Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14](=O)[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17]>>[OH:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[CH2:14][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccccc1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3ccccc3O)CC2)nc[nH]1

Procedure:
6-[4-(2-Hydroxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and salicylaldehyde. Mass spectrum (ES) MH+=287.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:23])[CH2:14][CH:15]([O:19][C:20](=[O:22])[CH3:21])[C:16]=1OC)([O:3][CH2:4][CH3:5])=[O:2].[C-:24]#[N:25].C([Al+]CC)C>>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:23])[CH2:14][CH:15]([O:19][C:20](=[O:22])[CH3:21])[C:16]=1[C:24]#[N:25])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCCCCC1=C(OC)C(OC(C)=O)CC1=O
Reactant: [C-]#N
Agent: CC[Al+]CC
Product: CCOC(=O)CCCCCCC1=C(C#N)C(OC(C)=O)CC1=O

Procedure:
According to the procedure similar to that of Step 3 (a) of Example 1, 0.52 g of 2-(6'-carbethoxyhexyl)-3-methoxy-4-acetoxy-2-cyclopenten-1-one prepared in Step 2 was caused to react with diethylaluminum cyanide. Further, the product was purified using chromatography on silica gel to provide 0.25 g of 2-(6'-carbethoxyhexyl)-3-cyano-4-acetoxy-2-cyclopenten-1-one as an oily material.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[OH:8][C:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][CH2:22][NH:23]S(C3C=CC(C)=CC=3)(=O)=O)([CH2:16][CH2:17]2)[CH2:14]1)=[O:11].[C:46]1([N:52]=[C:53]=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[OH:8][C:9]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N+:15]([CH2:21][CH2:22][NH:23][C:53]([NH:52][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:54])([CH2:20][CH2:19]2)[CH2:14]1)=[O:11]
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NCC[N+]23CCC(CC2)[C@@H](OC(=O)C(O)(c2ccccc2)c2ccccc2)C3)cc1
Agent: O=C([O-])C(F)(F)F
Product: O=C(NCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)Nc1ccccc1

Procedure:
This compound is made analogously to (R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-[2-(toluene-4-sulfonylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 49) by replacing p-toluenesulfonyl chloride with phenyl isocyanate.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:24])[N:10]([CH2:12][C:13]([NH:15][C:16]2[C:17]([NH2:23])=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=2)=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:24])[N:10]([CH2:12][C:13]2[NH:15][C:16]3[C:17]([N:23]=2)=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=3)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(CC(=O)Nc1cc(Br)cnc1N)C(=O)OCc1ccccc1
Solvent: CC(=O)O
Product: CN(Cc1nc2ncc(Br)cc2[nH]1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A solution of phenylmethyl{2-[(2-amino-5-bromopyridin-3-yl)amino]-2-oxoethyl}methylcarbamate (0.30 g, 0.76 mmol) in acetic acid (7.5 mL) was heated in a microwave apparatus (250 W) for 30 min. at 120° C. After cooling it to room temperature the reaction mixture was concentrated and the pH was adjusted to 8 by the addition of saturated aqueous sodium bicarbonate. The precipitating solid was collected by filtration, washed with water and dried in vacuo to give phenylmethyl[(6-bromo-1H-imidazo[4,5-b]pyridin-2-yl)methyl]methylcarbamate (0.22 g, 76%). MS (EI) for C16H15BrN4O2: 376 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH3:14])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:17][C:18](=[O:20])[CH3:19].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:17][C:18](=[O:20])[CH3:19])[CH3:14]
Reactant: COC(=O)[C@H](C)NCc1ccccc1
Reactant: CC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H](C)N(CC(C)=O)Cc1ccccc1
Temperature: 70 °C
Yield: 49.8 %

Procedure:
A mixture of N-benzylalanine methyl ester hydrochloride (1.00 g, 4.35 mmol), chloroacetone (1.21 g, 13.1 mmol), and sodium hydrogencarbonate (951 mg, 11.3 mmol) in 1,4-dioxane (11 mL) and water (1 mL) was heated at 70° C. for 2 days, then partitioned between EtOAc and 2 M aq. sodium carbonate solution. The organic layer was dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-EtOAc gradient) produced the title compound (540 mg, 50%). Colourless oil, MS: 250.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].[OH-].[Na+].Cl>C(Cl)(Cl)Cl.C(O)(C)C.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CN(C)C=CC(=O)c1ccc(Br)cc1
Reactant: Sc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CC=C(Sc1ccccc1)c1ccc(Br)cc1

