Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([S:19](Cl)(=[O:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>>[Br:7][C:6]1[C:2]([NH:1][S:19]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)(=[O:21])=[O:20])=[N:3][O:4][C:5]=1[CH3:8]
Reactant: Cc1onc(N)c1Br
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: Cc1onc(NS(=O)(=O)c2cccc3ccccc23)c1Br
Yield: 51 %

Procedure:
N-(4-Bromo-5-methyl-3-isoxazolyl)-1 -naphthalenesulfonamide was prepared from 3-amino-4-bromo-5-methylisoxazole and 1-naphthalenesulfonyl chloride as described in Example 2 in 51% yield. Recrystallization from ethyl acetate/hexanes gave a crystalline solid, m.p. 167°-170° C.
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN(Cc2ccccc2)Cc2ccccc2)CC1
Yield: 22.7 %

Procedure:
4-Amino-N-((1-(5-benzylaminopentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (1.11 g) as starting compound, benzaldehyde (0.28 g) and sodium cyanoborohydride (0.33 g) were reacted and treated in the same manner as in Example 136 to give 0.3 g of 4-amino-5-chloro-N-((1-(5-dibenzylaminopentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: C(OC(N[C@@H](CC1N=CNC=1)C(N(CC(NCC(C)(C1C=CC=CC=1)C)=O)CCC(OC)=O)=O)=O)C1C=CC=CC=1.Cl.[CH3:43][O:44][C:45](=[O:49])[CH2:46][CH2:47][NH2:48].Br[CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53].C(N(CC)CC)C>C(Cl)Cl>[CH3:43][O:44][C:45](=[O:49])[CH2:46][CH2:47][NH:48][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]
Reactant: COC(=O)CCN
Reactant: CC(C)(C)OC(=O)CBr
Agent: COC(=O)CCN(CC(=O)NCC(C)(C)c1ccccc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNCC(=O)OC(C)(C)C

Procedure:
Scheme 2 shows a method by which the compounds of the present invention can be prepared, by illustrating the synthesis of Example 4, methyl 3-([(2S)-2-[(benzyloxy)carbonyl]amino-3-(1H-4-imidazolyl)propanoyl]-2-[(2-methyl-2-phenylpropyl)amino]-2-oxoethylamino)propanoate. Reaction of β-alanine methyl ester hydrochloride with t-butyl bromoacetate was carried out in methylene chloride in the presence of triethylamine as the base to give 3-(tert-butoxycarbonylmethyl-amino)-propionic acid methyl ester which was then coupled to Cbz-His(trityl) in methylene chloride/acetonitrile with HBTU as coupling agent, and triethylamine as the base. The resulting product was treated with 95% aqueous TFA, to remove the trityl and the t-butyl groups, followed by coupling with β,β-dimethylphenethylamine in methylene chloride/dimethylformamide, with HBTU as coupling agent, and diisopropylethylamine as the base to give the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C)ncn1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(CCc2ccccc2)ncn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of 4,6-dimethylpyrimidine (1.08 g, 10 mmol) in THF (40 ml) was added dropwise at −78° C. a solution of n-butyllithium. To the solution was added benzylbromide (1.71 g, 10 mmol). The mixture was warmed up to 0° C. and stirred for 30 minutes. To the reaction mixture was added an aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate, washed with water, dried and concentrated. The obtained residue was chromatographed on silica gel (n-hexane-ethyl acetate). The obtained fraction was concentrated to give 4-methyl-6-phenethylpyrimidine (1.7 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:18])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]>>[CH3:9][O:10][C:11](=[O:18])[CH2:12]/[C:13](/[C:14]([O:16][CH3:17])=[O:15])=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)OC
Reactant: O=Cc1ccccc1
Product: COC(=O)C/C(=C/c1ccccc1)C(=O)OC
Yield: 4.9 %

