Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:12][CH:13](O)[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.C(OCC)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH:13]([CH3:14])[CH3:12])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CC(C)O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Oc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 69.3 %

Procedure:
A mixture of 5-fluoro-4-nitrophenol (314 mg, 2.0 mmol), propan-2-ol (120 mg, 2.0 mmol), diphenyl-2-pyridylphosphine (789 mg, 3.0 mmol) and di-tert-butyl azodicarboxylate (691 mg, 3.0 mmol) in tetrahydrofuran (15 ml) was stirred at room temperature under argon for 22 hrs. The mixture was treated with 1M HCl/diethyl ether (15 ml) and stirred at room temperature for 2 hrs, then concentrated under vacuum and the residue dissolved in diethyl ether (10 ml), treated with 5M HCl acid and stirred for 2 hrs. The organic layer was separated, washed with 5M HCl acid (15 ml), then 10% Na2CO3 solution (2×10 ml), dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with 5-70% ethyl acetate/60-80 petrol ether to afford the title compound as a yellow oil (276 mg, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([C@@H:14]([NH:16][C:17]2[N:22]=[C:21]([N:23]3[C:27]4[CH:28]=[C:29]([C:32]([OH:34])=O)[CH:30]=[CH:31][C:26]=4[N:25]=[CH:24]3)[CH:20]=[CH:19][N:18]=2)[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH:14]([NH:16][C:17]2[N:22]=[C:21]([N:23]3[C:27]4[CH:28]=[C:29]([C:32]([NH:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[O:34])[CH:30]=[CH:31][C:26]=4[N:25]=[CH:24]3)[CH:20]=[CH:19][N:18]=2)[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(C(=O)O)cc32)n1)c1ccccc1
Product: CC(Nc1nccc(-n2cnc3ccc(C(=O)Nc4ccccc4)cc32)n1)c1ccccc1

Procedure:
The title compound was prepared from aniline and 2-[(S)-1-phenylethylamino]-4-[6-carboxy-benzimidazol-1-yl]pyrimidine according to the procedure described in EXAMPLE 107. Partial 1H NMR (500 MHz CD3OD): δ 8.72 (br, 1H); 8.55 (br, 1H); 8.32 (br, 1H); 8.18 (s, 1H); 7.83 (d J=7.5 Hz, 1H); 7.76 (d J=7.5 Hz, 1H); 7.70 (d J=7.0 Hz, 2H); 6.78 (δ J=5.0 Hz, 1H); 5.23 (br, 1H); 1.63 (d J=6.0 Hz, 3H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([O:12][C@H:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][N+:18]([O-:22])=[CH:17][C:16]=1[Cl:23])=[O:11])=O)(C)(C)C>Cl.CCOC(C)=O>[NH2:8][C@H:9]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:10]([O:12][C@H:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][N+:18]([O-:22])=[CH:17][C:16]=1[Cl:23])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H](Cc1ccccc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
4-((S)-2-((R)-2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (2.9 g, 4.34 mmol) was dissolved in HCl 4M in EtOAc (15 ml). The reaction was stirred at RT for 30 minutes. A precipitate formed, and it was filtered and dried in the vacuum oven to give 4-((S)-2-((R)-2-amino-3-phenylpropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide as an hydrochloride salt. (2 g, 3.52 mmol, 81% yield).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]([CH3:15])=[CH:11][C:12](O)=[O:13].[CH3:16][S:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.O>CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.C1COCC1.C(OCC)(=O)C>[CH3:9][C:10]1[CH:15]=[C:22]([C:21]2[CH:24]=[CH:25][C:18]([S:17][CH3:16])=[CH:19][CH:20]=2)[NH:23][C:12](=[O:13])[CH:11]=1
Reactant: CC(C)=CC(=O)O
Reactant: CSc1ccc(C#N)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CSc1ccc(-c2cc(C)cc(=O)[nH]2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
To a stirred solution of lithium diisopropylamide (50 mL of a 2M solution in heptane/THF/ethyl benzene, 0.1 mol) in THF (50 mL) at −78° C. and under an atmosphere of nitrogen was added dropwise a solution of 3-methyl-2-butenoic acid (5 g, 0.05 mol) in THF (50 mL). The reaction was warmed to 0° C. for 30 minutes. After cooling to −78° C., a solution of 4-(methylthio)benzonitrile (7.45 g, 0.05 mol) in THF (50 mL) was added dropwise. Upon complete addition, the reaction was warmed to room temperature and stirred for 3 hours. Water (150 mL) and ethyl acetate (100 mL) were added to the reaction mixture and the resulting precipitate filtered, washed with ethyl acetate and dried to give the title compound (4.96 g, 43%) LC retention time 2.75 mins, MS m/z 232 (MH+).
Reaction SMILES: [N:1]1([C:7]([C@H:9]2[NH:13][CH2:12][C@@H:11]([S:14][C:15](=[O:17])[CH3:16])[CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28](Cl)(=[O:30])=[O:29].OS([O-])(=O)=O.[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28]([N:13]1[C@H:9]([C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[CH2:10][C@H:11]([S:14][C:15](=[O:17])[CH3:16])[CH2:12]1)(=[O:29])=[O:30]
Reactant: CC(=O)S[C@@H]1CN[C@H](C(=O)N2CCCCC2)C1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCCCC2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Yield: 53.6 %