Procedure:
By using a method similar to that described in Example 35, but starting from 1-(4-bromophenyl)-3-dimethylamino-2-propen-1-one (10 g), phosphorus oxychloride (3.64 g), thiophenol (4.2 cc) and sodium cyanoborohydride (1.47 g), a residue is obtained which is taken up in chloroform. The solution is adjusted to pH 10 by adding a concentrated aqueous solution of sodium hydroxide. The organic phase is separated and then the aqueous phase is extracted with methylene chloride. The organic phases are collected, dried over sodium sulphate, filtered and then evaporated to dryness under reduced pressure (2.6 kPa) at 30° C. to give a residue which is dissolved in isopropanol (30 cc). A 3N ether solution (13 cc) of hydrochloric acid gas is added to the solution obtained. The white solid which precipitates is separated off by filtration and recrystallised twice from isopropanol (40 cc). In this way 3-(4-bromophenyl)-1-dimethylamino-3-phenylthio-2-propene (E) hydrochloride (4.8 g) is obtained in the form of white crystals melting at 187° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:16]3)[C:12]3[CH:11]=[CH:10][S:9][C:8]=3[NH:7][C:6]=2[CH:26]=1.C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:29])[C@@H:17]([CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:16]3)[C:12]3[CH:11]=[CH:10][S:9][C:8]=3[NH:7][C:6]=2[CH:26]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sccc32)CCN1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sccc32)CCN1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.1 %

Procedure:
Combine (S)-6-fluoro-10-[3-(3-methoxy-propyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (220.1 mg, 0.59 mmol), formaldehyde (52.5 μL, 0.64 mmol, 37% in water), and dichloromethane (8.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (186.8 mg, 6.88 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (90:10) to give 195.1 mg (86%) of the title compound: mass spectrum (ion spray): m/z=389.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][C:22]4[N:23]3[CH2:26][CH2:27][N:28]=4)=[CH:18][C:17]=2[O:29][CH3:30])[C@@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.[ClH:37].Cl.COC1C=C2C(=CC=1CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)N1N=NN=C1CC2>>[ClH:37].[ClH:37].[ClH:37].[CH3:30][O:29][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[N:23]1[CH2:26][CH2:27][N:28]=[C:22]1[CH2:21][CH2:20]2
Reactant: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)N1CCN=C1CC2
Agent: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)-n1nnnc1CC2
Agent: Cl
Product: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)N1CCN=C1CC2

Procedure:
This compound was prepared from Compound 16 in the same manner of Compound 8.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[CH2:2][C:1]#[N:3])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CC#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCC(O)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of acetonitrile (1.05 mL, 20 mmol) in anhydrous THF (25 mL) under argon, was added lithium diisopropylamide (11 mL of a 2 M solution in THF, 22 mmol) dropwise. The resulting mixture was stirred at −78° C. for 15 min. A solution of 3-bromobenzaldehyde (7) (2.78 g, 15 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature, then concentrated under reduced pressure and diluted with EtOAc (75 mL). The solution was washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (20 to 100% EtOAc-hexanes gradient) gave 3-(3-bromophenyl)-3-hydroxypropanenitrile (120) as a light yellow oil. Yield (2.75 g, 81%): 1H NMR (400 MHz, DMSO-d6) δ 7.60 (t, J=1.6 Hz, 1H), 7.46 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 7.40 (dd, J=7.6, 2.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 6.05 (d, J=4.8 Hz, 1H), 2.94-2.80 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[C:9]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=1)#[N:2]>CO.[Pd]>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[C:9]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[N:12][CH:13]=1)#[N:2]
Reactant: COC(=O)c1cc(C(=O)OC)c(C#CCCCC#N)cn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(C(=O)OC)c(CCCCCC#N)cn1
Reaction time: 4 h

