Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:16]3[C:17]([O:25][CH3:26])=[N:18][C:19]([NH:22][CH2:23][CH3:24])=[N:20][CH:21]=3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:23]([NH:22][C:19]1[N:18]=[C:17]([O:25][CH3:26])[C:16]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:30]=[N:29][C:28]([CH3:27])=[CH:33][CH:32]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)=[CH:21][N:20]=1)[CH3:24]
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(OC)n1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-c4ccc(C)nc4)c3)c(C)n2)c(OC)n1
Temperature: 90 °C
Yield: 61.8 %

Procedure:
A solution of Example C1 (0.15 g, 0.4 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.57 mmol) in dioxane (4 mL) was sparged with Ar, treated with a solution of K2CO3 (0.11 g, 0.8 mmol) in water (1 mL) and heated at 90° C. for 2 h. The mixture was cooled to RT, diluted with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to afford N-ethyl-4-methoxy-5-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine as an orange foam (0.106 g, 61%). 1H NMR (400 MHz, DMSO-d6): δ 9.11 (d, J=2.4 Hz, 1H), 8.74 (s, 1H), 8.54 (d, J=5.7 Hz, 1H), 8.29 (dd, J=8.1, 2.4 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.02 (d, J=1.9 Hz, 1H), 6.79 (dd, J=5.7, 2.4 Hz, 1H), 3.96 (s, 3H), 3.36-3.34 (m, 2H), 2.51 (s, 3H), 2.38 (s, 3H), 1.15 (s, 3H); MS (ESI) m/z: 429.2 (M+H+).
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]([NH:29][CH2:30][CH2:31][O:32][CH2:33][C:34]#[CH:35])=[O:28]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(O)(=O)C>[F:25][C:26]([F:36])([F:37])[C:27]([NH:29][CH2:30][CH2:31][O:32][CH2:33][C:34]#[C:35][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1)=[O:28]
Reactant: C#CCOCCNC(=O)C(F)(F)F
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=C(NCCOCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 5-iodo-2'-deoxyuridine (3.54 g, 10 mmol), copper(1) iodide (0.19 g, 1 mmol) and tetrakis(triphenylphosphine)palladium(O) (0.58 g, 0.5 mmol) is dried in vacuo at 60° for 3 hours and placed under argon. A suspension of the mixture in dry DMF (20 ml) is stirred under argon and treated with dry triethylamine (1.7 ml, 12 mmol) followed by 3-(2-Trifluoroacetamidoethoxy)propyne (3.17 g, 16 mmol). The mixture is cooled at room temperature in a water bath and stirred for 17 hours. The mixture is treated with 2% acetic acid (100 ml), the catalyst is removed by filtration and washed with 50% methanol. The filtrates are combined and passed onto a LiChroprep RP-18 column (5×25 cm), the column is washed, then eluted with 1% acetic acid in 50% (v/v) methanol. The fractions with the main product are combined, evaporated, and dried in vacuo. The resultant foam is stirred with 150 ml of ether to give crystalline product; yield 3.6 g (85%); m.p. 145°-152°.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:7]2[CH:12]=[N:11][C:10]([Cl:13])=[CH:9][N:8]=2)[N:6]=1.[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH3:26])[NH:22][C:21]=1[C:27]([NH:29][C@@H:30]1[CH2:35][CH2:34][NH:33][CH2:32][C@@H:31]1[CH3:36])=[O:28].C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:33]3[CH2:34][CH2:35][C@@H:30]([NH:29][C:27]([C:21]4[NH:22][C:23]([CH3:26])=[C:24]([Cl:25])[C:20]=4[Cl:19])=[O:28])[C@@H:31]([CH3:36])[CH2:32]3)[S:3][C:4]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][CH:9]=1
Reactant: Cc1[nH]c(C(=O)N[C@@H]2CCNC[C@@H]2C)c(Cl)c1Cl
Reactant: CCOC(=O)c1sc(Br)nc1-c1cnc(Cl)cn1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](C)C2)nc1-c1cnc(Cl)cn1
Temperature: 50 °C
Yield: 76.7 %

