Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].Br[C:22]1[S:26][C:25]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:24][CH:23]=1>>[C:28]([NH:27][C:25]1[S:26][C:22]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:23][N:24]=1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C#Cc1cncc(C(=O)N=S(C)(=O)c2ccccc2)c1
Reactant: O=C(Nc1ncc(Br)s1)c1ccccc1
Product: CS(=O)(=NC(=O)c1cncc(C#Cc2cnc(NC(=O)c3ccccc3)s2)c1)c1ccccc1
Yield: 26.1 %

Procedure:
In a manner similar to that described in Example 462, 5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (74 mg, 0.26 mmol), N-(5-bromo-1,3-thiazol-2-yl)benzamide (74 mg, 0.26 mmol) were reacted to give the title compound as a cream solid (33 mg, 26%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C@@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)/[C:13](=[N:20]/[O:21][CH3:22])/[CH2:12][C:11]2([CH3:24])[CH3:23])[CH:7]=[N:8][CH:9]=1)=O.CC(C[AlH]CC(C)C)C.CO>ClCCl>[CH3:22][O:21][N:20]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:10]([N:6]2[C:5]([CH2:3][OH:2])=[CH:9][N:8]=[CH:7]2)[C:11]([CH3:24])([CH3:23])[CH2:12]1
Reactant: CO/N=C1\CC(C)(C)[C@H](n2cncc2C(=O)OC)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: CON=C1CC(C)(C)[C@H](n2cncc2CO)c2ccccc21
Reaction time: 1 h

