Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:13]1[N:18]([CH3:19])[C:17](=[O:20])[CH:16]=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:14]=1.C(N(CC)CC)C>>[CH3:19][N:18]1[C:17](=[O:20])[CH:16]=[C:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:14]=[C:13]1[N:9]1[CH2:10][CH2:11][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8]1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Product: Cn1c(N2CCC(c3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 88 %

Procedure:
A solution of 3-phenyl-pyrrolidine (449 mg, 3.05 mmol), 2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (436 mg, 1.97 mmol) and triethylamine (412 mg, 4.07 mmol) was refluxed for one hour. After removal of the solvent, the residue was partitioned between water and ethyl acetate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate/ethanol=10/1) to afford 3-methyl-2-(3-phenyl-pyrrolidin-1-yl)-6-pyridin-4-yl-3H-pyrimidin-4-one (576 mg, 88%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[CH3:1][C:2]1[C:10]([O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:30][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(Oc2ccc(C(N)=O)cn2)ccc2c1CCC2=O
Reactant: NCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: Cc1c(Oc2ccc(C(N)=O)cn2)ccc2c1CCC2NCCc1ccccc1
Yield: 81.7 %

Procedure:
Using a method similar to Example 14, using 6-(4-methyl-1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 12, 100 mg, 0.354 mmol), phenethylamine (52 mg, 0.425 mmol), Ti(iPrO)4 (201 mg, 0.708 mmol), TiCl4 (1.0M/DCM, 0.708 ml, 0.708 mmol), and NaBH3CN (44 mg, 0.708 mmol) gives the title compound (112 mg) as a white solid. Mass spectrum (ion spray): m/z=388 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.14 (d, 1H), 7.32-7.19 (m, 5H), 7.14 (d, 1H), 6.91-6.87 (m, 2H), 6.03 (br. s, 2H), 4.28 (t, 1H), 3.01 (t, 2H), 2.94 (m, 1H), 2.85 (m, 2H), 2.74 (m, 1H), 2.44 (m, 1H), 2.02 (s, 3H), 1.86 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH3:8])[C:3]=1[CH3:9].[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:7]([C:4]1[C:3]([CH3:9])=[C:2]([NH:1][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[O:6][N:5]=1)[CH3:8]
Reactant: CCc1noc(N)c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCc1noc(NS(=O)(=O)c2ccccc2)c1C
Yield: 68 %

Procedure:
N-(3-Ethyl-4-methyl-5-isoxazolyl)benzenesulfonamide was prepared as described in Example 42 from 5-amino-3-ethyl-4-methylisoxazole and benzenesulfonyl chloride in 68% yield. Purification was achieved by preparative HPLC to give a white solid, m.p. 94°-95° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[C:22]([Cu])#[N:23]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:9]2[C:8]3[N:7]=[CH:6][CH:5]=[N:4][C:3]=3[C:2]([C:22]#[N:23])=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: COc1cc(OC)cc(-c2ccc(Br)c3nccnc23)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(-c2ccc(C#N)c3nccnc23)c1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-8-(3,5-dimethoxy-phenyl)-quinoxaline (Step 179.4) (4.54 g, 13.2 mmol) and CuCN (1.54 g, 17.1 mmol, 1.3 equiv) in NMP (50 mL) was stirred for 2 h at 180° C., under an argon atmosphere. The reaction mixture was allowed to cool to rt, diluted with EtOAc/(10% aqueous solution of ethylenediamine) (150 mL), and filtered to afford 1.19 g (batch 1) of the title compound as a yellow solid. The filtrate was extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in EtOAc to provide 2.31 g (batch 2) of the title compound: ESI-MS: 292 [M+H]+; tR=4.53 min (System 1).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=O)[C:5]([OH:7])=[O:6].[NH2:10][C@H:11]([C:18]([NH:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1.C([BH3-])#N.[Na+]>>[C:5]([CH:4]([NH:10][C@H:11]([C:18]([NH:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)[CH2:3][CH:2]([CH3:9])[CH3:1])([OH:7])=[O:6]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(=O)O
Reactant: CC(C)CC(=O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CC(N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(C)C)C(=O)O)C(=O)O