Procedure:
To a stirred solution of ethyl 2-bromo-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate (Intermediate 47, 1.8 g, 5.142 mmol), and 3,4-dichloro-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide (Intermediate 39, 1.47 g, 5.142 mmol) in N-methyl 2-pyrrolidinone (1 mL) was added N,N-Diisopropylethylamine (1.7 mL, 10.284 mmol) at room temperature. The reaction mixture was heated to 50° C. for 5 h. The reaction mixture was cooled to room temperature, water (60 mL) was added, the precipitated product was collected by filtration, washed with water and dried to afford 2.2 g (78%) of ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-1,3-thiazole-5-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(O)C>[NH2:1][C:2]1[N+:7]([O-:19])=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: CNc1cc(Cl)nc(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: CNc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 10 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
4 g of 2-amino-4-methylamino-6-chloropyrimidine are suspended in 50 ml of ethanol. After having cooled to 10° C., 11.9 g of meta-chloroperbenzoic acid are added dropwise as a solution in 100 ml of ethanol. At the end of addition, room temperature is regained and stirring is continued for 3 hours. The reaction mixture is cooled to 5° C. and then filtered on sintered glass. The precipitate obtained is recrystallized from 160 ml of a 2/3-1/3 ethanol-water mixture. 1.60 g of 2-amino-4-methylamino-6-chloropyrimidine 3-oxide are obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f45) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].[K+].C1(C)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:18]1([C:2]2[CH:15]=[CH:14][C:13]3[C:12](=[O:16])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5](=[O:17])[C:4]=3[CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)c2cc(-c3ccccc3)ccc21
Yield: 87.1 %

Procedure:
Under an atmosphere of argon, 2-chloroanthraquinone (5.0 g, 21 mmole), phenylboronic acid (2.8 g, 23 mmole, 1.1 eq), tris(dibenzylideneacetone)dipalladium(0) (0.2 g, 0.22 mmole, 2% Pd) and potassium fluoride (4.4 g, 76 mmole, 3.3 eq) were suspended in anhydrous dioxane (30 ml). To the obtained suspension, a toluene solution of tri-t-butylphosphine (66%, 0.13 ml, 0.42 mmole, 1 eq) was added and the resultant mixture was stirred at 80° C. for 3 hours. The reaction mixture was filtered and washed with toluene (100 ml). The filtrate was washed with a saturated aqueous solution of sodium chloride (30 ml) and dried with magnesium sulfate. Then, the solvent was removed by distillation and a yellow solid was obtained. The obtained solid was washed with boiling ethanol (50 ml) and a yellow solid (5.2 g, 87%) was obtained. 1H-NMR (CDCl3, TMS) δ: 7.4 to 7.6 (3H, m), 7.6 to 7.9 (4H, m), 7.98 (1H, dd, J=8 Hz, 2 Hz), 8.2 to 8.4 (3H, m), 8.50 (1H, d, J=2 Hz)
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=1)[CH3:2].[Sn](Cl)Cl>C(OCC)(=O)C.CO>[CH2:1]([NH:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCNC(=O)c1ccc(N)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 87.8 %

Procedure:
N-Ethyl-3-benzyloxy-4-nitrobenzamide (5.40 g, 18.0 mmol) obtained in Example 312b) was dissolved in ethyl acetate (60 ml) and methanol (40 ml), anhydrous tin(II) chloride (17.6 g, 89.9 mmol, 5.0 eq.) was added, and the mixture was stirred at room temperature for 21 hr. The reaction mixture was concentrated, and methanol was evaporated. The residue was diluted with ethyl acetate (200 ml) and mixed with 1.44N sodium hydroxide (150 ml). The obtained suspension was filtered through celite (diameter 60 mm) and washed with ethyl acetate (100 ml). The filtrate and washing were combined, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography (elution solvent, ethyl acetate-hexane=1:1-2:1) on silica gel (manufactured by E. Merck, Art.7734, 50 g). The fraction obtained by elution with ethyl acetate-hexane (3:2) was concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (4.27 g, 15.8 mmol, 87.8%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH:9]([CH:12]=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[C:9](=[CH:12][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(s1)C(=O)C(C=O)CC2
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Yield: 89 %

