17H13IN4O, 417. Found, 417.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].C([Li])(C)(C)C.CN(P(N(C)C)(N(C)C)=O)C.Br[CH2:23][CH2:24][CH2:25][C:26]([CH3:28])=[CH2:27]>CCOCC.[OH-].[Na+].CCOCC>[CH3:28][C:26](=[CH2:27])[CH2:25][CH2:24][CH2:23][C:3]#[C:2][C:1]([OH:5])=[O:4]
Reactant: C#CC(=O)O
Reactant: C=C(C)CCCBr
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(C)CCCC#CC(=O)O
Reaction time: 24 h

Procedure:
0.13 Gram (1.85 mmol) propiolic acid is dissolved in 20 ml ether, under nitrogen, and the solution is cooled to -70°. 3.3 Milliliters of 1.1 M t-butyllithium (3.63 mmol) is added over a period of 1 hr, and the mixture is stirred for an additional hour at -60°. HMPA (10 ml) is added, followed by 0.32 g (1.96 mmol) 1-bromo-4-methyl-4-pentene (prepared as in either Example 1 or Example 3), keeping the solution cold. After 24 hr, the mixture is heated to 40°-45°. After 3 days, the reaction is worked up in 5% NaOH/ether, and the aqueous layer is extracted with ether. The basic phase is acidified with HCl and extracted with ether (2×). The latter ether phases are washed with water and brine, dried over Na2SO4, filtered and the solvent is removed to yield 7-methyl-7-octen-2-ynoic acid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2]C.[Cl:15]C1C=C2C(=CC=1)NC(=O)C2=O.C(Br)C>>[Cl:15][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:1][CH3:2])[C:5](=[O:14])[C:6]2=[O:13]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Solvent: CCBr
Product: CCN1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
Was made in an analogous fashion to 1-propylindoline-2,3-dione using commercially available 5-chloro isatin and ethyl bromide, both purchased from Fisher Scientific. 1H NMR δ 7.58 (m, 2H), 6.88 (d, 1H), 3.80 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: Cc1ccccc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 101.6 %

Procedure:
Beginning with 0.015 gm (0.065 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0094 mL (0.072 mMol) 2-methylbenzoyl chloride, 0.023 gm (100%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:24](B(O)O)[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:22]2[CH:21]=[C:20]([Cl:19])[CH:25]=[CH:24][C:23]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(C)cc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(F)cc1
Product: CCOC(=O)c1cc(C)cc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using [5-chloro-2-(4-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:12])[NH:10][NH:11][C:4]=2[CH:3]=1.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:12])[NH:10][N:11]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:4]=2[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(Cl)cc2[nH][nH]c(=O)c12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 6-chloro-4-methyl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (3.1 g, 16.85 mmol) and trityl chloride (4.93 g, 17.69 mmol) in DMF (50 mL) was charged with sodium hydride (60% in mineral oil, 1.011 g, 25.3 mmol) and stirred at room temperature for 1.5 h. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with Et2O (×3). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc/DCM) to provide 6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one. MS ESI calc'd. for C26H20ClN3O [M+1]+ 426. found 426.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:3]=1.Cl.Cl.[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[CH:33][CH:32]=[C:31]([NH:37][CH2:38][CH2:39][NH2:40])[N:30]=1.CCN(C(C)C)C(C)C>CS(C)=O>[NH2:28][C:29]1[N:30]=[C:31]([NH:37][CH2:38][CH2:39][NH:40][C:2]2[N:7]3[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:6]3[CH:5]=[C:4]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:3]=2)[CH:32]=[CH:33][C:34]=1[C:35]#[N:36]
Reactant: N#Cc1ccc(NCCN)nc1N
Reactant: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(Cl)n2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(NCCNc3ccc(C#N)c(N)n3)n2n1