Procedure:
300 mg (1.17 mmol) (3S,5S)-Thioacetic acid S-[5-(piperidine-1-carbonyl)-pyrrolidin-3-yl] ester in 25 ml CH2Cl2 were treated with 398 mg (1.75 mmol, 1.5 eq) 2-naphthalene sulfonylchloride in the presence of 214 mg (1.75 mmol, 1.5 eq) DMAP at RT for 1.5 h. The solution was added to 1M KHSO4, the phases were separated and the inorganic extracted with CH2Cl2, the combined organic phases were washed with 1M KHSO4, water and brine, dried over Na2SO4 and were concentrated. Flash chromatography yielded 280 mg (54%) (3S,5S)-Thioacetic acid S-[1-(naphthalene-2-sulfonyl)-5-(piperidine-1-carbonyl)-pyrrolidin-3-yl] ester as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[N:30]=[C:29]([CH3:31])[C:28]([OH:32])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:28]4[C:29]([CH3:31])=[N:30][C:25]([Cl:24])=[CH:26][CH:27]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Cc1nc(Cl)ccc1O
Product: Cc1nc(Cl)ccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 19 %

Procedure:
4-[4-(6-Chloro-2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared in 19% yield as a white powder using Method A described for the preparation of Example 92 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol) with 6-chloro-2-methyl-pyridin-3-ol (Intermediate 3; 28 mg, 0.19 mmol). 1H NMR (300 MHz, CDCl3) δ 1.50 (s, 9H), 1.96-2.06 (m, 2H), 2.20-2.35 (m, 2H), 2.42 (s, 3H), 2.92-3.05 (m, 2H), 4.26-4.38 (m, 2H), 4.90-5.02 (m, 1H), 7.27-7.30 (m, 1H), 7.48 (d, 1H, J=8.4 Hz), 8.15 (s, 1H), 8.47 (s, 1H). Mass spectrum (ES) MH+=445. HRMS Calcd. for C21H26ClN6O3 (MH+): 445.1750. Found: 445.1750.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:11].[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:8][CH2:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[O:11])[CH2:32][CH2:31]2)[CH:25]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1ccc(C(=O)CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C(=O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 3-chloro-1-(4-methylphenyl)-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 393.2 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH3:30][CH:31]1[CH:40]=[C:39]2[CH:34]([CH:35]([CH2:42][CH2:43][CH:44]3[CH2:49][CH:48]([OH:50])[CH2:47][C:46](=[O:51])[O:45]3)[CH:36]([CH3:41])[CH:37]=[CH:38]2)[CH:33]([O:52][C:53](=[O:58])[CH:54]([CH3:57])[CH2:55][CH3:56])[CH2:32]1>>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH3:56][CH2:55][C@@H:54]([C:53]([O:52][C@@H:33]1[C@@H:34]2[C@@H:35]([CH2:42][CH2:43][C@@H:44]([OH:6])[CH2:49][C@@H:48]([OH:50])[CH2:47][C:46]([OH:45])=[O:51])[C@@H:36]([CH3:41])[CH:37]=[CH:38][C:39]2=[CH:40][C@H:31]([CH3:30])[CH2:32]1)=[O:58])[CH3:57]
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(O)CC(=O)O3)C21
Agent: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Product: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21