Procedure:
To a solution of 2-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazole-6-carbaldehyde (2.0 g, 10.2 mmol) in dry toluene (8.1 mL), morpholine (1.0 mL, 1.0 g, 11.3 mmol) was added. The reaction mixture was heated under reflux for 2 h. On cooling a brown precipitate formed. The solvent was removed under vacuum and the brown solid residue was fractionated by flash column chromatography (20% EtOAc:hexane) to leave a yellow solid that was purified further by crystallisation from EtOH to afford the pure title product as yellow crystals (2.4 g, 87%): mp 186-187° C. Anal. RP-HPLC: tR 12.7 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 7.50 (s, 1H, CH), 3.80 (t, 4H, J 4.6), 3.55 (t, 4H, J 4.6), 3.00 (m, 4H, CH2—CH2), 2.80 (s, 3H, CH3). 13C-NMR (CDCl3): δ 182.0, 171.6, 162.3, 147.9, 133.2, 103.3, 67.0, 51.4, 26.7, 24.9, 20.2. MS (ESI+): m/z 287.05 (M+Na)+, 265.07 (M+H)+. Anal. (C13H16N2O2S)C, H, N.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:13]=[CH:12][C:11]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:39])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:30])[CH:23]=2)=[CH:6][CH:5]=1>O1CCCC1.CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:12][C:11]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:39])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:30])[CH:23]=2)=[CH:40][CH:41]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCc2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCc2ccc(F)cc2)c1
Yield: 64 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 10 eq) of sodium hydroxide and methyl 3-[2-(4-fluorobenzyloxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 310 mg of 3-[2-(4-fluorobenzyloxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=79° C.). Yield=64% over the two steps.
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:4]2=[C:3]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:2]=1>C(O)C.O1CCCC1.[C].[Pd]>[N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:4]2=[C:3]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:2]=1
Reactant: CCOC(=O)C=Cc1cnn2c1NCCC2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1cnn2c1NCCC2
Yield: 110.1 %

Procedure:
A solution of ethyl 3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)acrylate (45 g) in a mixture of ethanol (800 ml) and tetrahydrofuran (400 ml) was treated with 10% palladium carbon (2.2 g) under a hydrogen atmosphere at room temperature for 22 hours. After the catalyst was filtered off, the filtrate was concentrated in vacuo to give ethyl 3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)propionate (50 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][OH:14])[N:6]=[CH:5]2.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CN=C1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:6]=[CH:5]2
Reactant: OCCCn1ncc2cc(Br)ccc21
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCCn1ncc2cc(Br)ccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
Crude 3-(5-Bromoindazol-1-yl)-propan-1-ol (2s) (2.1 mmol) and imidzaole (0.22 g, 3.2 mmol) were dissolved in 10 mL CH2Cl2. tert-Butyldiphenylsilyl chloride (0.58 g, 2.1 mmol) was added to the solution and the reaction was stirred at room temperature for 4 hours. Additional amounts of imidazole (0.07 g, 1.0 mmol) and tert-butyldiphenylsilyl chloride (0.16 g, 0.63 mmol) were added and the reaction was stirred at room temperature overnight. The mixture was diluted with Et2O and washed sequentially with an aqueous 3% HCl solution and brine. The aqueous phases were extracted once with Et2O. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified on silica gel with 1:6 Et2O/hexane to afford (3s) (1.0 g, 96% over two steps) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.86 (s, 1H), 7.61 (d, J=7.8 Hz, 4H), 7.44-7.42 (m, 3H), 7.36-7.33 (m, 5H), 4.53 (t, J=10.2 Hz, 2H), 3.63 (t, J=9.0 Hz, 2H), 2.16-10 (m, 2H), 1.08 (s, 9H); HPLC (5 to 95%) 4.72 min.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[NH:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41]>>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[N:11]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: COC(=O)CCBr
Reactant: O=C1N(c2cc(Cl)nc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCNN12
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN1CCCC2(Cc3ccc(Br)cc3)C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)N12

