Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[Si:21]([O:38][CH2:39][C:40]1[C:45]([N:46]2[CH2:51][C@H:50]([CH3:52])[O:49][C@H:48]([CH3:53])[CH2:47]2)=[C:44]([Cl:54])[C:43]([F:55])=[CH:42][N:41]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:56][N:57]1[CH:61]=[CH:60][N:59]=[C:58]1[CH:62]=[O:63]>C1COCC1>[Si:21]([O:38][CH2:39][C:40]1[N:41]=[C:42]([CH:62]([C:58]2[N:57]([CH3:56])[CH:61]=[CH:60][N:59]=2)[OH:63])[C:43]([F:55])=[C:44]([Cl:54])[C:45]=1[N:46]1[CH2:51][C@H:50]([CH3:52])[O:49][C@H:48]([CH3:53])[CH2:47]1)([C:34]([CH3:37])([CH3:35])[CH3:36])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cn1ccnc1C=O
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(O)c3nccn3C)c(F)c2Cl)C[C@H](C)O1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65.9 %

Procedure:
Diisopropylamine (0.868 mL, 6.14 mmol) was added dropwise to a stirring solution of 2.5M butyllithium in hexanes (2.339 mL, 5.85 mmol) in THF (20 mL) at −78° C. The solution was warmed to 0° C. for 10 minutes and then cooled again to −78° C. Cannulation of the LDA at −78° C. into (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45, 1.5 g, 2.92 mmol) in THF (10 mL) at −78° C. Allowed dark solution to stir for 20 minutes then cannulated into a stirring solution of 1-methyl-1H-imidazole-2-carbaldehyde (0.644 g, 5.85 mmol) in THF (10 mL) at −78° C. The solution was allowed to warm to −50° C. then quenched with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and washed resulting organics with brine. After drying the organics over sodium sulfate, filtering, and evacuating the filtrate under vacuum, a crude yellow oil was obtained. The crude oil was purified on silica using 40% ethyl acetate in n-hexane to give 1.2 g (66%) of the title compound as oil.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:21]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:20])=[CH:9][CH:10]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.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>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:21]=1)[C:6]1[CH:7]=[C:8]([OH:20])[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(-c3cccnc3)cc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A 350-mL pressure vessel was charged with (R)-2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (4.00 g, 11.52 mmol), 3-pyridylboronic acid (3.54 g, 28.8 mmol), tetrakis(triphenylphosphine)palladium(0) (1.331 g, 1.152 mmol), THF (57.6 mL), and potassium carbonate (2.0M aq. solution) (28.8 mL, 57.6 mmol). The vessel was sealed and heated to 100° C. and stirred for 2 hours. The layers were partitioned between EtOAc (20 mL) and water (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (emulsion!), dried over sodium sulfate and filtered with the aid of 10% MeOH/DCM. The filtrate was evaporated to give a yellow solid. This solid was taken up in minimal DCM and sonicated for 5 min. The solid was filtered and washed with DCM (30 mL). Filtering and washing with DCM afforded (S)-2-amino-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a pale-yellow solid
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:24])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1.[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30]Br)[CH3:26]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([O:24][CH2:30][CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:32])[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCBr
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(O)c2cccc(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCOC(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a slurry of NaH (0.835 g, 0.0348 mol) in DMF (50 mL) was added a solution of (R)-tert-butyl 3-((3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (3.8 g, 0.0116 mol) in DMF (30 mL) dropwise at −15˜−5° C. and the reaction mixture was stirred for about 1 h at rt. A solution of 3-bromopropionic acid ethyl ester (4.2 g, 0.0232 mol) in DMF (30 mL) was added to the reaction mixture dropwise while the temperature was maintained at −15˜−5° C. and the mixture was warmed slowly to rt and stirred overnight. The reaction was cooled in an ice bath and quenched with satd aq NH4Cl (80 mL). The product was extracted with EtOAc, washed with brine, dried over NaSO4 and purified by flash chromatography to afford (3R)-tert-butyl 3-((3-chlorophenyl)(3-ethoxy-3-oxopropoxy)methyl)piperidine-1-carboxylate (2.0 g, 4.71 mmol, 41%). 1H NMR (400 MHz, CDCl3): 1.12-1.37 (m, 4H), 1.45 (s, 9H), 1.47-1.75 (m, 3H), 1.82-1.93 (m, 1H), 2.50-2.58 (m, 4H), 3.43-3.52 (m, 2H), 3.80-4.01 (m, 2H), 4.07-4.17 (m, 3H), 7.13-7.23 (m, 1H), 7.25-7.27 (m, 3H). MS (E/Z): 426 (M+H+).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1)[C:3]#[CH:4].Br[C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1/[C:17](=[CH:25]/[C:26]1[NH:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32])/[C:18](=[O:24])[NH:19]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1)[C:3]#[C:4][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1/[C:17](=[CH:25]/[C:26]1[NH:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32])/[C:18](=[O:24])[NH:19]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccc(OC)c(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1O