Procedure:
200 mg (0.52 mmol) of ethyl 5-chloro-7-(4-trifluoromethylphenyl)[1,2,4]triazolo[1,5-c]pyrimidine-2-carboxylate (Example 149A) and 133 mg (0.62 mmol) of 2-amino-6-[(2-aminoethyl)amino]pyridine-3-carbonitrile dihydrochloride (Example 111A) are introduced into DMSO (2 ml), 0.54 ml (3.1 mmol) of DIEA is added, and the reaction solution is irradiated in a microwave reactor at 90° C. for 30 min. The reaction mixture is purified by preparative HPLC. 98 mg (38% of theory) of the product are obtained as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:19])=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[C:3]([CH3:19])=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-c2cccc(F)c2)cc(F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(F)cc(-c2cccc(F)c2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 143 %

Procedure:
To a solution of methyl 3-fluoro-5-(3-fluorophenyl)-2-methyl-benzoate (1.0 g, 3.1 mmol, 1.0 eq) in a mixture of THF (4 mL) and MeOH (4 mL) was added NaOH (2 M aqueous solution, 10 mL, 20 mmol). The reaction mixture was stirred at room temperature for 3 h. The THF and MeOH were evaporated in vacuo and the pH of the aqueous phase was adjusted to pH 4-6 by addition of diluted HCl. The solid precipitate that formed was collected by filtration, washed with water and dried to give the title compound as a white solid (1.1 g, 100%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][C@@H:4]([NH2:8])[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[Na+].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1.O>[CH:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:21]([NH:8][C@H:4]([CH2:3][C:2]#[CH:1])[C:5]([OH:7])=[O:6])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C#CC[C@@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of d-propargylglycine (32.10 g, 88.46 mmol), Na2CO3 (20.62 g, 194.6 mmol), and benzenesulfonyl chloride (18.74 g, 106.2 mmol) in p-dioxane/H2O (1:1, 200 ml) was stirred overnight at rt. The reaction mixture was concentrated and the ph adjusted to 4.0 with 10% hcl. The aqueous layer was extracted with CHCl3 (3×), dried over mgso4, and concentrated to give the title compound. 1H NMR (400 mhz, CDCl3): δ 2.04 (s, 1h), 2.65 (s, 3h), 2.71 (m, 2h), 4.11 (m, 1h), 5.61 (d, 8.4 hz, 1h), 7.61 (m, 3h), 7.88 (m, 2h).
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[CH2:3][NH2:4].[S:7](Cl)([CH3:10])(=[O:9])=[O:8].C(N(CC)CC)C>C(Cl)Cl>[NH2:6][C:2]([CH3:5])([CH3:1])[CH2:3][NH:4][S:7]([CH3:10])(=[O:9])=[O:8]
Reactant: CC(C)(N)CN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(N)CNS(C)(=O)=O
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
2-Methyl-propane-1,2-diamine (2.00 g, 22.7 mmol, 2.38 mL, 1.1 eq.) was placed in CH2Cl2 (100 mL). Mesyl chloride (2.35 g, 20.7 mmol, 1.59 mL, 1.0 eq.) was added over a period of five minutes followed by triethylamine (6.27 g, 62.1 mmol, 8.71 mL, 3.0 eq.). The reaction was stirred for 30 minutes and then concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-15% MeOH/CH2Cl2 as the eluting solvent to obtain N-(2-amino-2-methyl-propyl)-methanesulfonamide as a white solid (1.15 g, 33%). LCMS (m/e) 167 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 2.98 (s, 3H), 2.95 (s, 2H), 1.17 (s, 3H), 1.16 (s, 3H).