Procedure:
The compound from Example 100 (80 mg) was dissolved in methyl 3-bromopropanoate (0.5 mL) and DIEA (0.089 mL) and heated at 73° C. for 3 days. The reaction mixture was concentrated and purified by chromatography (silica gel; EtOAc/hexanes; chromatotron) to give the titled compound (38 mg). MS (m/z) 557 (MH+); mp. 157° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[S:3])[NH2:2].[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O.C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)(Cl)Cl>[Cl:17][CH2:18][C:19]1[N:2]=[C:1]([N:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)[S:3][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
A solution of tert-butyl 4-thiocarbamoylpiperazine-1-carboxylate (650 mg, 2.65 mmol) and 1,3-dichloroacetone (672 mg, 5.3 mmol) in 1,2-dichloroethane was treated with sodium bicarbonate (22 mg, 2.65 mmol). The reaction mixture was stirred at 70° C. for 18 hours and then diluted with chloroform. The dilution was washed with water and brine, dried over sodium sulfate and concentrated. Product was purified from the residue on a silica gel column, using ethyl acetate/hexanes (3/7) as eluent, to provide tert-butyl 4-(4-chloromethylthiazol-2-yl)piperazine-1-carboxylate (830 mg, 100% yield). HNMR (dmso-d6): 6.92 (1H, s), 4.57 (2H, s), 3.40 (8H, m), 1.42 (9H, s).
Reaction SMILES: C([O:8][C:9](=[O:33])[CH2:10][N:11]1[C:16](=[O:17])[C:15]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]([CH3:30])[CH3:29])[CH:22]=2)=[N:14][C:13](Cl)=[C:12]1[CH3:32])C1C=CC=CC=1.N1C2C(=CC(CN)=CC=2)C=C1.C1C=CC2N(O)N=NC=2C=1.Cl.CN1CCOCC1>CO.O.[OH-].[OH-].[Pd+2].CN(C=O)C>[CH3:29][N:28]([CH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][CH2:19][NH:18][C:15]1[C:16](=[O:17])[N:11]([CH2:10][C:9]([OH:33])=[O:8])[C:12]([CH3:32])=[CH:13][N:14]=1)[CH3:30]
Reactant: Cc1c(Cl)nc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: NCc1ccc2[nH]ccc2c1
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cnc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 10 %

Procedure:
Benzyl-2-[3-chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 20) (137 mg, 0.29 mmol) was dissolved in methanol:water (10:2, 20 ml), treated with Pearlman's catalyst (10 mg) and stirred under a hydrogen atmosphere (60 psi, room temperature, 2.5 hr). The catalyst was removed by filtration, followed by evaporation of the solvent and azeotroping with CH2Cl2 to yield a crude yellow solid. To the crude mixture, 1H-indol-5-ylmethylamine (preparation 8) (43 mg, 0.29 mmol), HOBT (46 mg, 0.34 mmol), WSCDI.HCl (74 mg, 0.39 mmol), N-methylmorpholine (0.061 ml, 0.55 mmol) and DMF (5 ml) were stirred at room temperature for 18 hr. The resultant mixture was evaporated to dryness and azeotroped with CH2Cl2. Water (2 ml) was added followed by aq Na2CO3 (a few drops) and the residue treated with ethyl acetate and methanol. The organic layer was separated, dried over MgSO4. Filtration away from the drying agent followed by evaporation of the solvent gave the crude product which was purified by chromatography (SiO2, gradient elution with 100% CH2Cl2; 95:5 CH2Cl2:MeOH; 95:5:0.5 CH2Cl2:MeOH:NH3) to give the desired product (10 mg, 7%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([CH2:11][CH:12]2[O:16]C(=O)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([CH2:11][CH:12]2[OH:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC1CC2CC1CN(Cc1ccccc1)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC1CC2CC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of acetic acid 3-benzyl-3-aza-bicyclo[3.2.1]oct-6-yl ester (8 mmol) in methanol (50 mL) and water (20 mL) was added potassium hydroxide (32 mmol). Reaction was stirred 18 h at room temperature. The methanol was removed in vacuo and product was extracted with aqueous dichloromethane (4×50 mL). The organic extracts were dried over MgSO4, filtered and stripped to provide a quantitative yield of an oil. APCl MS m/z 218.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:38][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:40][CH:41]1[CH2:43][CH2:42]1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[CH:41]1([CH2:40][O:21][C:18]2[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][N:9]3[C:10](=[O:11])[C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[S:38][C:6]=4[N:7]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:26][CH:25]=4)[C:8]3=[O:22])=[CH:20][CH:19]=2)[CH2:43][CH2:42]1
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(O)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OCC4CC4)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 60 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
To a mixture of 4′-{[6-ethyl-3-[2-(4-hydroxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile, (bromomethyl)cyclopropane (0.42 mL) and N,N-dimethylformamide (7 mL) was added cesium carbonate (0.94 g), and the mixture was stirred at 60° C. for 12 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.61 g, 73%).