Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([CH2:12][NH2:13])[OH:11].C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([NH:13][CH2:12][CH2:10][OH:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCNc1nc(Cl)ncc1Br

Procedure:
In analogy to compound 1.1, a solution of 0.34 g (1.49 mmol) of 5-bromo-2,4-dichloropyrimidine in 5 ml of acetonitrile is reacted with 0.1 ml (1.61 mmol) of ethanolamine in the presence of 0.25 ml (1.81 mmol) of triethylamine. Recrystallization from hexane/ethyl acetate 7/3 results in 0.28 g (74% of theory) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[C:6]1[CH:11]([CH3:16])[N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: Clc1ccc(C#CBr)cc1
Reactant: CC1c2[nH]c3ccc(Cl)cc3c2CCN1C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: CC1c2c(c3cc(Cl)ccc3n2C#Cc2ccc(Cl)cc2)CCN1C
Temperature: 80 °C

Procedure:
6-chloro-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (220 mg, 1 mmol) was mixed with CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture was flushed with nitrogen and heated at 80° C. for 16 h. The reaction mixture was filtered through Celite and Celite bed was rinsed with dichloromethane. Combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain 6-chloro-9-((4-chlorophenyl)ethynyl)-1,2-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as brown semi solid (88 mg). 1H NMR (CDCl3) FREE BASE 7.51-7.43 (m, 4H), 7.39-7.36 (d, 1H), 7.30-7.22 (m, 2H), 4.05-3.97 (q, 1H), 3.24-2.80 (m, 4H), 2.60 (s, 3H), 1.68-1.58 (d, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:5]=[C:4]([S:21][CH3:22])[N:3]=1.[NH2:23][NH2:24]>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:2]([NH:23][NH2:24])[N:3]=[C:4]([S:21][CH3:22])[N:5]=2)=[CH:15][CH:16]=1
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(-c2ccc(Cl)cc2)n1
Reactant: NN
Solvent: C1CCOC1
Product: CSc1nc(NN)c(-c2ccccc2)c(-c2ccc(Cl)cc2)n1
Temperature: 60 °C

Procedure:
To a stirred solution of 4-chloro-6-(4-chlorophenyl)-2-(methylthio)-5-phenylpyrimidine (1.22 g, 3.52 mmol) in THF (15 mL) at room temperature under argon was added H2NNH2 (340 mg, 10.5 mmol). The reaction mixture was heated at 60° C. under argon for 2 h. Analysis by HPLC/MS indicated that the reaction was complete. The solvent was evaporated, and the resulting residue was coevaporated with toluene (2×5 mL) and then dichloromethane (2×10 mL), then dried under vacuum. The crude title compound was used directly in the next step. HPLC/MS: retention time=2.73 min, [M+H]30 =343.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.[NH2:40][O:41][CH2:42][C:43]([CH3:46])([OH:45])[CH3:44].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[OH:45][C:43]([CH3:46])([CH3:44])[CH2:42][O:41][N:40]=[C:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:20][CH:21]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:6][CH2:7]1
Reactant: CC(C)(O)CON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=NOCC(C)(C)O)CC2)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), 1-(aminooxy)-2-methylpropan-2-ol (0.4 g) and pyridine (5 mL) was stirred at 100° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with 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 colorless crystals (0.15 g, 63%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:21][CH2:22][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:24][CH2:25]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(-c3ccccc3O)nc2c1
Reaction time: 6 h
Yield: 101 %

Procedure:
To a suspension of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (2.0 g, 7.38 mmol) in CH2Cl2 (25 ml) at 0° C. under an N2 atmosphere was added dropwise a solution of tert-butyl piperidin-4-ylcarbamate (1.92 g, 9.6 mmol) in CH2Cl2 (10 ml) and triethylamine (2.0 ml, 14.76 mmol). The reaction was stirred for 6 hours, then it was quenched with water (25 ml), and the layers were separated. The aqueous phase was extracted twice with CH2Cl2 (10 ml), and the combined organic layers were dried over MgSO4, filtered, and concentrated to give tert-butyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate as a yellow solid (3.24 g, 100%). LC/MS: m/z 435.3 (M+H)+ at 2.79 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].BrCCBr.[CH2:10]=[C:11]([CH2:14][CH2:15][CH3:16])[CH:12]=[O:13].[Cl-].[NH4+]>CCOCC>[OH:13][CH:12]([C:11](=[CH2:10])[CH2:14][CH2:15][CH3:16])[CH2:4][C:3]#[CH:2]
Reactant: C#CCBr
Reactant: C=C(C=O)CCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: BrCCBr
Product: C#CCC(O)C(=C)CCC
Temperature: 0 °C