Reaction SMILES: [O:1]=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH:5]1[O:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:7][CH2:6]1.[CH3:25][Si](C)(C)N[Si](C)(C)C.C[Si](C)(C)Cl.C[Mg]Br.Cl>CCOCC.N1C=CC=CC=1>[OH:1][C:2]([CH3:25])([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH:5]1[O:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:7][CH2:6]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCCCCC(=O)CCC1CCC(CCCCCCCC(=O)O)O1
Agent: C[Mg]Br
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC(C)(O)CCC1CCC(CCCCCCCC(=O)O)O1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
IX (6.30 g, 0.0185 mole), hexamethyldisilazane (HMDS) (12 ml), trimethylchlorosilane (TMCS) (6 ml), and pyridine (40 ml) were mixed and kept overnight at room temperature. The resulting white suspension was evaporated to dryness (50° C, 10 mm Hg). Ether (100 ml) was added, and the suspension was filtered. The resulting clear, yellow solution of X was cooled to 0° C, and methylmagnesium bromide in ether (3.8N, 8.0 ml, 0.030 mole) was added dropwise during 20 minutes. After stirring for 2 hours at room temperature, the white suspension being formed was poured into a mixture of cold hydrochloric acid (0.25N, 140 ml) and ether (50 ml). The ethereal phase was separated, and the aqueous layer was extracted with ether (50 + 25 ml). The combined ethereal extracts were washed with water 50 ml) and dried over sodium sulfate. The solvent was removed from a water bath (60° C, 10 mm Hg), and the residual light yellowish oil (7.40 g) was distilled under reduced pressure to give 5.40 g (82%) of XI as a light yellowish oil, b0.08 203°-210° C, nD25 1.4710.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:22]=[N:23][C:24](Cl)=[N:25][CH:26]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[N:25]=[CH:26][C:21]([Br:20])=[CH:22][N:23]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: Clc1ncc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ncc(Br)cn2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (7.84 g) synthesized in Example 4 and 5-bromo-2-chloropyrimidine (5.0 g) were dissolved in N,N-dimethylformamide (70 mL), potassium tert-butoxide (3.47 g) was added, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (6.0 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=[C:4]2[CH:3]=1.[N:16]1([C:20]([C:22]2[CH:23]=[N:24][N:25]([CH3:30])[C:26]=2[C:27](O)=[O:28])=[O:21])[CH2:19][CH2:18][CH2:17]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:14]([O:13][C:11]([C:9]1[N:10]=[C:4]2[CH:3]=[C:2]([NH:1][C:27]([C:26]3[N:25]([CH3:30])[N:24]=[CH:23][C:22]=3[C:20]([N:16]3[CH2:19][CH2:18][CH2:17]3)=[O:21])=[O:28])[CH:7]=[CH:6][N:5]2[N:8]=1)=[O:12])[CH3:15]
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Reactant: CCOC(=O)c1nc2cc(N)ccn2n1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Yield: 63.9 %