Procedure:
Lovastatin is chemically represented as [1S-[1α(R*),3α,7β,8β(2S*,4S*),8αβ]]-2-methylbutanoic acid 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester, and strains producing the compound also produce an acid form of lovastatin, i.e., mevinolinic acid, which is converted into lovastatin(mevinolin) as a lactone form in the course of isolation and recovery.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1([CH2:23][CH3:24])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([NH:20]C=O)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]>C.CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1([CH2:23][CH3:24])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([NH2:20])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3NC=O
Agent: C
Solvent: CO
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3N
Yield: 49.9 %

Procedure:
1,8-Diethyl-4-formylamino-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester 10 (5.5 g, 0.01 mol) in 1N methan olic HCl (4.2 mL) and methanol (18 mL) was stirred at 25° C. for 72 hours, then concentrated in vacuo, diluted with water and extracted with ethyl acetate. The aqueous phase was basified with concentrated NaHCO3 solution and extracted with ether to afford the product (1.58 g, 50%), m.p. 230° C. (dec.) after recrystallization from ether.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:19])[C:4]([N:6]1[CH2:10][CH:9]2[CH2:11][C:12]([CH2:17][CH3:18])([N:14]=C=O)[CH2:13][CH:8]2[CH2:7]1)=[O:5].[OH-].[Na+]>>[CH3:19][N:3]([CH3:2])[C:4]([N:6]1[CH2:10][CH:9]2[CH2:11][C:12]([NH2:14])([CH2:17][CH3:18])[CH2:13][CH:8]2[CH2:7]1)=[O:5]
Reactant: CCC1(N=C=O)CC2CN(C(=O)N(C)C)CC2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC1(N)CC2CN(C(=O)N(C)C)CC2C1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 12 mL hydrochloric acid (8 N) was added 5-ethyl-5-isocyanato-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 19e obtained from the above step at room temperature. The reaction mixture was stirred for 30 minutes and adjusted to pH 9-10 with an 8 N aqueous sodium hydroxide solution. The separated aqueous layer was extracted with dichloromethane (30 mL×5). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-amino-5-ethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 19f (0.3 g, yield 71%) as a colorless oil.
Reaction SMILES: [CH:1]([CH2:3][N:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])=O.[F:19][C:20]([F:35])([F:34])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>O.ClCCCl.C(O)(=O)C>[CH:7]1([C:5]([N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:3][CH2:1][N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][C:20]([F:34])([F:19])[F:35])[CH2:33][CH2:32]2)=[O:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=CCN(C(=O)C1CCCCC1)c1ccccn1
Reactant: FC(F)(F)Oc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: O=C(C1CCCCC1)N(CCN1CCN(c2ccccc2OC(F)(F)F)CC1)c1ccccn1
Reaction time: 4 h
Yield: 51.1 %

