Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:21](OCC)(=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[OH:27][C:21]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(O)Cc2cccnc2N1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
To a stirred solution of 2-tert-butoxycarbonylamino-3-methylpyridine (1.0 g, 4.8 mmol) in THF (10 mL) at −10° C. under Ar was added dropwise a solution of n-butyllithium (1.6 M, 6.0 mL, 9.6 mmol). The mixture was stirred for 30 min then added dropwise via cannula to a stirred solution of diethyl oxalate (2.1 g, 14.4 mmol) in THF (10 mL) at 0° C. under Ar. The mixture was stirred for 1 h and partitioned between water (50 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were washed (water, brine), dried (sodium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:1)] to give the product as a clear oil (0.61 g, 47%). IR νmax (film)/cm−1 3475, 2982, 2935, 2237, 1740, 1695, 1606, 1592, 1433, 1371, 1310, 1248, 1209, 1188, 1159, 1099, 1065, 1023, 912, 855, 785, 770, 732 and 645; NMR δH (400 MHz, CDCl3) 1.27 (3H, t, J 7Hz), 1.53 (9H, s), 3.18 (1H, d, J 17 Hz), 3.40 (1H, d, J 17 Hz), 4.27 (2H, q, J 7 Hz), 6.90 (1H, dd, J, 2.5,5 Hz), 7.43 (1H, d, J 7 Hz), 8.26 (1H, d, J 3.5 Hz).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][S:9]/[C:8]/2=[N:13]\[CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.CC(=O)OCC>[O:27]1[C:19]2[CH:18]=[CH:17][C:22](/[CH:23]=[C:10]3/[C:11](=[O:12])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)/[C:8](=[N:13]/[CH:14]([CH3:16])[CH3:15])/[S:9]/3)=[CH:21][C:20]=2[O:25][CH2:26]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)/N=C1\SCC(=O)N1c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)/N=C1\S/C(=C\c2ccc3c(c2)OCO3)C(=O)N1c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-phenyl-2-[(Z)-isopropylimino]-thiazolidin-4-one (150 mg, 0.64 mmol), piperonal (192 mg, 1.28 mmol) and sodium acetate (105 mg, 1.28 mmol) in acetic acid (3 mL) is stirred at 110° C. for 4 h. The dark yellow to brown solution is cooled to rt, diluted with EA (75 mL), washed with sat. aq. NaHCO3, followed by water, and evaporated. The crude product is purified by crystallisation from a small amount of methanol (approx. 5 mL) to give 5-benzo[1,3]dioxol-5-ylmeth-(Z)-ylidene-2-[(Z)-isopropylimino]-3-phenyl-thiazolidin-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]2=[O:18])([O-])=O.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 3 h

Procedure:
100 parts by weight of 5-nitrotetrahydroanthraquinone is added to and suspended in 1500 parts by weight of ethanol, to which is added 38.5 parts by weight of a 40 wt% sodium hydroxide aqueous solution, followed by agitation at about 75°C for 3 hours. Then, the resultant solution is cooled down to about 10°C, followed by filtration, washing with water and dripping. The resulting wet cake is then introduced into 1500 parts by weight of water for suspension, into which is dropped 990 parts by weight of a 16 wt% sodium sulfide aqueous solution at 95°C over a period of about 30 min with agitation, followed by further agitation at 95°C for 1 hour. The resultant solution is subjected to filtration followed by cooling to crystalize 1-aminoanthraquinone, then the 1-aminoanthraquinone is separated by filtration, washed with water and dried at 85°-95°C. The purity of 1-aminoanthraquinone thus obtained is determined by a KBr method using an infrared absorption spectrum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CN(C=O)C.[CH3:32][C:33]([CH3:37])([CH3:36])[C:34]#[CH:35].C(OCC)(=O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:32][C:33]([CH3:37])([CH3:36])[C:34]#[C:35][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:26]=[N:25][CH:24]=[N:23][CH:22]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 90 °C