Procedure:
64 mg of dimethyl 5-(5-cyano-1-pentinyl)-pyridine-2,4 -dicarboxylate (from Example 11) are dissolved in 25 ml of methanol and, after addition of the palladium catalyst (10% strength on charcoal), are hydrogenated The reaction has ended after 4 hours (thin layer control). The catalyst is filtered off and the solution is concentrated in vacuo. The colorless oil is chromatographed on silica gel.
Reaction SMILES: [C:1]1([CH3:12])[C:2](S(OC)(=O)=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:13][C:14](C)([O-:16])[CH3:15].[K+]>C1(C)C=CC=CC=1>[CH2:12]([O:16][CH:14]([CH3:15])[CH3:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COS(=O)(=O)c1ccccc1C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,3-diPEGoxy-2-benzyloxypropane [MW poly(ethylene glycol) (PEG)=9 kDa] (5.0 g, 0.55 mmoles) from Step A was placed in a two-necked round bottom flask and dissolved in 150 ml of toluene. The flask was fitted with a septum and a Dean-Stark trap and the compound was azeotropically dried under an inert atmosphere. The trap was replaced with a reflux condenser and the temperature of the flask was kept at 45° C. by placing the flask in a constant temperature oil bath. Methyl toluenesulfonate (1.62 ml, 5.4 mmoles) and 2.8 ml of potassium t-butoxide solution (1.0 M in THF) was added and the reaction stirred for 3 hours. Methyl toluenesulfonate (0.81 ml) and 1.4 ml of potassium t-butoxide solution were then added and the reaction was stirred for an additional 3 hours. The flask was removed from the oil bath and cooled to room temperature. The solution was transferred to a single-necked round bottom flask and the solvent was removed by rotary evaporation. The residue was dissolved in 5 ml of methylene chloride and precipitated by the addition of 50 ml of diethyl ether. The product was collected by filtration and dried under vacuum.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[C:5]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:4]=1[N+:15]([O-:17])=[O:16].[CH3:18][O-:19].[Na+]>CO>[CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:19][CH3:18])[CH:6]=[C:5]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: CNc1cc(Cl)cc(NCCOC)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1cc(OC)cc(NCCOC)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
0.019 mole (5 g) of 2-methylamino-6-(β-methoxyethyl)amino-4-chloronitrobenzene was refluxed with 35 ml of 26% sodium methylate in methanol for 45 minutes then diluted with 100 ml of ice water to precipitate the desired product. Following filtering, water washing and drying under vacuum in the presence of P2O5, the product obtained was recrystallized from isopropanol. It melted at 84° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:20])([CH3:19])[C:7](=[O:18])[CH:8](Br)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+].O.O.O.O.O.O.O.O.[C:40]1([S:54]([OH:57])(=[O:56])=[O:55])[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([S:50]([OH:53])(=[O:52])=[O:51])[C:44]=2[CH:43]=[CH:42][CH:41]=1>CC(C)=O>[C:40]1([S:54]([OH:57])(=[O:56])=[O:55])[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([S:50]([OH:53])(=[O:52])=[O:51])[C:44]=2[CH:43]=[CH:42][CH:41]=1.[C:1]([O:4][CH2:5][C:6]([CH3:20])([CH3:19])[C:7](=[O:18])[CH:8]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 70.3 %

Procedure:
A solution of 36.3 g (0.2 mol) of crude 4-acetoxy-1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one in 50 ml of acetone was added dropwise, at the boil, to a suspension of 21 g (0.3 mol) of 1,2,4-triazole and 30g (0.2 mol) of potassium carbonate in 200 ml of acetone. After heating for 15 hours under reflux, the mixture was filtered and the filtrate was concentrated by distilling off the solvent in vacuo. The residue was taken up in 200 ml of methylene chloride and the solution was washed three times with 50 ml of water at a time, dried over sodium sulphate and concentrated. The residue was dissolved in 100 ml of acetone and 36 g (0.1 mol) of 1,5-naphthalenedisulphonic acid octahydrate in 100 ml of acetone were added. The crystalline precipitate which resulted was filtered off and dried. 45 g (45% of theory) of 4-acetoxy-1-(4-chloro-phenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one 1,5-naphthalenedisulphonate of melting point 155°-160° C. were obtained.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([NH2:26])=[C:22]4[O:27][C:28](Cl)=[CH:29][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F:31][C:32]1[CH:33]=[C:34]([C:38]2[CH:46]=[CH:45][C:41]3[CH:42]=[N:43][S:44][C:40]=3[C:39]=2B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:36][CH:37]=1>>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:18]2[CH:17]=[N:16][N:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([OH:8])[CH2:10][CH2:11]3)[CH:19]=2)=[C:21]2[CH:29]=[C:28]([C:39]3[C:40]4[S:44][N:43]=[CH:42][C:41]=4[CH:45]=[CH:46][C:38]=3[C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([F:31])[CH:33]=3)[O:27][C:22]=12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: CC1(C)OB(c2c(-c3cccc(F)c3)ccc3cnsc23)OC1(C)C
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3c(-c4cccc(F)c4)ccc4cnsc34)oc12

