Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[N:26]1[CH:27]=[CH:28][C:23]([O:22][C:2]2[N:6]3[CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=4)[CH:9]=[CH:10][C:5]3=[N:4][N:3]=2)=[CH:24][CH:25]=1
Reactant: FC(F)(F)Oc1ccc(-c2ccc3nnc(Cl)n3c2)cc1
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)Oc1ccc(-c2ccc3nnc(Oc4ccncc4)n3c2)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 23.6 %

Procedure:
In a 15 mL round-bottom flask 3-chloro-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg), 4-hydroxypyridine (60 mg), and potassium carbonate (88 mg) were suspended in DMA (3 mL). The reaction mixture stirred at 150° C. for 6 h, concentrated, the residue subjected to gradient chromatography (MeOH/dichloromethane) to produce 3-(pyridin-4-yloxy)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridine as amber oil (28 mg, 24%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[C:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1>CO.[Pd]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)C#Cc1cnc(N)cn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cnc(N)cn1
Reaction time: 16 h

Procedure:
To a solution of methyl 3-(5-aminopyrazin-2-yl)propiolate (30 mg, 0.169 mmol) in MeOH (847 μL) was added Pd—C (36.0 mg, 0.034 mmol). The solution was degassed by N2 stream for 15 min. After flushed with hydrogen gas and equipped with a hydrogen balloon, the reaction mixture was stirred for 16 h. The reaction mixture was filtered through Celite. The volatile materials were removed in vacuo. The crude methyl 3-(5-aminopyrazin-2-yl)propanoate was obtained (81%) and used for the next step without further purification. LCMS (m/z): 182.1 (MH+), 0.31 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[OH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[OH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:22])=[O:21])[CH2:18][CH2:19]2)=[CH:35][CH:34]=1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Reactant: OCc1ccc(B(O)O)cc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccc(CO)cc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Yield: 28.5 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 27) (50 mg, 0.10 mmols), [4-(hydroxymethyl)phenyl]boronic acid (50 mg, 0.30 mmols), cesium carbonate (200 mg), and Pd(PPh3)4 (5 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (15 mg, 29%)
Reaction SMILES: [CH:1]1([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([NH2:18])=[N:12][C:13]=3N)[S:5][C@H:4]([CH2:6][OH:7])[CH2:3][CH2:2]1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:21]>CC[N+](CC)(CC)CC.[Br-]>[C@@H:1]1([N:8]2[C:9]3[N:10]=[C:11]([NH2:18])[NH:12][C:13](=[O:21])[C:14]=3[N:15]=[CH:16]2)[S:5][C@H:4]([CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: Nc1nc(N)c2ncn(C3CC[C@@H](CO)S3)c2n1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Product: Nc1nc2c(ncn2[C@H]2CC[C@@H](CO)S2)c(=O)[nH]1
Reaction time: 288 h
Yield: 80 %

Procedure:
To a solution of 17 (50 mg, 0.18 mmol) in 20 mL of a 0.75 M TEAB buffer was added 6 μL of adenosine deaminase. The reaction was stirred for 12 days followed by lyophilization. The residue was purified by preparative TLC with 4:1 CHCl3 -MeOH. The crude product was recrystallized from hot EtOH to give 19 (40 mg, 80%); mp. 180°-183° C., FAB MS 268 (M+H)+ ; 1H NMR (DMSO-d6) δ 10.8 (br, 1, NH), 8.0 (s, 1, H-8), 6.6 (s, 2, NH2), 5.90 (m, 1, 1'-H), 5.12 (brs, 1, 5'-OH), 3.72 (m, 1, 4'-H), 3.55 (m, 2, 5'-H), 2.35 (m, 2, 2'-H), 2.15 (m, 1, 3'-H), 1.95 (m, 1, 3'-H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:31])[C:5]([NH:8][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)=[C:13]([O:29][CH3:30])[CH:12]=2)[CH3:10])=[CH:6][CH:7]=1.Cl[CH2:33]C1C=CC(C(F)(F)F)=NC=1.C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:24]=4)=[C:13]([O:29][CH3:30])[CH:12]=3)[CH3:10])[CH:33]=[N:31][C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: COc1cc(C(C)Nc2ccc(I)cc2N)ccc1OCc1ccc(C(F)(F)F)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: COc1cc(C(C)n2cnc3cc(I)ccc32)ccc1OCc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To stirred solution of 4-iodo-N1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)benzene-1,2-diamine [prepared from 5-(chloromethyl)-2-(trifluoromethyl)pyridine using the procedures described in Example 3-45-1 through Example 3-45-5] (1.04 g, 1.91 mmol) in ethanol (30 mL) was added triethyl orthoformate (1.0 mL, 5.89 mmol) and p-toluenesulfonic acid monohydrate (0.025 g, 0.13 mmol). The yellow solution was heated to reflux. After 30 min, the mixture was allowed to cool to room temperature and was concentrated to provide a yellow oil. Chromatographic purification (CombiFlash, 24 g SiO2 gold column, 1-5% methanol/dichloromethane elute) afforded 0.803 g (76%) of 5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[N:9]=[N:10][N:11]([CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](O)=[O:15])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:48][O:49][C:50]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:51]=1[NH2:52].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[C:23]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[N:9]=[N:10][N:11]([CH:13]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:14]([NH:52][C:51]3[C:53]([O:59][CH3:60])=[CH:54][C:55]([O:57][CH3:58])=[CH:56][C:50]=3[O:49][CH3:48])=[O:15])[N:12]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)C(c1ccccc1)n1nnc(C(c2ccccc2)c2ccccc2)n1
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: COc1cc(OC)c(NC(=O)C(c2ccccc2)n2nnc(C(c3ccccc3)c3ccccc3)n2)c(OC)c1