Procedure:
Combined (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (120 mg, 0.293 mmol), tetrakis(triphenylphosphine)palladium (33.8 mg, 0.029 mmol), copper(i) iodide (11.14 mg, 0.059 mmol) and DMF (1950 μL, 0.293 mmol). Added 3,3-dimethylbut-1-yne (96 mg, 1.170 mmol) and DIPA (2085 μL, 14.63 mmol), flushed with argon, sealed and heated at 90° C. overnight. The reaction was diluted with water (25 mL) and poured into a separatory funnel containing ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in DCM with 0.1% ammonium hydroxide) to provide (S)-3-(3,3-dimethylbut-1-ynyl)-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a tan solid. Found MS: MH+=412.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:24][C:11]3=[N:12][C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:14]([C:16](C)=[CH2:17])[CH:15]=[C:10]3[C:9]=2[C:25]([NH:27][CH3:28])=[O:26])=[CH:4][CH:3]=1.C([B-](F)(F)F)=C.[K+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:24][C:11]3=[N:12][C:13]([NH:19][S:20]([CH3:23])(=[O:21])=[O:22])=[C:14]([CH:16]=[CH2:17])[CH:15]=[C:10]3[C:9]=2[C:25]([NH:27][CH3:28])=[O:26])=[CH:4][CH:3]=1
Reactant: C=C(C)c1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1NS(C)(=O)=O
Agent: C=C[B-](F)(F)F
Agent: [K+]
Product: C=Cc1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1NS(C)(=O)=O

Procedure:
2-(4-Fluorophenyl)-N-methyl-6-(methylsulfonamido)-5-vinylfuro[2,3-b]pyridine-3-carboxamide is prepared by analogy to 2-(4-Fluorophenyl)-N-methyl-6-(methylsulfonamido)-5-(prop-1-en-2-yl)furo[2,3-b]pyridine-3-carboxamide, step A of Example 33. Potassium vinyltrifluoroborate may be used as the coupling partner.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]1[C:14]([O:21][CH3:22])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN(C=O)C>[CH:16]([C:15]1[C:14]([O:21][CH3:22])=[C:13]([CH:20]=[CH:19][CH:18]=1)[O:12][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[O:17]
Reactant: COc1ccc(C#N)c(F)c1
Reactant: COc1c(O)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c(Oc2cccc(C=O)c2OC)c1
Yield: 74.5 %

Procedure:
2-Fluoro-4-methoxy-benzonitrile (0.28 g, 1.8 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.28 g, 1.8 mmol) and cesium carbonate (0.90 g, 2.4 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 40 h. The reaction mixture was cooled, poured into 1N sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (4×), water (4×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-formyl-2-methoxy-phenoxy)4-methoxy-benzonitrile (0.38 g, 73%) as a tan oil.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.I[C:32]1[CH:36]=[C:35]([CH3:37])[N:34]([CH3:38])[N:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>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.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[CH:36]=[C:35]([CH3:37])[N:34]([CH3:38])[N:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1cc(I)nn1C
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3c(c2)ncn3C2CC2)nn1C
Temperature: 100 °C
Yield: 62.5 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (120 mg, 0.292 mmol), 3-iodo-1,5-dimethyl-1H-pyrazole (129.6 mg, 0.584 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.96 mL, 0.96 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (33.7 mg, 0.029 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give off-white solids, 69.2 mg (yield 62.5%). 1H NMR (300 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.59 (broad s, 1H), 7.49 (d, J=1.1 Hz, 1H), 7.23 (d, J=1.2 Hz, 1H), 6.50 (s, 1H), 4.75 (p, J=6.0 Hz, 1H), 3.75 (s, 3H), 3.72-3.63 (m, 1H), 3.44-3.35 (m, 1H), 3.26-3.15 (m, 1H), 2.91-2.71 (m, 1H), 2.41-2.20 (m, 2H), 2.28 (s, 3H), 1.31 (d, J=6.0 Hz, 3H), 1.13-1.05 (m, 2H), 1.05-0.95 (m, 1H) ppm; MS (ESI+) m/z 381.01 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:16]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ncc(Cl)cn1
Yield: 48.6 %

Procedure:
(S)-2-Aminomethyl pyrrolidine-1-carboxylic acid tert-butyl ester (3.38 g), 2,5-dichloropyrimidine (2.50 g), potassium carbonate (4.67 g) and diisopropylethylamine (8.79 ml) were heated in xylene (60 ml) at 100° C. for 3.75 h. The cooled reaction mixture was filtered and the filtrate evaporated to a gum which was chromatographed on silica gel, eluting with ethyl acetate-pentane fractions, to afford the title compound as a pale yellow solid (2.55 g). Mass Spectrum (API+): Found 213 (MH+−tBoc). C14H2135ClN4O2 requires 312.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N:16][CH:17]([NH2:21])[C:18]([NH2:20])=[O:19])=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:28][CH2:29][C:30](Cl)=[O:31]>C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N:16][CH:17]([NH:21][C:30](=[O:31])[CH2:29][Cl:28])[C:18]([NH2:20])=[O:19])=[O:8]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)C(N)N=Nc1ccccc1C(=O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: NC(=O)C(N=Nc1ccccc1C(=O)c1ccccn1)NC(=O)CCl
Reaction time: 0.75 h