Procedure:
Benzaldehyde (21.2 g) and succinic acid dimethyl ester (40.9 g) are treated in the same manner as in Reference Example 1, and the resulting product is purified by silica gel column chromatography to give (Z)-3-methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester (2.3 g) as colorless syrup.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2I)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH:20][C:2]2[CH:11]=[CH:10][C:9]3[C:8]([NH:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=2)=[CH:16][CH:15]=1
Reactant: NC1CCOCC1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(NC4CCOCC4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=338.4 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-5-iodo-quinoline (CAS 455955-26-7), 5-methyl-2-furanmethanamine and 4-amino-tetrahydropyran.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]=[CH:17][C:18]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:19][C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])([CH3:22])[CH3:21])[N:7]=1)=O)C.[BH4-].[Na+]>>[Cl:29][C:27]1[CH:26]=[CH:25][C:24]([O:30][CH3:31])=[C:23]([C:20]([CH3:21])([CH3:22])[CH2:19][C:18]([C:32]([F:33])([F:34])[F:35])([OH:36])[CH2:17][NH:16][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[CH:15][C:6]([CH2:4][OH:3])=[N:7]3)[CH:28]=1
Reactant: CCOC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(Cl)ccc3OC)C(F)(F)F)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(Cl)cc1C(C)(C)CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F

Procedure:
Analogously to Example 40, 120 mg (0.23 mmol) of 5-[4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl pentylidenamino]-quinoline-2-carboxylic acid ethyl ester is reacted with 35 mg (0.92 mmol) of sodium borohydride. After working-up and purification on silica gel with hexane-ethyl acetate (0–100%) as well as with ethyl acetate-methanol (0–20%), 61 mg (55% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:28][CH2:27][CH:26]([CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH2:25][CH2:24]2)[CH:3]=1.[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35]>C1COCC1>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([CH:23]2[CH2:24][CH2:25][CH:26]([CH2:29][C:30]3[O:31][C:34](=[O:35])[NH:33][N:32]=3)[CH2:27][CH2:28]2)[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)CC1CCC(c2cc(N)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Solvent: C1CCOC1
Product: Nc1cc(C2CCC(Cc3n[nH]c(=O)o3)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 20 mL scintillation vial was charged 2-(4-(7-amino-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetohydrazide (0.12 mmol), THF (5 mL), and 1,1′-carbonyldiimidazole (0.12 mmol, 25 mg). The resulting solution was stirred at room temperature for 2 hours. After 2 hours, the solvent was removed in vacuo and the residue taken up in 3:1 DMSO:MeCN. The solids are removed via centrifugation, and the title compound was purified via reverse-phase HPLC.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:7])[CH2:4][CH2:5][CH3:6].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([O:30][CH3:31])[CH:17]=1.Cl>O1CCCC1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:8]([C:3](=[O:7])[CH2:4][CH2:5][CH3:6])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:17][C:18]=1[O:30][CH3:31])#[N:29]
Reactant: COc1cc(CBr)ccc1-c1ccccc1C#N
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(OC)c1)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (1.80 g) in tetrahydrofuran (50 mL) was added dropwise a solution of ethyl butyrylacetate (9.50 g) in tetrahydrofuran (30 mL). After stirring for 30 min, 4′-(bromomethyl)-2′-methoxybiphenyl-2-carbonitrile (8.79 g) was added. The mixture was stirred at room temperature for 15 hr, and 1 M hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give ethyl 2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate. Then, a solution of the obtained ethyl 2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate, ethanimidamide hydrochloride (3.25 g) and 28% sodium methoxide (9.91 g) in methanol (70 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and saturated aqueous ammonium chloride solution was added to the residue. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (5.63 g, 52%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[Cl-].[CH2:9]([O:11][C:12]([C:14]1([NH3+:17])[CH2:16][CH2:15]1)=[O:13])[CH3:10].[N:18]1[CH:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[N:20][CH:19]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[N:18]1[CH:23]=[C:22]([C:24]([NH:17][C:14]2([C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:16][CH2:15]2)=[O:25])[CH:21]=[N:20][CH:19]=1
Reactant: O=C(O)c1cncnc1
Reactant: CCOC(=O)C1([NH3+])CC1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cncnc2)CC1
Reaction time: 16 h