Procedure:
To a stirred mixture of 12.16 g. of magnesium in 120 ml. of ether containing 200 mg. of mercuric chloride is added 2 ml. of propargyl bromide and 0.5 ml. of 1,2-dibromoethane. This mixture is stirred under argon until the reaction begins. To this is added with stirring a solution of 41.57 g. of 2-methylene valeraldehyde and 64.95 g. of propargyl bromide in 90 ml. of ether, dropwise, at a rate to maintain reflux. After addition is complete the mixture is refluxed 15 minutes, stirred at room temperature one hour, cooled to 0° C. and saturated ammonium chloride solution is added dropwise until reflux stops. The mixture is filtered through Celite, dried over magnesium sulfate and the ether is removed giving the product as a light orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1.FC(F)(F)C(O)=[O:37].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:37])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6,6′-trimethyl-[2,2′]bipyridine (compound 446) (75 mg) was dissolved in methylene chloride (2 ml) to prepare a solution. The solution was brought to 0° C., trifluoroacetic acid (1 ml) was added thereto, and the mixture was stirred at 0° C. for 30 min and then at room temperature for 4 hr. The reaction solution was brought to 0° C., was stirred and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (48 mg, yield 61%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][Si](C(C)(C)C)(C)C)=[CH:30][CH:29]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:45][O:46][C:47](=[O:49])[CH3:48])(=[O:3])[CH3:2].C(O)(=O)C.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][OH:37])=[CH:32][CH:33]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:45][O:46][C:47](=[O:49])[CH3:48])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C#N)c(Cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C#N)c(Cc3ccc(OCCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(2-((tert-butyl dimethyl silyl)oxy)ethoxy)benzyl)-4-cyanophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (180.0 mg, 0.25 mmol), was added acetic acid (1.5 mL) and water (0.5 mL) and the reaction mixture was stirred overnight at r.t. After the completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethyl acetate (50 mL) followed by neutralization with sodium bicarbonate solution till effervescence ceased. The organic layer was separated, washed with water (2×20 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 3:2 EtOAc:Pet Ether) to afford title compound (140.0 mg, 95%) as a solid.
Reaction SMILES: O.FC1C(F)=CC=CC=1C1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2OC=C(C(O)=O)N=2)CC1)=[O:20].Br[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][N:43]=[C:42]2[C:48]([NH:50][CH2:51][CH:52]1[CH2:57][CH2:56][N:55]([CH2:58][C:59]2[O:63][C:62]([C:64]([O:66]CC)=[O:65])=[CH:61][CH:60]=2)[CH2:54][CH2:53]1)=[O:49].[CH3:69][O:70][C:71]1[CH:76]=[CH:75][C:74](B(O)O)=[CH:73][CH:72]=1>>[OH2:20].[CH3:69][O:70][C:71]1[CH:76]=[CH:75][C:74]([C:39]2[CH:40]=[C:41]3[C:45](=[CH:46][CH:47]=2)[NH:44][N:43]=[C:42]3[C:48]([NH:50][CH2:51][CH:52]2[CH2:57][CH2:56][N:55]([CH2:58][C:59]3[O:63][C:62]([C:64]([OH:66])=[O:65])=[CH:61][CH:60]=3)[CH2:54][CH2:53]2)=[O:49])=[CH:73][CH:72]=1
Reactant: CCOC(=O)c1ccc(CN2CCC(CNC(=O)c3n[nH]c4ccc(Br)cc34)CC2)o1
Reactant: O=C(O)c1coc(CN2CCC(CNC(=O)c3n[nH]c4ccc(-c5cccc(F)c5F)cc34)CC2)n1
Reactant: COc1ccc(B(O)O)cc1
Solvent: O
Product: COc1ccc(-c2ccc3[nH]nc(C(=O)NCC4CCN(Cc5ccc(C(=O)O)o5)CC4)c3c2)cc1
Reaction time: 0.25 h

Procedure:
5-({4-[({[5-(4-Methoxyphenyl)-1H-indazol-3-yl]carbonyl}amino)methyl]piperidin-1-yl}methyl)furan-2-carboxylic acid hydrate 18 was prepared, according to the procedure described for compound 12, from compound 15 and (4-methoxyphenyl)boronic acid and using the following preparative HPLC parameters for the purification: channel A=CH3CN+0.1% formic acid; channel B=H2O+0.1% formic acid: flow=40 ml/min; gradient=15%-50% of eluent A in 15 minutes. Yield: 14 mg, 5%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:18]1([S:24]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]3[CH:10]=[CH:9]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cnc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.7 %