Procedure:
To a solution of 0.85 g. of [2-(2-pyridinecarbonyl)-phenyl]azo-aminoacetamide in 30 ml. of anhydrous benzene are added 0.42 g. of potassium carbonate and 1.0 ml. of chloroacetyl chloride. The mixture is refluxed with stirring for 45 minutes, and then cooled. The precipitated crystals are collected by filtration, and partitioned between saturated aqueous sodium hydrogen carbonate solution and chloroform. The chloroform layer is separated, washed with water, dried over sodium sulfate, and then the solvent is removed by distillation to give [2-(2-pyridinecarbonyl)phenyl]azo-(2-chloroacetamido)acetamide as crystals. Recrystallization from ethanol gives yellow needles, melting at 204° to 205° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([O:30]C)=[O:29])[CH2:27][CH2:26]1)=[O:24].O.O.[OH-].[Li+:35]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([O-:30])=[O:29])[CH2:27][CH2:26]1)=[O:24].[Li+:35]
Reactant: COC(=O)C1(C(=O)Nc2cc(F)c(Oc3ccnc(-c4cnn(C)c4)c3)cc2F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)C4(C(=O)[O-])CC4)cc3F)ccn2)cn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89.8 %

Procedure:
To a suspension of methyl 1-((2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylate (5.8 g, 13.54 mmol) in THF (100 mL) were added water (50.0 mL) and lithium hydroxide monohydrate (2.84 g, 67.7 mmol). The reaction mixture was stirred at RT for 40 minutes. The layers were separated and the organic phase washed with brine (50 mL), dried (MgSO4) and concentrated to dryness to afford lithium 1-((2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylate (5.11 g, 86% yield) as an off-white foam. MS (ESI): m/z 415.1 [M+1]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:25])C(=O)C1>C(#N)C>[Br:25][C:10]1[N:9]2[CH:13]=[C:14]([CH2:16][OH:17])[N:15]=[C:8]2[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[N:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cn2ccnc(N3CCOCC3)c2n1
Solvent: CC#N
Product: OCc1cn2c(Br)cnc(N3CCOCC3)c2n1
Temperature: -20 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a solution of compound 1d (2.40 g, 10.3 mmol) in ACN (200 mL) was added NBS (2.40 g, 13.5 mmol) in portions at −20° C. The resulting solution was stirred at −20° C. for 2 h, and was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:1 v/v) to obtain compound 1e as a yellow solid (1.48 g, 41% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C11H13BrN4O2: 313.0 (M+H). Found 313.2.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Reactant: Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
To the mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.7 g, 2.364 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-methylbenzene (0.525 g, 2.84 mmol) and potassium carbonate (0.980 g, 7.09 mmol). The resulting reaction mixture was stirred at 90° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜70% EtOAc in Hexane) to give the product as oil (0.686 g, 73%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.31 (s, 3H) 2.57 (s, 3H) 3.01-3.18 (m, 4H) 3.75-3.92 (m, 4H) 5.24 (s, 2H) 6.64 (d, J=2.02 Hz, 1H) 6.75-6.89 (m, 2H) 7.03-7.17 (m, 2H) 7.18-7.26 (m, 1H); MS (ES+) m/e 400.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC1N(C)C=CN=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:15]([CH3:16])[CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Agent: Cn1ccnc1Br
Product: Cc1ccc(-c2nccn2C)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 2-bromo-1-methyl-1H-imidazole. ESI-MS (m/z): 217 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([CH2:18][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Cl:1])=[O:20])[CH3:23]
Reactant: CCOC(=O)CCl
Reactant: Clc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cn1c(Cl)nc2ccccc21