Procedure:
A mixture comprising 0.459 g of Compound 1B, 0.445 g of 1-(2-trifluoromethoxyphenyl)piperaine (prepared as described by D. Clarke et al, in European Patent EP 711 757, 1996), 0.634 g sodium triacetoxyborohydride, 0.23 mL of glacial acetic acid and 15 mL of 1,2-dichloroethane was stirred for 4 h, under a nitrogen atmosphere. The resultant solution was then kept overnight at room temperature, followed by the addition of 10 mL of water, and alkalinization with a 20% aqueous Na2CO3 solution. This was followed by separation of phases, with the isolated aqueous phase being extracted with 2×20 mL dichloromethane, and with the collected organic phases being dried over anhydrous sodium sulphate. This was followed by the removal of solvents, via vacuum evaporation to dryness. The obtained product residue was purified by flash chromatography (ethyl acetate—petroleum ether gradient 90:10 to 10:0). This was followed by evaporation of the solvents, affording 0.44 g of the title compound (yield 51%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)=[CH2:18])=[CH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][C:34](=[CH2:37])[CH:35]=[O:36].B(F)(F)F>C(Cl)Cl>[CH3:33][C:34]1([CH:35]=[O:36])[CH2:37][CH2:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:24]=2)[CH2:18]1
Reactant: C=C(C(=C)c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Reactant: C=C(C)C=O
Agent: FB(F)F
Solvent: ClCCl
Product: CC1(C=O)CCC(c2ccc(OCc3ccccc3)cc2)=C(c2ccc(OCc3ccccc3)cc2)C1
Reaction time: 3 h

Procedure:
To a solution of 2,3-di(4-benzyloxy-phenyl)-1,3-butadiene (1.2 g, 2.8 mmol) and 2-methyl-propenal (0.602 g, 8.4 mmol) in DCM (10.5 mL) was added BF3.OCH2CH3 (0.596 mL, 4.2 mmol) at −10° C. After 3 h at −10° C., the reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL). The reaction mixture was then extracted with ethyl acetate (2 10 mL), dried over MgSO4 and purified by SiO2 twice (15% ethyl acetate/hexane) to yield 1-methyl-3,4-di(4-benzyloxy-phenyl )-cyclohex-3-ene carbaldehyde.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:13]([OH:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].N>CN1CCN(C)C1=O>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:18]3[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][OH:21])=[CH:16][CH:17]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(Br)Cc1ccccc1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: OCCc1ccc(-n2cnc(-c3ccccc3)c2)cc1
Temperature: 180 °C
Reaction time: 36 h
Yield: 50.6 %

Procedure:
A mixture of 4-phenylimidazole (4.32 g, 30 mmol), Bromophenethyl alcohol (10.5 ml, 75 mmol), CuBr (10.4 g, 72 mmol) and Na2CO3 (3.8 g, 36 mmol) in 1,3-dimethyl-2-imidazolidinone (100 mL) was stirred at 180° C. for 36 h. After cooling, to the mixture was added 25% NH3 aq. (50 mL). After 30 min, insoluble materials were removed by Celite filtration and washed with dichloromethane. The aqueous layer was extracted with dichloromethane. The organic phase was dried (MgSO4) and concentrated under reduced pressure. To the residue was added diisopropylether (100 mL) and the flask was cooled to 0° C. Filtration of the diisopropylether gave 4.01 g of the title compound as colorless solid (51%): MS (ESI) m/z 265 [M+H]+, 1H-NMR (CDCl3) δ 2.94 (2H, t, J=6.4 Hz), 3.93 (2H, br), 7.26-7.30 (2H, m), 7.35-7.44 (5H, m), 7.55 (1H, d, J=1.2 Hz), 7.82-7.86 (3H, m).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>ClCCl>[N:6]1[CH:7]=[CH:8][C:3]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:4][CH:5]=1
Reactant: Clc1ccncc1
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(Nc2ccncc2)cc1
Temperature: 140 °C