Procedure:
In the manner described in Example 54, 4-methyl-2-oxopentanoic acid and L-histidyl-L-leucine are condensed in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-methylbutyl)-L-histidyl-L-leucine. In this case the product is eluted from the ion exchange resin with 10% ammonia. The mass spectrum shows a molecular ion at 408 m/e for the disilylated species minus 18. The nmr spectrum is consistent with structure.
Reaction SMILES: C(N1CCCCC1)C.[CH3:9][C:10]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([C:12](=[O:15])[CH2:13][CH3:14])[CH3:11].C(O[C@H:25]1[NH:28][C:27](=[O:29])[C@@H:26]1[C@H:30]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH3:31])(=O)C>ClCCl>[Si:33]([O:32][C@@H:30]([C@@H:26]1[C@@H:25]([C@@H:13]([CH3:14])[C:12](=[O:15])[C:10]([CH3:9])([O:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[CH3:11])[NH:28][C:27]1=[O:29])[CH3:31])([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:34])[CH3:35]
Reactant: CCC(=O)C(C)(C)O[Si](C)(C)C
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CCN1CCCCC1
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(C)(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a suspension of stannous trifluoromethanesulfonate (2.18 g) and N-ethylpiperidine (590 mg) in dichloromethane (15 ml) was added dropwise a solution of 2-methyl-2-(trimethylsilyloxy)-3-pentanone (785 mg) in dichloromethane (2 ml) at -78° C. under argon atmosphere. After stirring for 30 minutes, a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone (300 mg) in dichloromethane (3 ml) was added dropwise to the mixture. The reaction mixture was allowed to warm to room temperature and stirred at the same temperature for 3 hours. The mixture was quenched with phosphate butter (pH 7). The organic layer was filtered with celite, washed with dichloromethane, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (9 g) eluting with a mixture of ethyl acetate and hexane (1:10, V/V) to give (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1R)-1,3-dimethyl-3-(trimethylsilyloxy)-2-oxobutyl]-2-azetidinone (159 mg).
Reaction SMILES: [CH:1]1([C@H:4]([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:15]3[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[N:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1.[C:24](OCC)(=[O:28])[C:25]([CH3:27])=O>C(O)C>[CH:1]1([C@H:4]([N:7]2[C:8]3[N:9]=[CH:10][N:11]=[C:12]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:13]=3[N:14]=[C:25]([CH3:27])[C:24]2=[O:28])[CH2:5][CH3:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)=O
Reactant: CC[C@@H](Nc1ncnc(-c2ccc(OC)nc2C)c1N)C1CC1
Solvent: CCO
Product: CC[C@H](C1CC1)n1c(=O)c(C)nc2c(-c3ccc(OC)nc3C)ncnc21
Reaction time: 18 h

Procedure:
(R)-N4-(1-Cyclopropyl-propyl)-6-(6-methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine (0.20 g, 0.64 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.73 ml, 6.4 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 2.0 mg of (R)-8-(1-cyclopropyl-propyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one (Example 644a). 1H NMR (300 MHz, CDCl3) δ ppm 8.92 (s, 1 H), 7.68 (d, J=8.05 Hz, 1 H), 6.68 (d, J=9.15 Hz, 1 H), 4.84 (m, 1 H), 3.99 (s, 3 H),), 2.51 (s, 3 H), 2.39 (s, 3 H), 1.20 (m, 2 H), 0.86 (m, 8 H). MS (EI) 366.3 [(M+H)+, 100].
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][C@@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1.Cl.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C1COCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 48 %

Procedure:
0.60 g (2 mmol) of Z-Phe-OH, 0.51 g (2 mmol) of H-D-Trp-OMe.HCl, 0.46 g (2.4 mmol) of EDCI, 0.32 g (2.4 mmol) of HOBT and 0.44 ml (4 mmol) of NMM are dissolved at -10° C. in 10 ml THF and stirred at room temperature for 15 hours. The THF is distilled off under vacuum, the residue dissolved in 50 ml ethyl acetate and the organic phase washed three times with 10 ml 0.5 N HCl, 10% NaHCO3 solution and water respectively. The organic phase is dried with MgSO4 and the solvent distilled off under vacuum. 0.48 g (48%) of thin-layer chromatographically identical Z-Phe-D-Trp-OMe are obtained as a colourless powder.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]1[C@@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23](OC(C)(C)C)=O)[CH2:7]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].BrC1[S:38][C:39]2[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1>>[CH2:1]([NH:5][C@H:6]1[C@@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:38][C:39]3[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 65 %