Procedure:
2-Chlorobenzimidazole was treated with potassium carbonate and ethyl chloroacetate to yield 1-(ethoxycarbonylmethyl)-2-chlorobenzimidazole. This compound (1 eq.) was combined with L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester (1.1 eq., prepared as described in Method L) and 2 drops of acetonitrile in a sealed tube and the reaction was heated for two days at 120° C. and the resultant mixture purified by column chromatography (1:3 ethyl acetate/hexanes) to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.O.CCOC(C)=O.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>[CH3:11][C@H:10]1[C:3]2[C:2]([C:16]3[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH2:8][CH2:9]1
Reactant: OB(O)c1ccc(O)cc1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CCc2ncnc(-c3ccc(O)cc3)c21
Temperature: 100 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (137 mg, 0.812 mmol) and 4-hydroxybenzeneboronic acid (123 mg, 0.894 mmol) was dissolved in isopropyl alcohol (1.6 mL). Sodium carbonate in water (0.97 mL, 1.0M) was added slowly, followed by bis(triphenylphosphine)palladium chloride (26.5 mg, 0.0378 mmol). The mixture was stirred at 100° C. (bath) for 16 hours. The contents were diluted with water (5 mL) and EtOAc (10 mL). The aqueous layer was separated and extracted with EtOAc (2×5 mL). The combined EtOAc solutions were washed with brine (5 mL) and dried (Na2SO4). The crude was purified by flash chromatography to give (R)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenol (160 mg, 87%) as viscous oil which solidified upon standing.
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=[CH:12]C=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[N:38]=[CH:37][CH:36]=[N:35]1)=[O:27])[CH2:20]2.ClC1N=C(C)C=C(C)N=1>>[CH3:12][C:11]1[CH:16]=[C:15]([CH3:14])[N:8]=[C:9]([N:24]2[CH2:25][CH:19]3[CH:23]2[CH2:22][N:21]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[N:38]=[CH:37][CH:36]=[N:35]2)=[O:27])[CH2:20]3)[N:10]=1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: O=C(c1ccccc1-n1nccn1)N1CC2CNC2C1
Agent: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-n4nccn4)CC32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 25 and 2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for C20H21N7O, 375.44; m/z found, 376.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]([N:30]([CH3:34])[CH2:31][CH2:32][OH:33])([CH3:29])[C:27]#[CH:28]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:28]#[C:27][C:26]([N:30]([CH3:34])[CH2:31][CH2:32][OH:33])([CH3:29])[CH3:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2c(ccn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: C#CC(C)(C)N(C)CCO
Product: CN(CCO)C(C)(C)C#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1

Procedure:
In analogy to example 17.3, Trifluoro-methanesulfonic acid 1-(4-fluoro-phenyl)-1H-indol-5-yl ester and 2-[(1,1-Dimethyl-prop-2-ynyl)-methyl-amino]-ethanol were converted to yield 2-({3-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-1,1-dimethyl-prop-2-ynyl}-methyl-amino)-ethanol as orange viscous oil, MS: 351 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>O1CCCC1.ClCCl>[CH2:26]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: c1ccsc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCc1cccs1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 17.4 %

Procedure:
7.2 g of thiophene was dissolved in 100 ml of tetrahydrofuran and cooled to 0° C. To this solution, 56 ml of n-butyllithium solution (1.6 mol/l hexane solution) was added dropwise and stirred for 3.5 hours. To this solution, 25 g of hexadecylbromide was added dropwise and stirred at room temperature for 5.5 hours. 100 ml of water and 100 ml of dichloromethane were added to the resulting solution to separate the organic layer. The organic layer was washed with 300 ml of water and dried over anhydrous magnesium sulfate. The resulting solution was concentrated by a rotary evaporator and purified by a column chromatography (filler: silica gel, eluent: hexane) to obtain 4.4 g of 2-n-hexadecylthiophene represented by the following formula.
Reaction SMILES: C(O[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[N:18]1([S:24]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[C:12]1([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:35]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][C:27]=2[S:24]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:25])=[O:26])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(c1cc2ccccc2[nH]1)N1CCCCC1
Product: O=S(=O)(c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1)N1CCCCC1
Yield: 81.7 %

Procedure:
Substantially the same procedure as in Example 263 was repeated using benzhydryl acetate (0.78 g, 3.41 mmol) and 2-(piperidinosulfonyl)indole (0.95 g, 3.59 mmol) to give 1.2 g (yield: 75%) of the title compound.