Procedure:
When in the general procedure of Example 88 an appropriate amount of (±)-5-(diphenylmethyl)-α-phenyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-tri-methoxyaniline was substituted for 2,6-diisopropyl-aniline, the title compound was obtained, mp 114°-117° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].[H-].[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[CH:6][CH:7]=1
Reactant: O=C1CCCN1
Reactant: BrCCc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCCN1CCc1ccc(Br)nc1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
To a mixture of dibromide 290 (1.7 g, 6.4 mmol) in 2-pyrrolidone (10 mL, 130 mmol) at room temperature was added sodium hydride, 40% dispersion in mineral oil (1.16 g, 19.3 mmol). This reaction mixture was then heated to 100° C. for 2 h, then cooled to RT and partitioned between water and ethyl acetate. The organic phase was collected, washed with water, saturated aqueous ammonium chloride, and brine. It was then dried (anhydrous MgSO4), filtered and concentrated. Silica gel chromatography (10% methanol/ethyl acetate) gave title compound 291 (1.3 g, 75% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.17-8.16 (m, 1H); 7.42-7.37 (m, 2H); 3.49 (t, J=7.4, 2H); 3.28 (t, J=6.9, 2H); 2.79 (t, J=7.2, 2H); 2.30 (t, J=7.8, 2H); 1.95 (quintet, 7.6, 2H). MS (M+H): 269.1, 271.1
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[CH2:13][CH2:14][C:15]([OH:17])=[O:16]>[OH-].[K+]>[N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([O:1][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2ncccc12
Reactant: O=C(O)CCCl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CCOc1cccc2ncccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-hydroxyquinoline (4.91 g, 0.0340 mole) (Aldrich) in 17 ml 2 N potassium hydroxide was refluxed while an ice cold solution of 3-chloropropionic acid (4.05 g, 0.0373 mole) (Aldrich) in 18.6 ml 2 N potassium hydroxide was added during 1 minute. The pH was maintained at pH 9.5 by addition of 2 N potassium hydroxide. After 10 minutes, the mixture was allowed to come to room temperature and stirred for 16 hours. The pH of the solution was adjusted to pH 3.8 and the mixture evaporated in vacuo to a residue which was column chromatographed on silica gel by elution with 4:1 ethyl acetate:methanol. Material of Rf =0.45 (thin layer chromatography using 1:1 ethyl acetate:methanol) was obtained and recrystallized from water; m.p. 217°-219° C.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Br:15][C:16]1[C:17]([O:27][CH2:28][CH3:29])=[C:18]([CH:24](O)[CH3:25])[CH:19]=[C:20]([Cl:23])[C:21]=1[CH3:22]>C(Cl)Cl>[Br:15][C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[C:18]([CH:24]([Cl:3])[CH3:25])[C:17]=1[O:27][CH2:28][CH3:29]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOc1c(C(C)O)cc(Cl)c(C)c1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Cl)cc(Cl)c(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (1.7 g, 9.2 mmol) and N,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperature for 10 minutes and then a solution of 1-(3-bromo-5-chloro-2-ethoxy-4-methylphenyl)ethanol (1.72 g, 6.15 mmol) in methylene chloride (34 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 10% EtOAc in hexanes (1.01 g, 60%).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[C:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:19])[CH:9]=1)=[O:6])[CH2:2][CH3:3].C([BH3-])#N.[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O.C(OCC)C>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:19])[CH2:9]1)=[O:6])[CH2:21][CH3:22]
Reactant: CCCN(CCC)C(=O)Cc1cn(C)c2ccc(OC)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCCN(CCC)C(=O)CC1CN(C)c2ccc(OC)cc21
Reaction time: 12 h
Yield: 66.8 %