Procedure:
To a solution of (R)- or (S)-3-{4-[(E)-methoxyimino]-2,2-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl}-3H-imidazole-4-carboxylic acid methyl ester (ca. 100 mg, ca. 0.299 mmol), which can be prepared as described in Example 34, in dichloromethane (2 mL) at −78° C. is added DIBAL-H (1.0M in hexane, 0.91 mL, 0.91 mmol) portion wise over 45 minutes. Methanol (0.1 mL) is then added and the cooling bath is removed. The mixture is diluted with dichloromethane and an aqueous solution of Rochelle's salt is added. The mixture is vigorously stirred for 1 hour, further diluted with aqueous Rochelle's salt, then extracted with dichloromethane. The organic extract is dried over MgSO4, filtered, and concentrated to give a residue, which is purified by silica gel flash chromatography (dichloromethane-methanol, 97:3 to 19:1) to give (R)- or (S)-4-(5-hydroxymethyl-imidazol-1-yl)-3,3-dimethyl-3,4-dihydro-2H-naphthalen-1-one O-methyl-oxime as a 19:1 mixture of geometric isomers; MS: (ESI) m/z 300.0 (M+H)+; 1H NMR (400 MHz, MeOD) of Major Isomer: δ ppm 0.96 (s, 3 H), 1.09 (s, 3 H), 2.71 (d, J=17.9 Hz, 1 H), 2.86 (d, J=17.9 Hz, 1 H), 4.06 (s, 3 H), 4.74 (d, J=13.9 Hz, 1 H), 4.78 (d, J=13.9 Hz, 1 H), 5.46 (s, 1 H), 6.99 (s, 1 H), 7.14-7.16 (m, 1 H), 7.22 (s, 1 H), 7.34-7.40 (m, 2 H), 8.11-8.15 (m, 1 H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:19])(=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17].[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH:27]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][CH:29]=[O:30].Cl>C1COCC1>[CH2:15]([CH:14]([CH:29]([OH:30])[CH2:28][CH:27]([O:26][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:13]([OH:19])=[O:18])[CH:16]=[CH2:17]
Reactant: C=CCCC(=O)O
Reactant: CCCCCCCCCCCC(CC=O)OC1CCCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCC(C(=O)O)C(O)CC(CCCCCCCCCCC)OC1CCCCO1
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
C)a) 2 ml of diisopropylamine in 30 ml of dry THF were cooled to -20° C. and thereupon 9.68 ml of butyl lithium (1.6M/hexane) were added dropwise in such a manner that the temperature did not exceed -20° C. The mixture was subsequently stirred for 15 minutes and then cooled to -50° C. Thereafter, 0.720 ml of 4-pentenoic acid in 10 ml of THF was added dropwise and the mixture was stirred at 50° C. for a further 10 minutes. The mixture was stirred at room temperature for 1 hour and subsequently again cooled to -50° C. 2 g of rac-3-[(tetrahydro-2H-pyran-2-yl)oxy]-tetradecanal in 10 ml of THF were now added dropwise and the mixture was stirred at -50° C. for a further 30 minutes, then at room temperature for 72 hours. After hydrolysis with 2N hydrochloric acid the reaction mixture was evaporated. The residue was extracted with ether. The organic phase was dried over sodium sulfate, filtered and evaporated. The material obtained was filtered through a column of silica gel. There was obtained 2-allyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.Br[C:48]1[C:49]([CH2:56][CH2:57][CH2:58][O:59][CH3:60])=[CH:50][C:51]([O:54][CH3:55])=[N:52][CH:53]=1>>[C:20]([O:19][C:18](=[O:24])[NH:17][CH2:16][CH:15]([C:25]1[CH:30]=[CH:29][C:28]([C:48]2[CH:53]=[N:52][C:51]([O:54][CH3:55])=[CH:50][C:49]=2[CH2:56][CH2:57][CH2:58][O:59][CH3:60])=[CH:27][C:26]=1[CH3:40])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:44][C:43]([CH3:45])=[CH:42][C:41]=2[Cl:46])=[CH:9][CH:10]=1)([CH3:22])([CH3:21])[CH3:23]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Reactant: COCCCc1cc(OC)ncc1Br
Product: COCCCc1cc(OC)ncc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and 5-bromo-2-methoxy-4-(3-methoxypropyl)pyridine (V.17) as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:47][C@@H:48]1[NH:53][CH2:52][CH2:51][N:50]([S:54]([C:57]2[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=2)(=[O:56])=[O:55])[CH2:49]1.C[C@@H]1NCCN(S(C2C=CC(OC(F)(F)F)=CC=2)(=O)=O)C1>CN(C)C=O.CC#N.CS(C)=O>[CH3:47][C@H:48]1[CH2:49][N:50]([S:54]([C:57]2[CH:58]=[CH:59][C:60]([C:63]([F:66])([F:64])[F:65])=[CH:61][CH:62]=2)(=[O:55])=[O:56])[CH2:51][CH2:52][N:53]1[C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][CH:2]=[N:1]2)=[CH:6][CH:7]=1)=[O:13]
Reactant: O=C(O)c1ccc2cccnc2c1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[C@H]1CN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CCN1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1ccc2cccnc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
7-Quinolinecarboxylic acid (112 mg, 0.649 mmol) was weighed into a vial with the HATU (247 mg, 0.649 mmol), suspended in N,N-dimethylformamide (DMF) (2 ml) and treated with N,N-diisoproylethylamine (0.170 ml, 0.973 mmol). This mixture was stirred about 15 mins at ambient temperature. (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared in a similar manner as described in Intermediate 14; 100 mg, 0.324 mmol) was then added and stirring was continued. Stirring was stopped and the reaction mixture was left to stand overnight. The mixture was partitioned between DCM and sat aq. NaHCO3 solution (10 ml each). The layers were separated (hydrophobic frit) and the aqueous was washed with further DCM (2×5 ml). The combined organic layers were concentrated to leave an orange gum (still contained DMF). This was diluted with a mixture of MeCN and DMSO to give ˜1.8 ml orange solution which was purified by MDAP as two injections. The product fractions from the two runs were combined and concentrated to give the title compound as a colourless solid (119 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:4][C:3]=1[F:23].C(N(CC)CC)C.[C]=O>CO.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:23][C:3]1[CH:4]=[C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:6]=[CH:7][C:2]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C(OCc1ccccc1)N1CCCC1c1ccc(Br)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1F
Temperature: 25 °C
Yield: 120.1 %