Procedure:
Using Method D above, 3-hydroxy-3-(3-hydroxy-4-methoxyphenyl)-1-propyne (105 mg, 0.59 mmol) (from Example 34 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (122 mg, 0.38 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (34 mg) (Aldrich) and CuI (15 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 18 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(3-hydroxy-4-methoxyphenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 101 mg, 64%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH:12]=O)[CH:6]=1)[CH3:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CCO>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH2:12][NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=1)[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1ccc(Br)c(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(Br)c(CNCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-3-formyl-benzoic acid ethyl ester (3.3 g, 12.9 mmol) and benzylamine (2.1 mL, 19.3 mmol) were combined in EtOH (150 mL) with 4 Å molecular sieves. Sodium cyanoborohydride (1.21 g, 19.3 mmol) was added, followed by acetic acid (1.1 mL, 19.3 mmol), and the reaction was stirred at room temperature for 1 hour. Aqueous work-up provided 3-(benzylamino-methyl)-4-bromo-benzoic acid ethyl ester.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C.C(=O)(O)[O-].[Na+].CC1(C)C(C)(C)OB([C:44]2[CH:49]=[CH:48][C:47]([C:50]3([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:53][CH2:52][CH2:51]3)=[CH:46][CH:45]=2)O1>C1(C)C=CC=CC=1>[CH2:20]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]3[N:16]=[CH:17][CH:18]=[CH:19][C:7]=3[N:6]2[C:2]=1[C:44]1[CH:45]=[CH:46][C:47]([C:50]2([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:59])([CH3:58])[CH3:60])[CH2:51][CH2:52][CH2:53]2)=[CH:48][CH:49]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Brc1c(CCc2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CCc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
To a suspension of 3-bromo-2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.197 g, 1 eq.) in a mixture of toluene (10 mL), ethanol (10 mL), and saturated sodium bicarbonate (4 mL) was added tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (0.353 g, 2 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.054 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (100 mL). The aqueous phase was extracted with dichloromethane (2×100 mL) and the organic extracts were combined and washed with brine (1×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (10-60% ethyl acetate in hexanes) gave tert-butyl (1-(4-(2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.042 g, 15%) as a yellow solid. LCMS: 584 [M+H].
Reaction SMILES: [CH:1]([CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14](C(OCC)=O)=[CH:13][C:12]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)=[O:2].C[O-].[Na+].[CH:34]([NH2:36])=[O:35]>>[CH:1]([CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][CH:14]=[C:13]([C:34]([NH2:36])=[O:35])[C:12]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:9][CH:10]=1)=[O:2]
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(NCC=O)cc2)s1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-c2c(C(N)=O)csc2-c2ccc(NCC=O)cc2)cc1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
A mixture of ethyl 5-[4-(N-formylmethylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylate (0.34 g) and sodium methoxide (0.13 g) in formamide (2 ml) was stirred at 100° C. for 2.5 hours. The mixture was poured into ice-water and the precipitates were collected to give 5-[4-(N-formylmethylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-3-carboxamide (0.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)cc1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution of 4-fluorophenol (2.00 g, 17.84 mmol) in DMF (10 mL) was added dropwise to a stirred suspension of NaH in DMF (2.0 mL) at around 10° C. Ethyl bromoacetate (2.483 mL, 22.30 mmol) was added dropwise and then the reaction mixture was allowed to warm up to room temperature for 4 hours. The solvent was removed under vacuum and the residue was dissolved in methylene chloride and washed 2 times with water, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on silica gel using (4:1 heptane:EtOAc as eluent) to give ethyl 2-(4-fluorophenoxy)acetate (3.12 g, 95%).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[H-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C)C=O>[CH2:12]([N:4]1[C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=[C:3]1[CH3:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCBr
Reactant: Cc1nc(C)c(C)[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCn1c(C)nc(C)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dissolve 16.0 g (0.019 mole) of 2,4,5-trimethyl-1H-imidazole hydrochloride in 125 ml dry N,N-dimethylformamide and cool to 0° C. Add 8.75 g (0.218 mole) of sodium hydride (60%), stir at 0° C. for 30 minutes and then heat reaction mixture to 100° C. for one hour. Cool to 0° C. and then add 18.0 ml (0.114 mole) of n-heptyl bromide to reaction mixture. Upon completion of addition, heat to 100° C. for four hours, following the progress of the reaction by thin-layer chromatography on silica gel (methanol:1M sodium chloride, 95:5). At the completion of the reaction, cool to room temperature and add 2 ml water. Filter precipitated salts and evaporate solvent.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:45])[N:15]([CH3:44])[C@@H:16]([C:28](=[O:43])[N:29]([C@@H:31]([C:39](=[O:42])[NH:40][CH3:41])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:44][N:15]([C@@H:16]([C:28](=[O:43])[N:29]([CH3:30])[C@@H:31]([C:39](=[O:42])[NH:40][CH3:41])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:14]([CH:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1)=[O:45]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)C1CCC(N)CC1
Reaction time: 0.08 h
Yield: 49.3 %