Procedure:
To a solution of 3-(di-n-propylaminocarbonylmethyl)-5-methoxy-1-methylindole (78.5 mg, 0.310 mmol) in 0.75 mL of trifluoroacetic acid was added sodium cyanoborohydride (79 mg, 1.3 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 12 h, the reaction mixture was diluted with diethyl ether, and neutralized by 40% sodium hydroxide aqueous solution. The separated organic layer was washed with saturated NaHCO3 aqueous solution and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography to obtain the title compound (63 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:68]=[CH:67][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][CH:64]([F:66])[F:65])[CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:68]=[CH:67][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][CH:64]([F:66])[F:65])[CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 100 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-difluoromethoxy-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 4 h at rt, the reaction mixture was diluted with 50 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 114 mg white solid (67%). MS(ISP) 512.2 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:28]([O:37][CH3:38])(=[O:36])[C:29]1[C:30](=[CH:32][CH:33]=[CH:34][CH:35]=1)[NH2:31]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH3:38][O:37][C:28](=[O:36])[C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH:31][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)c1ccccc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1NC(=O)CNC(=O)OCc1ccccc1
Yield: 10.7 %

Procedure:
To a solution of N-α-Cbz-glycine (2.0 g, 9.56 mmol) in tetrahydrofuran (20 mL) was added 1,1′-carbonyldiimidazole (1.64 g, 10.13 mmol), followed 2 h later by methyl anthranilate (1.28 g, 8.47 mmol). After stirring overnight the tetrahydrofuran was removed in vacuo and the residue was redissolved in ethyl acetate, washed with 10% aqueous hydrochloric acid (2×), saturated aqueous sodium hydrogen carbonate (2×), dried (MgSO4) and concentrated to give an oily residue which was subjected to silica-gel column chromatography [eluent: Ethyl acetate:Hexane, 30:70, ν/ν->Ethyl acetate] to give the title benzoate (1) (0.31 g, 11%) as a white solid:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)I)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH3:38][CH:39]([OH:42])[C:40]#[CH:41]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I.N1CCCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:41]#[C:40][CH:39]([OH:42])[CH3:38])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC(C)O
Reactant: CC(C)(C)OC(=O)N1CCC(=C(I)c2ccccc2)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1CCNCC1
Solvent: N#Cc1ccccc1
Product: CC(O)C#CC(=C1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
To a mixture of 4-(1-phenyl-1-iodomethylene)-piperidine-1-carboxylic acid tert-butyl ester (0.537 g, 1.60 mmol), PdCl2(PhCN)2 (0.032 g, 0.083 mmol), tri-2-furylphosphine (0.0806 g, 0.347 mmol), and CuI (0.034 g, 0.178 mmol) was added piperidine (10 mL), followed by 3-butyn-2-ol (0.25 mL, 3.19 mmol). The mixture was heated at 100° C. for 8 h and then the solvent was removed in vacuo. The residue was partitioned with EtOAc-H2O and the aqueous phase was separated and re-extracted with EtOAc (×2). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated, and the residue was purified by flash chromatography (SiO2/hexane:EtOAc, 3:2) to give the title compound (0.402 g, 73%) as a yellow orange oil which solidified on standing:
Reaction SMILES: [OH:1][N:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[C:5]([O:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[C:3]1=[O:29].C(N(CC)CC)C.Cl[C:38]([O:40][CH3:41])=[O:39]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([N:2]([O:1][C:38]([O:40][CH3:41])=[O:39])[C:3](=[O:29])[C:4]([C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[C:5]2[O:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH2:7][CH2:8]1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(O)C12CCN(OC)CC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(OC(=O)OC)C12CCN(OC)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of carbonic acid ethyl ester 1-hydroxy-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (preparation example 13, step 1; compound P1ii.11) (140 mg, 0.33 mmol), triethylamine (93 μl, 68 mg, 0.67 mmol) and 4-dimethylaminopyridine (2 mg) in tetrahydrofuran (3 ml) at 0° C. was added a solution of methyl chloroformate (33 μl, 41 mg, 0.43 mmol) in tetrahydrofuran (2 ml) dropwise. The suspension was stirred at 0° C. for one hour, and at room temperature for one hour. The reaction mixture was evaporated, diluted with ethyl acetate and filtered to remove salts. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution (2×15 ml) and brine, dried over sodium sulfate and concentrated. The oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:2). Yield: 30 mg of carbonic acid ethyl ester 8-methoxy-1-methoxycarbonyloxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound P1ii.13) as a colorless gum.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].CC(C)=O.CO.S(=O)(=O)(O)O.[C:20]([O-:23])(O)=O.[Na+].[C:25]1([CH3:31])[CH:30]=C[CH:28]=[CH:27][CH:26]=1>>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([O:23][CH3:20])([CH3:28])[O:5]2)=[CH:7][CH:8]=1
Reactant: Oc1cccc(O)c1
Reactant: Cc1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: COC1(C)CC(C)(C)c2ccc(O)cc2O1
Temperature: 25 °C
Yield: 17 %