Procedure:
A mixture of benzyl 2-(4-bromo-3-fluorophenyl)pyrrolidine-1-carboxylate (15.3 g, 40.6 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride (1.67 g, 2.0 mmol) and triethylamine (8.4 mL, 60.9 mmol) in methanol (180 mL) was stirred under 60 psi of carbon monoxide at 100° C. for 4 hour. After cooling to ambient temperature, the mixture was concentrated and the residue purified by flash chromatograph on silica gel using a gradient of 8-15% ethyl acetate in petroleum ether to give benzyl 2-(3-fluoro-4-(methoxycarbonyl)phenyl)pyrrolidine-1-carboxylate as colorless oil (8.71 g, yield 60%). LC-MS (ESI) m/z: 358 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)(=[O:10])[CH3:9]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Oc2ccc(Br)cc2C(C)=O)cc1

Procedure:
5′-bromo-2′-hydroxyacetophenone (compound 12) (1.80 g, 10.6 mmol) was added to a pyridine solution (40 ml) that contained 4-methoxybenzoyl chloride (2.01 g, 9.35 mmol) in an ice bath. The obtained mixture was reacted at room temperature for 30 minutes, and the reaction solution was then poured into 1 N hydrochloric acid under cooling on ice. The obtained mixture was intensively stirred. The obtained precipitate was collected by filtration, and the filtrate was then washed with purified water, so as to obtain a product of interest, 4-methoxybenzoic acid 2-acetyl-4-bromophenyl ester (compound 13). Yield: 3.15 g (yield constant: 96.5%) 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.5 Hz, 1H), 8.06 (d, J=7.2 Hz, 1H), 8.86 (s, 1H), 10.13 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11](OC)=[O:12])[O:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[CH2:11][OH:12])[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCCCC12OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCCCC12OCCO2
Reaction time: 5 h

Procedure:
To a solution of methyl 1,4-dioxaspiro[4.5]decane-6-carboxylate (3.87 g, 19.3 mmol) in THF (40 mL) and cooled to 0°C. LiAlH4 was added dropwise and stirred for 5 hours. The reaction was quenched by subsequent dropwise addition of water (1.3 mL) 15% NaOH (1.3 mL) and water (2.6 mL) and filtered thru a CELITE® pad. Concentration of the filtrate afforded the title compound as clear oil that was carried to the next step without further purification. MS m/z 173.1 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:6][C:7]([N:9]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]1[C:15](OC)=[O:16])=[O:8])[CH:4]=[CH2:5].CC(C)=O>C(O)C>[CH2:3]([O:6][C:7]([N:9]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]1[CH2:15][OH:16])=[O:8])[CH:4]=[CH2:5]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO
Temperature: 40 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
To a suspension of sodium borohydride (5 g) in ethanol (50 ml) was added (2S,4R)-1-allyloxycarbonyl-2-methoxycarbonyl-4-hydroxypyrrolidine (10 g) in ethanol (10 ml) at 5° C. and the resulting mixture was stirred at 40° C. for 4 hours. After cooling to 0° C., the reaction mixture was added dropwise to cooled acetone (20 ml) at 10° C. The mixture was evaporated in vacuo and the residue was extracted with ethyl acetate (200 ml×2). The organic layer was washed with brine, dried over magnesium sulfate, evaporated and chromatographed on silica gel (120 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1 V/V) to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-hydroxymethylpyrrolidine (4.45 g).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([O:13]CC)=[O:12])[N:9]=1)[C:2]([NH2:4])=[O:3].[OH-].[K+]>CO.O>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([OH:13])=[O:12])[N:9]=1)[C:2]([NH2:4])=[O:3]
Reactant: CCOC(=O)Cc1csc(NC(N)=O)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)Nc1nc(CC(=O)O)cs1
Yield: 89.7 %