Procedure:
To a solution of (4-[N-Methyl-N-{(1R)-1-(N-methyl-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)-ethyl}carbamoyl]cyclohexyl)carbamic acid tert-butyl ester (240 mg, 0.38 mmol) in 1 ml dichloromethane was added 0.5 ml trifluoroacetic acid and the mixture was stirred for 5 min. Sodium bicarbonate was added until gas evolution has ceased, and the mixture was extracted with dichloromethane (3×15 ml). The combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (16 g) with dichloromethane/methanol (4:1). The obtained product was dissolved in 3 ml of methanol and added 40 ml of water and 0.5 ml of acetic acid and lyophilized to give 99 mg of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)Oc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(CO)cc1
Yield: 83.1 %

Procedure:
By the method of Example 1, Step G, 11.1 g (0.0533 mole) of methyl 2-(4-formylphenoxy)propionate and 2.02 g (0.0533 mole) of sodium borohydride were reacted in methanol, yielding 9.31 g of methyl 2-(4-hydroxymethylphenoxy)propionate as a yellow oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)=[O:5])[CH3:2].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].CN([CH:27]=[O:28])C>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:27]=[O:28])=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C=O
Temperature: 60 °C

Procedure:
To a stirred solution of 2.36 g (0.011 mol) of 6-chloro-1H-indole-2-carboxylic acid ethyl ester in DMF (20 ml) was added phosphorus oxychloride (1.08 ml, 0.012 mol) at RT. The solution was heated at 60° C. for 2 hours, then cooled to RT, and poured into water. The ph was adjusted to 7 by careful addition of aq. NaOH 2N. The resulting brown precipitate was collected by filtration and dried over night in a vacuum oven (50° C.). The title compound was obtained as light brown solid, 2.05 g (77%).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[Cl:8][C:9]1[CH:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH2:16])[N:10]=1>CS(C)=O>[NH2:16][C:11]1[N:12]=[C:13]([NH:15][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH:14]=[C:9]([Cl:8])[N:10]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CCCCN=C=O
Solvent: CS(C)=O
Product: CCCCNC(=O)Nc1cc(Cl)nc(N)n1
Temperature: 80 °C