Procedure:
To a mixture of 5-methyl-1H-pyrrolo[2,3-b]pyridine (3.5 g, 26.5 mmol), triethylamine (8.03 g, 79.5 mmol), and 4-dimethylaminopyridine (0.32 g, 2.65 mmol) in dichloromethane (100 mL) at 0° C. was added benzenesulfonyl chloride (7.0 g, 39.8 mmol). After stirring for 48 h at room temperature, the reaction was quenched with water (50 mL) and extracted with dichloromethane (2×120 mL). The organic layer was washed with a saturated sodium bicarbonate solution (2×30 mL), water (2×30 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 33% dichloromethane/hexanes) to afford 1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridine (4.6 g, 64%) as white solid: LC/MS m/e calcd for C14H12N2O4S [M+H]+ 273.33, observed 272.9.
Reaction SMILES: C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.[CH3:33][C:34]([CH3:64])([CH3:63])[C@H:35]([NH:38][C:39](=[O:62])[C@H:40]([N:45]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[CH:46]1)[CH2:41][C:42](O)=[O:43])[CH2:36][OH:37].[O:65]([NH2:83])[Si:66]([C:79]([CH3:82])([CH3:81])[CH3:80])([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CO.C(Cl)Cl>[O:65]([NH:83][C:42](=[O:43])[CH2:41][C@@H:40]([N:45]1[CH:49]=[CH:48][C:47]([C:50]2[CH:51]=[CH:52][C:53]([C:56]3[CH:57]=[CH:58][N:59]=[CH:60][CH:61]=3)=[CH:54][CH:55]=2)=[CH:46]1)[C:39]([NH:38][C@H:35]([CH2:36][OH:37])[C:34]([CH3:33])([CH3:64])[CH3:63])=[O:62])[Si:66]([C:79]([CH3:81])([CH3:80])[CH3:82])([C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Reactant: CC(C)(C)[Si](ON)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)NO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Yield: 43 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butyloxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, N-(2,2-dimethyl-1(S)-hydroxymethyl-propyl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid (prepared as described in Example 5(a)) and t-butyldiphenylsiloxyamine were coupled with TBTU. Flash column chromatography with 0-5% MeOH/CH2Cl2 gradient eluant furnished in 43% yield N4 -t-butyldiphenylsiloxy-N1 -[2,2-Dimethyl-1(S)-(hydroxymethyl)propyl]-2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamide as an amorphous solid. 1H NMR (DMSO-d6): δ 10.73 (s, 1H), 8.59 (d, 2H, J=6.3 Hz), 7.85-7.70 (m, 5H), 7.65-7.56 (m, 6H), 7.45-7.34 (m, 6H), 7.29 (s, 1H), 6.79 (s, 1H), 6.43 (s, 1H), 5.20-5.14 (m, 1H), 4.38-4.36 (m, 1H), 3.54-3.50 (m, 2H), 2.82-2.70 (m, 1H), 0.99 (s, 9H), 0.84 (s, 9H). Anal: Calculated for C41H48N4O4Si.0.4 H2O: c, 70.74; H, 7.07; N, 8.05. Found: C, 70.83; H, 7.04; N, 8.33.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:21]#[N:22])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2([C:21]#[N:22])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(I)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(I)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a stirred solution of 4-cyano-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1.95 g, 4.73 mmol) in CH2Cl2 (37.5 mL) at 0° C. was added TFA (12.5 mL). The mixture was stirred at room temperature for 3 h. TLC (4:1 hexanes/EtOAc) showed no starting material left. The solvent was removed by rotary evaporation and the resulting liquid was evaporated from toluene (2×20 mL), diluted with EtOAc (100 mL) and washed with 10% aqueous NaHCO3 (2×50 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation, dried under high vacuum for 1 h to yield 4-(4-iodo-phenyl)-piperidine-4-carbonitrile as a reddish solid (1.46 g, ˜4.7 mmol, ˜100%). 1H NMR (300 MHz, CDCl3): δ 7.82 (dd, 2H), 7.37 (dd, 2H), 3.25 (m, 4H), 2.15 (m, 4H).