Procedure:
To a solution of ethyl 2-ureidothiazol-4-ylacetate (3.1 g.) in a mixture of methanol (62 ml.) and water (41 ml.) was dropwise added 1 N potassium hydroxide aqueous solution (13.6 ml) with stirring under ice-cooling, and the solution was stirred for overnight at room temperature, and then the solvent was distilled off therefrom. The residue was dissolved in water (150 ml.), washed with ethyl acetate and then adjusted to pH 3.5 with 10% hydrochloric acid. Thus obtained aqueous layer was cooled with ice, and the precipitates were collected by filtration, washed with cold water (10 ml.) and then dried to give colorless crystals of 2-ureidothiazol-4-ylacetic acid (2.44 g.), mp 189° C. (dec.).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][S:20][C:21](SC)=[CH:22][N+:23]([O-:25])=[O:24].[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30]>O1CCCC1>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[N+:23]([CH2:22][CH:21]([S:20][CH3:19])[NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)([O-:25])=[O:24]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: CSC(C[N+](=O)[O-])NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
A mixture of 3-[3-[(1-piperidinyl)methyl]phenoxy]propaneamine (4.97 g.) and 1,1-bis-(methylthio)-2-nitroethene (6.61 g.) in tetrahydrofuran (100 ml.) was heated under reflux for 19 hours. A solution of oxalic acid (6.25%) in tetrahydrofuran (4 ml.) was added, the suspension filtered and to the filtrate was added a solution of oxalic acid (6.25%) in tetrahydrofuran (36 ml.). The solid which separated on trituration was filtered, washed with tetrahydrofuran and dried to give the title compound (7.36 g.), m.p. 71°-75°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20](C3SC=CN=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Brc1cccnc1
Product: CCO[C@H]1CN(c2cccnc2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting 3-bromo pyridine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ) 7.97, 7.51, 7.46, 7.33–7.28, 7.11, 5.31, 4.92, 4.31, 3.92, 3.85, 3.78–3.33, 2.73, 2.49, 1.35–1.29, 1.16; HRMS (ESI) calcd for C25H29N5OCl2+H1 486.1827. found 486.1834.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]([CH2:9][CH2:10][C@@H:11]([OH:19])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15](O)=[O:16])[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:5]=1[C:33]([NH:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:34])[CH3:3].[NH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:66])[CH2:47][CH2:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52]/[CH:53]=[CH:54]\[CH2:55]/[CH:56]=[CH:57]\[CH2:58]/[CH:59]=[CH:60]\[CH2:61]/[CH:62]=[CH:63]\[CH2:64][CH3:65].C(O)(=O)CCC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CC>>[OH:19][C@@H:11]([CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([NH:42][CH2:43][CH2:44][NH:45][C:46](=[O:66])[CH2:47][CH2:48][CH2:49]/[CH:50]=[CH:51]\[CH2:52]/[CH:53]=[CH:54]\[CH2:55]/[CH:56]=[CH:57]\[CH2:58]/[CH:59]=[CH:60]\[CH2:61]/[CH:62]=[CH:63]\[CH2:64][CH3:65])=[O:16])[CH2:10][CH2:9][N:8]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:5]([C:33]([NH:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:34])=[C:4]1[CH:2]([CH3:3])[CH3:1]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCN
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Agent: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCNC(=O)C[C@H](O)C[C@H](O)CCn1c(-c2ccc(F)cc2)c(-c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C

Procedure:
The same procedures outlined in example 6 were employed, substituting (5Z,8Z,11Z,14Z,17Z)—N-(2-aminoethyl)icosa-5,8,11,14,17-pentaenamide as the appropriate amine component during the amide coupling with atorvastatin. (5Z,8Z,11Z,14Z,17Z)—N-(2-aminoethyl)icosa-5,8,11,14,17-pentaenamide, in turn, was prepared according to the procedures outlined in WO 2012115695 using (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid as the starting material. MS calculated for C55H69FN4O5: 884.53. found: [M+H]+ 885.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:23][C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=[O:22])[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:24][CH3:25].[BH4-].[Na+]>CO.ClCCl.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:23][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][OH:22])=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:24][CH3:25]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3[nH]1)cn2C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(nc1OC)c(-c1cc3c(CO)ccnc3[nH]1)cn2C
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.9 %