Procedure:
8.6 cm3 of n-butylisocyanate was added to a suspension of 5 g of 4-chloro-2,6-diaminopyrimidine in 50 cm3 of DMSO then heated to 80° C. until the starting compound was shown by TLC to have disappeared.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:14].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[ClH:17].[Cl:14][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: OCc1ccc(-n2ccnc2)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 11.3 parts of 4-(1H-imidazol-1-yl)benzenemethanol in 375 parts of trichloromethane was acidified with gaseous hydrogen chloride at room temperature. Then there were added dropwise 10.6 parts of thionyl chloride at room temperature. Upon completion, stirring was continued first for 30 minutes at reflux and further for 30 minutes at room temperature. The reaction mixture was evaporated. The residue was taken up a few times in methylbenzene and the latter was evaporated each time. The residue was stirred for 1 hour in 2,2'-oxybispropane. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo overnight, yielding 13.5 parts of 1-[4-(chloromethyl)phenyl]-1H-imidazole monohydrochloride (intermediate 20).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Reactant: COc1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: COc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cn23)cc1

Procedure:
The title compound, white solid (56 mg, 44%), MS (ISP) m/z=385.5 [(M+H)+], mp 162° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-methoxy-phenyl)-imidazo[1,2-a]pyridine (intermediate L) (0.1 g, 0.33 mmol) and 1-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (0.11 mg, 0.38 mmol).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]([O-])=[CH:4][CH:3]=1.[CH3:13][S:14]([O:17]S(C)(=O)=O)(=[O:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[CH3:13][S:14]([O:17][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: [O-][n+]1ccc(O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Oc1cnc2ccccc2c1O
Reaction time: 4 h

Procedure:
A mixture of 4-hydroxyquinoline-1-oxide (1 g), methanesulphonic anhydride (2 g) and potassium carbonate (2 g) in dichloromethane (20 ml) was stirred at 0° for 4 hours. Water (20 ml) was added to the mixture and the dichloromethane layer separated. The aqueous layer was extracted with dichloromethane (2×60 ml). The combined dichloromethane layer and extracts were dried over magnesium sulphate and evaporated to give a gum which was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (19:1) to give the novel compound 4-hydroxyquinol-3-yl methanesulphonate, m.p. 224°.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].[C:22]([O:26][C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN=C=NCCCN(C)C.Cl.O>C(Cl)Cl>[S:12]([N:9]1[C:6]2=[N:7][CH:8]=[C:3]([NH:1][NH:2][C:35]([C@@H:32]3[CH2:33][CH2:34][C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:31]3)=[O:36])[N:4]=[C:5]2[CH:11]=[CH:10]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)[C@@H]4CC[C@H](NC(=O)OC(C)(C)C)C4)cnc32)cc1
Reaction time: 4.5 h
Yield: 99.1 %

Procedure:
To mixture of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.50 g, 8.24 mmol, Preparation #9) and (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.08 g, 9.07 mmol, Peptech) in DCM (30 mL) was added EDC.HCl (1.90 g, 9.89 mmol). After about 4.5 h at ambient temperature, water (30 mL) was added and the layers were separated. The aqueous layer was then extracted with EtOAc (15 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was dissolved in DCM (15 mL) and purified by silica gel chromatography eluting with a gradient of 40-100% EtOAc in heptane to give tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate (4.20 g, 97%): LC/MS (Table 2, Method a) Rt=2.27 min; MS m/z: 515 (M+H)+.