Procedure:
Triethylamine (7.026 g, 69.44 mmol) was added to a suspension of 1-(ethoxycarbonyl)cyclopropanaminium chloride (11.50 g, 69.44 mmol), pyrimidine-5-carboxylic acid (8.617 g, 69.44 mmol), EDC (13.312 g, 69.44 mmol), and HOAT (0.945 g, 69.44 mmol) in CH2Cl2 (125 mL) and allowed to stir for 16 hours. The reaction was adsorbed onto silica and purified by silica gel chromatography and eluted with ethyl acetate to yield ethyl 1-[(pyrimidin-5-ylcarbonyl)amino]-cyclopropanecarboxylate as a white solid. Low resolution mass spectrometry: (M+H+)=236.2.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[I-].C([Zn+])C(C)(C)C.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:29][CH2:30][O:31][CH3:32])=[C:20]([C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:29][CH2:30][O:31][CH3:32])=[C:20]([C:22](=[N:7][S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=1
Reactant: CCOC(=O)C(=O)c1cc(Br)ccc1OCOC
Reactant: CC(C)(C)[S@@](N)=O
Agent: CC(C)(C)C[Zn+]
Agent: [I-]
Product: CCOC(=O)C(=N[S@@](=O)C(C)(C)C)c1cc(Br)ccc1OCOC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
A flask was charged with (S)-2-methylpropane-2-sulfinamide (0.764 g, 6.31 mmol) and neopentylzinc (II) iodide (0.5 M in THF, 10.0 mL, 5.00 mmol) was added under nitrogen atmosphere. The mixture was stirred at RT for 15 minutes and ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-oxoacetate (1.00 g, 3.15 mmol) was added in one portion. The reaction mixture was quenched with saturated aqueous ammonium chloride after 8 h. The reaction was partitioned between EtOAc and water. The organic phase was separated, washed with NH4Cl, water and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (10-30% EtOAc/hexane) to provide 0.675 g (S)-ethyl 2-(5-bromo-2-(methoxymethoxy)phenyl)-2-(tert-butylsulfinylimino)acetate.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:54])[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][C:20]=2[CH3:52])[N:16]=[N:15][C:14]=1Cl)[CH3:9].[H][H]>C(O)C.C(OCC)C.[Pd]>[CH2:8]([O:10][C:11](=[O:54])[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C:39]([CH3:42])([CH3:41])[CH3:40])=[C:32]([CH3:51])[CH:31]=3)([CH2:26][CH3:27])[CH2:28][CH3:29])=[CH:21][C:20]=2[CH3:52])[N:16]=[N:15][CH:14]=1)[CH3:9]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1cc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)nnc1Cl
Agent: [Pd]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Cc1cnnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)c1
Yield: 81.9 %

Procedure:
10% Pd-C (2 mg) and triethylamine (0.011 mL, 0.079 mmol) were added to a solution of {6-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-3-chloro-pyridazin-4-yl}acetic acid ethyl ester (Example 183-(2); 4.8 mg, 0.007 mmol) in ethanol (0.6 mL) at room temperature. After replacement with hydrogen, the mixture was stirred in a hydrogen atmosphere at room temperature for seven hours. The reaction mixture was diluted with diethyl ether and filtered. The filtrate was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (3.7 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
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: CC#N
Solvent: O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1ccccc1)c(OCc1ccccc1)c2=O
Temperature: 90 °C
Yield: 90.8 %

Procedure:
Intermediate 174, N-(4-Fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.150 g, 0.266 mmol) in a mixture of acetonitrile (10 ml) and water (10 ml) was treated with phenylboronic acid (0.042 g, 0.35 mmol), sodium carbonate (0.062 g, 0.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.070 g). The reaction mixture was degassed, flushed with argon and heated at 90° C. for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.124 g (91% yield) of the title material as a light yellow solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.61 (6H, s, 2×CH3), 4.03 (4H, m, 2×CH2), 4.49 (2H, d, J=6.1 Hz, NCH2), 7.02 (2H, m, aromatics), 7.29–7.51 (12H, m, aromatics and NH). HRMS (ESI+) calculated for C30H29FN3O4 [M+H+]: 514.2142. Found: 514.2137.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][C@H:15]1[NH:23][C:24]([C:26]1[S:27][C:28]3[CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][C:33]=3[N:34]=1)=[O:25])=[O:12])=[CH:5]2.Cl.[CH2:37]([NH2:39])[CH3:38].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([NH:39][CH2:37][CH3:38])=[O:21])[CH2:16][C@H:15]1[NH:23][C:24]([C:26]1[S:27][C:28]3[CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][C:33]=3[N:34]=1)=[O:25])=[O:12])=[CH:5]2
Reactant: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)O)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCNC(=O)[C@H]1CC[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 87.9 %