Procedure:
To a solution of 0.07 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde in 7 cm3 of methanol and 20 cm3 of dichloromethane, at a temperature in the region of 20° C., is added 0.012 g of sodium borohydride. The reaction medium is stirred at room temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 10 cm3 of water and 20 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. 0.045 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]methanol is obtained with the following characteristics:
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[CH:28]([NH2:30])[CH3:29])[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[CH:28]([NH:30][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:29])[CH:15]=[CH:16][CH:17]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1ccc2ccccc2c1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1ccc2ccccc2c1-c1cccc(F)c1

Procedure:
A mixture of 6-bromo-9H-purine (0.02696 g, 0.1355 mmol), 1-[1-(3-fluorophenyl)-2-naphthyl]ethanamine (0.030 g, 0.11 mmol), and N,N-diisopropylethylamine (0.024 mL, 0.14 mmol) in ethanol (0.9 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the product as a TFA salt. LCMS calculated for C23H19FN5(M+H)+: m/z=384.2; found: 384.3. 1H NMR (DMSO-d6, 400 MHz) δ 8.92 (1H, br s), 8.30 (2H, m), 7.97 (1H, d, J=9.2 Hz), 7.90 (1H, d, J=7.6 Hz), 7.79 (1H, m), 7.57 (1H, m), 7.47 (1H, m), 7.40 (2H, m), 7.31 (1H, m), 7.19 (2H, m), 5.23 (1H, m), 1.49 (3H, m) ppm. 19F NMR (DMSO-d6, 376.28 MHz) δ −74.6 ppm.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3([C:15]([O:17]CC)=[O:16])[CH2:11][CH:12]=[CH:13][CH2:14][CH:8]3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O-].[K+]>O1CCCC1.CCCCCCC>[CH:1]1[C:10]2[C:9]3([C:15]([OH:17])=[O:16])[CH2:11][CH:12]=[CH:13][CH2:14][CH:8]3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C12CC=CCC1CSc1ccccc12
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C(O)C12CC=CCC1CSc1ccccc12
Yield: 68.1 %

Procedure:
To a solution of the product from Example 18 (7.36 g) in tetrahydrofuran (200 ml) was added potassium trimethylsilanolate (5.30 g). The solution was refluxed for 7 hours then diluted with heptane and filtered. The precipitated solid was dissolved in water/ethyl acetate and acidified with dilute hydrochloric acid. The organic phase was washed with water then extracted with dilute sodium hydroxide (x2). The aqueous layer was washed with ethyl acetate then layered with fresh ethyl acetate and acidified. The solution was washed with water and dried (Na2SO4) and evaporated to a oil which was triturated with ethyl acetate/heptane to give the title compound as a cream colored solid (4.5 g), mp 152°-155° C. and a darker colored second crop (1.7 g) combined yield 94%.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([NH2:49])([CH3:48])[CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)CCC>[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([NH:49][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)([CH3:48])[CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC1(N)CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Yield: 42.8 %

Procedure:
To a solution of 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (580 mg, 1.7 mmol) in n-butanol (20 mL) were added diisopropylethylamine (DIPEA) (1.4 mL, 8.4 mmol) and 3-Amino-3-methyl-piperidine-1-carboxylic acid benzyl ester (420 mg, 1.7 mmol). The mixture was heated to reflux overnight, and LCMS showed 1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine consumed. The reaction mixture was purified by column chromatography (eluting with 30˜35% ethyl acetate in hexane) to give 400 mg (43%) of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-3-methyl-piperidine-1-carboxylic acid benzyl ester. LCMS (Method J, ESI): RT=1.32 min, m+H=549.8; 1H NMR (400 MHz, CDCl3) δ: 9.60 (s, 1H), 9.10 (s, 1H), 8.20 (m, 2H), 7.70-7.50 (m, 4H), 7.40-7.30 (m, 5H), 5.34 (m, 2H), 3.90-3.80 (m, 1H), 2.30-2.20 (m, 1H), 1.90-1.50 (m, 9H).