Procedure:
The same operation as in Example (1h) was performed using tert-butyl cis(±)-3-(butylamino)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained by the method described in Example (77d) (12.3 mg, 0.029 mmol), sodium carbonate (45 mg, 0.42 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (10.4 mg, 0.036 mmol), to obtain 10.0 mg of the title compound (65%).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH2:12][CH2:11][O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13]O.O.C(Cl)Cl>C(O)C.Cl>[C:1]1([S:7]([C:8]2[CH2:12][CH2:11][O:10][N:9]=2)=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OO
Reactant: c1ccc(SC2=NOCC2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: O=S(C1=NOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-(phenylsulfinyl)-4,5-dihydroisoxazole I-249a and I-249b were prepared by the oxidation of racemic 3-(phenylthio)-4,5-dihydroisoxazole I-248. 3-(Phenylthio)-4,5-dihydroisoxazole I-248 (1.0 equiv) was dissolved in ethanol (0.15 M) followed by the addition of excess hydrogen peroxide in water (30% by weight, >50 equiv) and 1N HCl (0.29 M). The reaction was stirred at room temperature for 14 h after which it was transferred to a separatory funnel with excess water and methylene chloride. The water layer was extracted with methylene chloride (1×), dried over magnesium sulfate, and concentrated to provide crude product that was recrystallized from hexanes to provide the desired racemic 3-(phenylsulfinyl)-4,5-dihydroisoxazole I-249. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=355.5 m/z. Activity: C
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].F[C:11]1[CH:19]=[N:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:16]1[CH:17]=[N:18][CH:19]=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: NCc1ccccc1Br
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccccc1Br
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield from 2-bromobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. [M+H] calc'd for C13H11BrN2O2, 307, 309. Found 307, 309.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:11][OH:12])=[N:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH:11]=[O:12])=[N:4][C:5]([N:8]([CH3:9])[CH3:10])=[N:6][CH:7]=1
Reactant: CN(C)c1ncc(Br)c(CO)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CN(C)c1ncc(Br)c(C=O)n1
Reaction time: 8 h
Yield: 53 %

Procedure:
To [5-bromo-2-(dimethylamino)pyrimidin-4-yl]methanol (19 g, 82 mmol) in DCM (10 mL) was added Dess-Martin periodinane (41.7 g, 98 mmol) at room temperature. The reaction was stirred overnight and the reaction was diluted with hexanes, filtered and was concentrated before purification by column chromatography to yield 5-bromo-2-(dimethylamino)pyrimidine-4-carbaldehyde (10 g, 43.5 mmol). 1H NMR (500 MHz, CDCl3) δ 9.95 (s, 1H), 8.52 (s, 1H), 3.24 (s, 6H).
Reaction SMILES: [CH3:1]I.[Mg].[CH2:4]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH:21]=[O:22])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C>[CH2:4]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH:21]([OH:22])[CH3:1])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CI
Reactant: O=CC1Cc2ccccc2N(Cc2ccccc2)C1
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)C1Cc2ccccc2N(Cc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
1.12 ml of methyliodide are added dropwise to 0.435 g of magnesium powder, suspended in 50 ml of diethyl ether, in the course of 10 min. After the mixture has been subsequently stirred for 0.5 h, 1.5 g of 1-benzyl-3(R,S)-formyl-1,2,3,4-tetrahydroquinoline, dissolved in 10 ml of diethyl ether, are added dropwise. The mixture is subsequently stirred for 0.5 h and then poured onto ice-water. The crude product extracted with methylene chloride is purified by means of FC over 150 g of silica gel (mobile phase B): Rf (B)=0.31; Rf (D)=0.15.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH:26]([CH3:28])[CH3:27])[C:23]([NH2:25])=[O:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH:26]([N:22]([C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:29])([CH3:30])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)[C:23]([NH2:25])=[O:24])([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N(C(N)=O)C(C)C)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C(N)=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 8.9 %

Procedure:
A mixture of 2-[3-(1-isopropyl-ureido)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (347 mg, 0.85 mmol) in methanol (5 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(1-isopropyl-ureido)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (29 mg, 8%) as a white solid: LC/MS m/e calcd for C22H27N3O3 (M+H)+: 382.48, observed: 382.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[C:7]=1[CH:8]=[CH:9][C:10](Cl)=[O:11])#[N:2].[CH3:24][C:25](=[N:27][OH:28])[CH3:26].C(N(CC)CC)C.Cl>O1CCCC1.CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.O>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=2)[C:7]=1[CH:8]=[CH:9][C:10]([O:28][N:27]=[C:25]([CH3:26])[CH3:24])=[O:11])#[N:2]
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl
Reactant: CC(C)=NO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)=NOC(=O)C=Cc1c(C#N)cnn1-c1ncc(C(F)(F)F)cc1Cl
Temperature: 30 °C
Reaction time: 5 h
Yield: 25.1 %