Reaction SMILES: C1(N)C([F:7])=C(F)C(F)=C(N)C=1F.Cl.Cl.C(O[C:20]([NH:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:39]=[C:38](F)[CH:37]=[CH:36][C:33]=2C#N)[CH2:28][CH2:27]1)=[O:21])(C)(C)C.[N+](C1C=CC(OC([N:53]2[C@@H:57]([C:58]3[CH:63]=[CH:62][C:61]([F:64])=[C:60]([F:65])[CH:59]=3)[C@@H:56]([CH2:66][N:67]3[CH:71]=[CH:70][N:69]=[CH:68]3)[O:55][C:54]2=[O:72])=O)=CC=1)([O-])=O.C(N(CC)C(C)C)(C)C>>[F:7][C:37]1[CH:36]=[CH:33][C:32]([CH:29]2[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][CH2:23][NH:22][C:20]([N:53]3[C@@H:57]([C:58]4[CH:63]=[CH:62][C:61]([F:64])=[C:60]([F:65])[CH:59]=4)[C@@H:56]([CH2:66][N:67]4[CH:71]=[CH:70][N:69]=[CH:68]4)[O:55][C:54]3=[O:72])=[O:21])[CH2:31][CH2:30]2)=[CH:39][CH:38]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1C(=O)O[C@H](Cn2ccnc2)[C@@H]1c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(c2cc(F)ccc2C#N)CC1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCN1CCC(c2ccc(F)cc2)CC1)N1C(=O)O[C@H](Cn2ccnc2)[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of the dihydrochloride salt of 3-[4-(4-fluorophenyl)piperidin-1-yl]propylamine (77 mg, 0.25 mmol) (see Example 1) and (4S, 5R) 4-(3,4-difluorophenyl)-5-(imidazol-1-ylmethyl)-2-oxo-oxazolidine-3-carboxylic acid (4-nitrophenyl) ester (112 mg, 0.25 mmol) in dry, degassed N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (88 μL, 0.50 mmol). The reaction mixture was stirred at ambient temperature for 20 h when the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with 10% aqueous sodium carbonate solution (6×50 mL), brine (1×50 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure to give a foam. The hydrochloride salt was prepared according to standard procedures to afford (4S, 5R)-4-(3,4-difluorophenyl)-5-imidazol-1-ylmethyl-2-oxo-oxazolidine-3-carboxylic acid{3-[4-(4-fluorophenyl)piperidin-1-yl]propyl}amide as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:17][C:18]2[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(-c2ccccc2)[nH]n1
Reactant: OCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(-c2ccccc2)n(Cc2ccc(CO)cc2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A mixture of 3-tert-butyl-5-phenyl-1H-pyrazole (2.0 g, 10 mmol), 4-(chloromethyl)benzyl alcohol (1.70 g, 10.8 mmol), potassium carbonate (2.76 g, 20 mmol) and N,N-dimethylformamide (20 mL) was stirred at 120° C. for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (5%-80% ethyl acetate/hexane) to give the title compound (640 mg, yield 20%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[S:39]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=1)(=[O:41])=[O:40].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:45]2[CH:44]=[C:43]([NH:42][S:39]([C:32]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=3[O:30][CH3:29])(=[O:41])=[O:40])[CH:48]=[CH:47][CH:46]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(S(=O)(=O)Nc2cccc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)c(OC)c1
Yield: 71.9 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) was treated with 2,4-dimethoxy-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (191 mg, 0.45 mmol), 2N cesium carbonate (340 μl, 3.08 mmol) and bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (20 mg, 0.02 mmol) according to the method described in Example 3 to give 108 mg (73% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]1[C:19](=[O:21])[CH3:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O.[Li+].[OH-]>[C:19]([N:6]1[CH:5]([CH2:4][C:3]([OH:22])=[O:2])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2)(=[O:21])[CH3:20]
Reactant: COC(=O)CC1c2ccccc2-c2ccccc2N1C(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2ccccc2-c2ccccc2C1CC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (5-acetyl-5,6-dihydro-phenanthridin-6-yl)-acetic acid methyl ester (210 mg, 0.71 mmol) dissolved in a mixture of dioxane (10 mL) and water (10 mL), LiOH×H2O (42 mg, 1 mmol) was added. The solution was allowed to stir at r.t. for 4 h. Citric acid (5% solution in water) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with citric acid (2×), water (1×), and brine (1×). After drying over MgSO4, the solvent was removed in vacuo to give a colourless oil that solidified on standing ar r.t. Yield, 70%. (+)-ESI-MS: m/z=282 [M+H]+, 240, 222, 180.