Procedure:
The compound (150 mg) obtained in Example 58 was dissolved in N,N-dimethylformamide (3 ml), to which N-ethylamine hydrochloride (119 mg), 1-hydroxybenzotriazole monohydrate (79 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (112 mg) and triethylamine (326 μl) were added, and the mixture was stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to conduct extraction with methylene chloride. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (methylene chloride:methanol=47:3). The thus-obtained solid was dissolved in methylene chloride, to which 1N ethanol solution (171 μl) of hydrochloric acid was added. The solvent was distilled off under reduced pressure, and methanol and diethyl ether were added to the residue to collect precipitate formed by filtration, thereby obtaining the title compound (74 mg).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Cl:25])[CH:24]=1)C=O>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(c2cc(Cl)cc(Cl)c2)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.5 mL of methyl acetoacetate, 1.0 g of NaH 60% dispersion in oil, 12.5 mL of 2.0M n-butyl lithium in hexane, 5.1 g of 3,5-dichlorobenzaldehyde and 75 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 135°-137° C.). 1H NMR (CDCl3) δ 2.78 (dd, 1 H), 2.97 (dd, 1 H), 3.63 (dd, 2 H), 5.64 (dd, 1 H), 7.31-7.40 (m, 3 H).
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:19])[CH2:11][CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])=[CH:3][C:4]([OH:6])=O.[CH3:20][CH2:21]OCC.C([Li])C.Cl>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:19])[CH2:11][CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])=[CH:3][C:4](=[O:6])[CH2:20][CH3:21]
Reactant: CCC(C)(C)CCCC(C)CC=CC(C)=CC(=O)O
Reactant: CCOCC
Agent: Cl
Agent: [Li]CC
Solvent: c1ccccc1
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)(C)CC
Reaction time: 3 h

Procedure:
To a stirred solution of 2.5 g. of 3,7,11,11-tetramethyltrideca-2,4-dienoic acid in 30 ml. of dry ether is added slowly, at 0°, 23 ml. of a one molar solution of ethyl lithium in benzene. After about three hours at 20°, the mixture is poured into iced 1N hydrochloric acid (100 ml.) with vigorous stirring. The ether layer is separated, combined with ethereal washings of the aqueous phase, washed with water, saturated potassium bicarbonate, and then saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to yield 5,9,13,13-tetramethylpentadeca-4,6-dien-3-one which is purified by high vacuum distillation or chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14]#[N:15])[CH:9]=[CH:10][CH:11]=1.[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][CH2:13][C:14]1[NH:23][N:22]=[N:21][N:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc(C)c1COc1cccc(CCC#N)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cccc(CCc2nnn[nH]2)c1
Temperature: 90 °C

Procedure:
A mixture of 3-(3-(2,6-dimethylbenzyloxy)phenyl)propanenitrile (Step C, 2.62 g, 9.9 mmol), sodium azide (0.899 g, 13.8 mmol) and ammonium chloride (0.740 g, 13.8 mmol) in dry DMF (20 ml) was heated under argon at 90° C. for 16 hours or until all the starting material is consumed, the reaction mixture was cooled, diluted with water and extracted with EtOAc (30 ml×4). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 95:592.5:7.5) to give semi solid product. The semi solid was stirred with 1:2 ethyl acetate:hexane (15 ml) for 10 minutes, and filtered to give product as a white solid.
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.[CH2:21]([N:23](CC)CC)C>C(Cl)Cl>[CH3:21][NH:23][C@@H:9]1[C:14]2[C:15](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][C@H:8]1[N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCN(CC)CC
Reactant: O[C@@H]1Cc2ccccc2[C@H]1N1CCCC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1

Procedure:
A solution of methanesulfonyl chloride (6 g) in methylene chloride (50 ml) was added dropwise rapidly to a stirred and cooled (0°-5°) solution of trans-2,3-dihydro-2-hydroxy-(pyrrolidin-1-yl)-1H-indene (5.5 g) and triethylamine (6 ml) in methylene chloride (200 ml). After the addition was complete, the mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was treated with a 33% solution of methylamine in ethanol (100 ml) and the mixture was stirred at reflux for 3 hours and evaporated under reduced pressure. The residue was treated with water and extracted twice with ether. The combined ether extracts were washed successively with 2N sodium hydroxide solution and water, dried over magnesium sulfate and evaporated under reduced pressure to yield a liquid which was distilled under vacuum to give trans-2,3-dihydro-1-methylamino-2-(pyrrolidin-1-yl)-1H-indene (6.3 g) b.p. 118°-120°/0.25 torr.