Procedure:
At 30° C. a solution of 0.6 gram (0.002 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid chloride in 15 mL of tetrahydrofuran was added in portions to a stirred solution of 0.2 gram (0.002 mole) of acetone oxime, 0.3 gram (0.003 mole) of triethylamine, and a catalytic amount of 4-dimethylaminopyridine in 35 mL of toluene. Upon completion of the addition, the reaction mixture was stirred at 30° C. for five hours. After this time, the reaction mixture was diluted with water, and the pH was adjusted to about 3.0 with concentrated hydrochloric acid. The organic layer was separated and washed with an aqueous sodium chloride solution and then with water. The organic layer was concentrated under reduced pressure to a residual solid. The solid was subjected to column chromatography on silica gel with 1:1 hexane/ethyl acetate as eluant. Those fractions found by thin layer chromatography to contain a major constituent other than eluent and starting materials were combined and concentrated at 40° C. under reduced pressure, yielding 0.2 gram of isopropylideneamino 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:17]=[CH:16]C(F)=[CH:14][C:13]=1O[C@H](CC=C)C>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][C@H:17]([CH2:12][CH:13]=[CH2:14])[CH3:16]
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1Br
Reactant: Oc1cc(F)c(F)cc1Br
Product: C=CC[C@H](C)Oc1cc(F)c(F)cc1Br
Yield: 61 %

Procedure:
Prepared in 61% yield from 2-bromo-4,5-difluorophenol following the same procedure as (S)-1-bromo-4-fluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 7.42-7.35 (m, 1H), 6.77 (dd, J=11.9, 7.2 Hz, 1H), 5.88 (ddt, J=17.2, 10.1, 7.1 Hz, 1H), 5.21-5.06 (m, 2H), 4.40-4.27 (m, 1H), 2.61-2.36 (m, 2H), 1.35 (d, J=6.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.N1CCCC1.[CH2:17]([OH:21])[CH2:18][C:19]#[CH:20]>[Cu]I.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.[Cl-].[NH4+]>[NH2:11][C:6]1[C:5]2=[CH:4][CH:3]=[C:2]([C:20]#[C:19][CH2:18][CH2:17][OH:21])[N:10]2[N:9]=[CH:8][N:7]=1
Reactant: C#CCCO
Reactant: Nc1ncnn2c(Br)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCNC1
Product: Nc1ncnn2c(C#CCCO)ccc12
Temperature: 85 °C

Procedure:
7-Bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (1.0 g, 4.69 mmol), copper(I) iodide (89 mg, 0.47 mmol, 0.1 eq.) and tetrakis(triphenylphosphine)palladium(0) (542 mg, 0.47 mmol, 0.1 eq.) were charged into a microwave reactor vial and evacuated for 1 h. The vessel was then vented with argon, pyrrolidine (15 mL) and 3-butyn-1-ol (3.36 g, 47 mmol, 10 eq.) were added, and the vessel was crimp-capped and heated to 85° C. for 120 min in a single-mode microwave device. After cooling, the reaction mixture was poured into 120 mL of concentrated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated, and the residue was purified by flash chromatography (Biotage silica column, ethyl acetate). The resulting product (735 mg) was sufficiently pure (66% by HPLC) for further transformations.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[CH:3]=2)=[O:22])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc2c(c1)CCCC2=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc3c(c2)CCCC3=O)cc1
Yield: 92 %

Procedure:
Reaction of 6-Amino-3,4-dihydro-2H-naphthalen-1-one (80 mg, 0.50 mmol) in THF (6 mL) with p-anisoyl chloride (90 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave 4-methoxy-N-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzamide (135 mg, 0.46 mmol, 92% yield) as a white powder after purification by flash chromatography on silica gel (eluent: EtOAc/DCM 0/10 to 2/8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Solvent: CO
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)[C@@H](C)c2ccc(Cl)cc2)CC1

Procedure:
Example 166 was prepared from (2S)-2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; [α]D=+5.2° (C=1.03, MeOH): 1H NMR (400 MHz, CDCl3) δ 7.55 (d, 1 H, J=2.0 Hz), 7.46 (s, 1 H), 7.34–7.24 (m, 4 H), 7.23–7.17 (m, 1 H), 7.07 (d, 1 H, J=8.0 Hz), 7.04–6.97 (m, 1 H), 3.54 (q, 1 H, J=7.2 Hz), 3.41–3.24 (m, 2 H), 2.95 (ABq, 2 H), 2.72–2.59 (m, 1 H), 2.57–2.45 (m, 1 H), 2.42–2.37 (m, 2 H), 2.27 (s, 3 H), 2.05–1.91 (m, 2 H), 1.82–1.55 (m, 6 H), 1.50 (d, 3 H, J=6.8 Hz), 1.22 (d, 6 H, J=6.8 Hz); ESMS m/e: 484.3 (M+H)+.