Procedure:
30 ml glass autoclave was charged with 2.2 g (20 mmol) of resorcin, 2.32 g (40 mmol) of acetone, 3.2 g (100 mmol) of methanol, 0.2 g (2 mmol) of conc. sulfuric acid and 10 ml of toluene, then sealed, and allowed to react at 70° C. for 4 hours. Then, the reaction mixture was cooled to room temperature, neutralized with saturated NaHCO3, washed with water, and toluene was distilled off under reduced pressure. The residue was purified by column chromatography on silicagel using hexane-ethyl acetate as an eluent to give 0.75 g (17.0%) of 7-hydroxy-2-methoxy-2,4,4-trimethylchroman as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([I:13])[CH:6]=1.[CH3:16]N(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:16][O:11][C:10]([C:8]1[S:9][C:5]([C:4]#[C:3][C:2]([CH3:15])([CH3:14])[CH3:1])=[CH:6][C:7]=1[I:13])=[O:12]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C#Cc1cc(I)c(C(=O)O)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid (1.0 g, 3.0 mmol) and DMF (20 μL) in dry dichloromethane (10 mL) was added oxalyl chloride (508 μL, 6.0 mmol) at room temperature. After stirring at room temperature for 90 min, the reaction was concentrated in vacuo to remove volatiles. The residue was dissolved in pyridine (5 mL) and methanol (5 mL) and stirred for 2 h. The volatiles were removed in vacuo and the residue was participated between ether (150 mL) and saturated NH4Cl solution (50 mL). The organic layer was washed with saturated NH4Cl solution (50 mL) and dried over Na2SO4. After concentration in vacuo, the residue was purified by silica gel chromatography (EtOAc/hexanes) to give the desired product (835 mg, 80%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:21](=[O:22])[N:20]([C:23]3[CH:35]=[CH:34][C:26]([O:27][CH:28]([CH3:33])[C:29](OC)=[O:30])=[CH:25][CH:24]=3)[C:19]([CH3:36])=[N:18][C:17]=2[CH2:37][CH2:38][CH3:39])=[CH:11][CH:10]=1)#[N:2].C(OCC)(=O)C.O>O1CCCC1>[OH:30][CH2:29][CH:28]([CH3:33])[O:27][C:26]1[CH:34]=[CH:35][C:23]([N:20]2[C:21](=[O:22])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:17]([CH2:37][CH2:38][CH3:39])[N:18]=[C:19]2[CH3:36])=[CH:24][CH:25]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(C)n(-c2ccc(OC(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of methyl 2-(4-{5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl}phenoxy]propanoate (1.60 g) in tetrahydrofuran (30 mL) was added lithium tetrahydroboron (80 mg), and the mixture was stirred at room temperature for 40 hr. Ethyl acetate and water were 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 magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.34 g, 88%).
Reaction SMILES: [NH3:1].[C:2]([O:6][C:7]([N:9]1[CH2:12][CH:11]([C:13]2[N:17]3[CH:18]=[CH:19][N:20]=[C:21](Cl)[C:16]3=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[N:14]=2)[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].CC(O)C>O>[C:2]([O:6][C:7]([N:9]1[CH2:12][CH:11]([C:13]2[N:17]3[CH:18]=[CH:19][N:20]=[C:21]([NH2:1])[C:16]3=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[N:14]=2)[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC(c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(Cl)nccn23)C1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC(c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn23)C1
Reaction time: 8 h

Procedure:
20 M of NH3 in H2O (3 mL) was added to a suspension of 3-[8-chloro-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-azetidine-1-carboxylic acid tert-butyl ester in i-PrOH (4 mL, 0.05 mol). The mixture was heated in an oil bath set at 105° C. overnight. The solvent was removed under reduced pressure and the residue was carried on to the next step without further purification. MS (ES+): m/z 467.82 (100)[MH+]. HPLC: tR=2.66 min (Open Lynx, polar—5 min).