Procedure:
A stirred mixture of 4-chloropyridine hydrochloride (2 g) and 4-methoxyaniline (4.9 g) was heated at 140° C. for 5 hours. After cooling the residue was dissolved in dichloromethane (250 ml), the solution extracted with water (2×100 ml). The aqueous extracts were treated with sodium hydroxide solution and then extracted with ethyl acetate (4×100 ml). The combined organic extracts were washed with water, and saturated sodium chloride solution, then dried and the solvent evaporated. Purification by flash chromatography on silica, eluting with 10% v/v methanol/dichloromethane gave 4-(4-pyridylamino)-methoxybenzene, 2 g, as a fawn solid: m.p. 159°-160° C.; NMR (d6DMSO) δ8.47 (1H, s), 8.09 (2H, d), 7.10 (2H, d), 6.92 (2H, d), 6.70 (2H, dd), 3.73 (3H, s); m/e 201 (M+H)+ ; calculated for C12H12 N2O3 : C, 72.0; H, 6.0; N, 14.0. found: C, 71.4; H, 6.1; N, 13.8%.
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][N:10]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[C:25](O)=[O:26])[CH:19]=[CH:20][C:12]=2[S:11]1(=[O:38])=[O:37].[NH2:39][C:40]1[CH:44]=[CH:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:41]=1.N1C=CC=CC=1>C(Cl)Cl.O.C(OCC)(=O)C>[CH3:9][N:10]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([O:21][C:22]3[CH:23]=[C:24]([C:25]([NH:39][C:40]4[CH:44]=[CH:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[N:41]=4)=[O:26])[CH:28]=[C:29]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[CH:19]=[CH:20][C:12]=2[S:11]1(=[O:37])=[O:38]
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)S3(=O)=O)cc(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)S3(=O)=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reaction time: 1 h
Yield: 16.6 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.13 mL, 1.01 mmol) was added to a solution of 3-[(2-methyl-1,1-dioxido-3,4-dihydro-2H-5,1,2-benzoxathiazepin-7-yl)oxy]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (0.22 g, 0.50 mmol) in DCM (8 mL) and stirred for 1 hour. 1,1-Dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (231 mg, 1.26 mmol) then pyridine (0.1 mL, 1.26 mmol) were added and the reaction stirred until the reaction was complete. The reaction mixture was reduced in vacuo and ethyl acetate (50 mL) and water (50 mL) were added. The aqueous layer was further extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo to give a golden oil which was chromatographed on silica, eluting with 25-70% ethyl acetate in isohexane then 0-5% methanol in DCM, to give the desired compound as a colourless oil (50 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=O)#[N:2]>P(Cl)(Cl)(Cl)=O>[C:1]([CH2:3][C:4]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[CH:7][N:6]=1)#[N:2]
Reactant: N#CCC(=O)NCc1ccccn1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCc1ncc2ccccn12
Temperature: 25 °C

Procedure:
Heat under reflux for 0.5 hours a mixture of 9 gm (0.06 mol) 2-cyano-N-(2-pyridylmethyl)acetamide and 100 ml phosphorous oxychloride. Cool the reaction mixture to room temperature and remove the phosphorus oxychloride under reduced pressure. Partition the residue between chloroform and a solution of sodium bicarbonate. Separate the chloroform layer and dry over anhydrous potassium carbonate. Filter and remove the chloroform under reduced pressure. Chromatograph the resulting residue on silica gel using ethyl acetate-chloroform to give the desired product, 3-cyanomethyl imidazo[1,5-a]pyridine, as determined by IR, NMR and elemental analysis, m.p. 64°-66°.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:31]=[N:30][C:29]([CH3:28])=[N:34][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cn1
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 60 mg, 0.134 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (44.4 mg, 0.202 mmol), Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol) and Na2CO3 (42.8 mg, 0.403 mmol) were added to a MW vial and treated with DME (570 μL), EtOH (81 μL) and water (163 μL). The vial was sealed, evacuated/purged with argon, and subjected to MW irradiation at 80° C. with stirring for 2 h, diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 52.9 mg, 0.067 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, 20% for 0.2 min then 20% to 50% in 12 min) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=1.82 min, m/z=458.2 [M+H]+, m/z=443.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.80 (m, 1H) 1.79-1.92 (m, 1H) 2.69 (s, 3H) 2.91 (d, J=11.00 Hz, 1H) 3.14-3.49 (m, 3H) 4.13-4.28 (m, 1H) 4.83 (br. s, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.80-7.91 (m, 2H) 8.05 (d, J=2.45 Hz, 1H) 8.75 (s, 2H) 8.78 (d, J=2.20 Hz, 1H) 10.14 (s, 1H).