Procedure:
A mixture of ethyl 7-amino-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (540 mg, 2.62 mmol), 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (548 mg, 2.62 mmol), propylphosphonic anhydride (50% in ethyl acetate, 3.86 ml, 6.55 mmol) and diisopropylethylamine (1.37 ml, 7.86 mmol) in tetrahydrofurane (10 ml) is refluxed for 18 hours. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed several times with water and dried affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (665 mg, 63.9%) as a light brown solid. mp.: 252-5° C. MS: m/z=398.2 (M+H+).
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)(O)=[O:2].C(=O)(O)[O-].[Na+]>C1COCC1>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][CH:4]([CH2:1][OH:2])[CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)=[CH:23][CH:22]=1)#[N:25]
Reactant: COC(=O)c1ccc(CC(CCc2ccc(C#N)cc2)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(CO)CCc2ccc(C#N)cc2)cc1
Reaction time: 4 h
Yield: 57.3 %

Procedure:
24.28 ml of a 1 M borane-THF complex solution (24.28 mmol) are added dropwise to a solution of 5.32 g (77% purity, 12.14 mmol) of methyl 4-[2-carboxy-4-(4-cyanophenyl)butyl]benzoate from Example 14A in 40 ml of THF at −15° C., and the solution is stirred at this temperature for 4 h. After reaction is complete, saturated sodium bicarbonate solution is added to the reaction mixture, and the solvent is concentrated to dryness. The residue is taken up in dichloromethane, dried over sodium sulfate and, after filtration, again freed of solvent. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). 2.25 g (55% yield) of a colorless solid are obtained.
Reaction SMILES: [CH3:1]N(C)C(CC)CN(C)C.N#N.CCO.[Li]C(CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>C1COCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH3:1])[CH:23]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCC(CN(C)C)N(C)C
Agent: N#N
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(Cl)ccc1C(=O)O
Temperature: -50 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
In a dry round-bottomed flask (3L) equipped with a mechanical stirrer under N2, anhydrous N,N,N′,N′-tetramethylethylethylenediamine (TMEDA, 99.7 mL, 660 mmol, 2.2 eq.) and anhydrous THF (600 mL) were added and the mixture was cooled to −90° C. in a bath of liquid N2/EtOH. Freshly titrated sec-BuLi (550 mL, 1.2M in cyclohexane, 660 mmol., 2.2 eq.) was added slowly via cannula as to maintain the temperature at −50° C. The solution was cooled to −90° C. and 4-chlorobenzoic acid (47.0 g in 400 mL anhydrous THF, 300 mmol) was added slowly via cannula, while stirring carefully to maintain the temperature at −90° C. The reaction mixture was stirred at −90° C. for 1 h before allowed to warm-up to −80° C. and CH3l (80 mL, 1.28 moles) was added very slowly. The reaction mixture was stirred for 10 min at −80° C., then quenched slowly with H2O (600 mL) and allowed to warm-up to room temperature. The aqueous layer was separated, washed with Et2O (2×500 mL) and then acidified with HCl (2.5 N, 600 mL) while cooling in an ice bath; cooling was continued for 16 h at 4° C. to allow crystallization of the desired product. The crude product was dried under vacuum and over anhydrous P2O5 and then re-crystallized from hot toluene (700 mL) to obtain pure 4-chloro-2-methylbenzoic acid (40 g).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1
Reactant: OCc1nccc(N2CCCCC2)n1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: ClCc1nccc(N2CCCCC2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Thionyl chloride (3.01 ml) was added dropwise to a stirred solution of 2-hydroxymethyl-4-piperidino-pyrimidine (2.66 g) in chloroform (20 ml) cooled in an ice/salt bath. The mixture was allowed to warm to room temperature and stirred for a further 2.5 hours. The solution was poured onto ice, the pH raised to ca. 8 (NaOH), and extracted with chloroform. The extracts were dried and stripped to give 2-chloromethyl-4-piperidino-pyrimidine (2.92 g) as an unstable oil which was used immediately.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.[C:27](Cl)(=[O:29])[CH3:28]>CCN(CC)CC>[C:27]([NH:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=[O:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2F)C1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NCCO[C@@H](c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-2-fluorophenyl)methyl)-piperidine-1-carboxylate (160 mg, 0.41 mmol) and Et3N (1 mL) at 0° C. was added acetyl chloride (32.3 mg, 0.41 mmol). The mixture was allowed to warm to rt and stirred overnight. The mixture was concentrated in vacuo to give crude (R)-tert-butyl 3-((R)-(2-acetamidoethoxy)-(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (95 mg, 54%), which was used in the next step without further purification. 1H NMR: (400 MHz, CDCl3): 1.20 (m, 1H), 1.40 (s, 9H), 1.70 (m, 2H), 1.98 (s, 3H), 2.60 (m, 2H), 3.48 (m, 4H), 3.90 (m, 1H), 4.42 (m, 1H), 5.82 (m, 1H), 7.10(m, 1H), 7.20 (m, 1H), 7.34 (m, 1H); MS (E/Z): 429 (M+1). MS (E/Z): 429 (M+)
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[F:5][C:6]1[CH:7]=[C:8](Br)[CH:9]=[C:10]([F:12])[CH:11]=1.[Mg].O>O1CCCC1>[CH2:3]([C:8]1[CH:7]=[C:6]([F:5])[CH:11]=[C:10]([F:12])[CH:9]=1)[CH:2]=[CH2:1]
Reactant: C=CCBr
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1cc(F)cc(F)c1
Temperature: 20 °C

Procedure:
A solution of allyl bromide (2.5 g) in dry tetrahydrofuran (10 ml) was added dropwise with stirring to 3,5-difluorobromobenzene (4.0 g) with magnesium (0.5 g) in dry tetrahydrofuran) in dry tetrahydrofuran (40 ml), whilst maintaining the temperature of the mixture at about 20° C. When the addition was complete the mixture was allowed to warm to the ambient temperature (ca. 25° C.). After a period of 18 hours the mixture was poured into water (100 ml) and the resultant mixture extracted with diethyl ether, the extract washed with water, dried over anhydrous magnesium sulphate and the ether removed by distillation at atmospheric pressure. The residual oil was purified by distillation at atmospheric pressure to yield allyl-3,5-difluorobenzene (b.p. 154°-155°) as a colourless oil.