Procedure:
The title compound was prepared from 4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]-2-chlorofuro[2,3-c]pyridin-7-amine and 6-(3-fluorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-benzothiazole by a procedure analogous to Example 229. 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 8.55 (d, J=7.58 Hz, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.97 (s, 1H), 7.79 (d, J=7.83 Hz, 1H), 7.59-7.72 (m, 3H), 7.34-7.43 (m, 1H), 6.34 (br s, 2H), 4.70 (d, J=4.29 Hz, 1H), 4.21 (tt, J=3.98, 11.56 Hz, 1H), 3.49-3.60 (m, 1H), 2.09 (br d, J=12.40 Hz, 2H), 1.83-2.02 (m, 4H), 1.33-1.46 (m, 2H); MS (ESI): 526.08 [M+H]+; HPLC tR=2.37 min (ZQ3: nonpolar—4 min).
Reaction SMILES: Cl.[CH:2]([C:5]1[S:9][C:8]([NH:10][S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH:18]([NH2:23])[CH2:17]3)(=[O:13])=[O:12])=[N:7][N:6]=1)([CH3:4])[CH3:3].CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([O:55][C:56]1[CH:64]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:62]=[CH:61][C:57]=1[C:58](O)=[O:59])[CH3:54]>C(N(CC)CC)C>[CH2:53]([O:55][C:56]1[CH:64]=[C:63]([C:65]([F:66])([F:67])[F:68])[CH:62]=[CH:61][C:57]=1[C:58]([NH:23][CH:18]1[CH2:17][C:16]2[C:20](=[CH:21][CH:22]=[C:14]([S:11](=[O:13])(=[O:12])[NH:10][C:8]3[S:9][C:5]([CH:2]([CH3:4])[CH3:3])=[N:6][N:7]=3)[CH:15]=2)[CH2:19]1)=[O:59])[CH3:54]
Reactant: CC(C)c1nnc(NS(=O)(=O)c2ccc3c(c2)CC(N)C3)s1
Reactant: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)NC1Cc2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2C1
Temperature: 25 °C

Procedure:
The mixture of 2-amino-indan-5-sulfonic acid (5-isopropyl-[1,3,4]thiadiazol-2-yl)-amide hydrochloride (40 mg), 1.5 ml of dimethyl formamide, 0.037 ml of triethylamine, 41 mg of HATU and 25 mg of 2-ethoxi-4-trifluoromethyl-benzoic acid was stirred at room temperature over night. The solvents were evaporated in vacuo and the resulting crude material was purified by column chromatography (silica gel, eluent: dichloromethane:methanol=95:5).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5])[CH3:2].[Br:11]N1C(=O)CCC1=O.[Na+].[Cl-]>CN(C=O)C>[Br:11][C:8]1[CH:7]=[C:6]([CH3:10])[C:4]([NH2:5])=[C:3]([CH2:1][CH3:2])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccc(C)c1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)cc(C)c1N
Yield: 100.6 %

Procedure:
To a solution of 2-ethyl-6-methylaniline (2.03 g, 15 mmol) in DMF (50 mL) at 0° C. was added N-bromosuccinimide (2.66 g, 14.9 mmol). The mixture was stirred at room temperature for 10 minutes before addition to saturated aqueous NaCl. The mixture was extracted with EtOAc, the organic phase was washed with sat aqueous NaCl (2×), concentrated and the crude material was purified by Biotage chromatography (40M, 15% EtOAc/heptane) to provide 4-bromo-2-ethyl-6-methylbenzenamine as a red brown liquid (3.21 g, 100%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+]=[N-].C1COCC1.CP(C)C.O>C(Cl)Cl>[NH2:1][CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CP(C)C
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A solution of 7-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.23 g, 4.65 mmol) in THF (33 mL, 410 mmol) was cooled to 0° C. and treated dropwise with a 1.0 M solution of trimethylphosphine in THF (9.3 mL, 9.3 mmol). The cold bath was removed and the reaction mixture was allowed to warm to RT with stirring for 1 h; no starting material remained by HPLC. At 1.5 h, water (4.3 mL, 240 mmol) was added and the reaction mixture was stirred for 1 h 15 min; TLC indicated one product. The reaction mixture was concentrated in vacuo to afford a light orange paste. The residue was diluted with CH2Cl2 (120 mL) and washed with water (2×40 mL) and brine (1×40 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford an orange oil. Purification by column chromatography (2×22 cm silica; 0-5% 7 N NH3 in CH3OH/CH2Cl2) afforded the title compound (1.97 g, 53% over 3 steps) as a colorless foam: MS (ESI+) for C24H31N5O4 m/z 454.3 (M+H)+; HPLC purity>95% (ret. time, 2.541 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH:24][C:18]([C@@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[O:20]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: Nc1c(F)cccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (200 mg, 721 μmol, Eq: 1.00) and 2,6-difluoroaniline (121 mg, 101 μL, 938 μmol, Eq: 1.3) in pyridine (2 mL) at 0° C. was added dropwise phosphorus oxychloride (166 mg, 101 μL, 1.08 mmol, Eq: 1.5). The cooling bath was removed and the reaction stirred at RT overnight. The reaction mixture was concentrated in vacuo and water was added to the residue. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with 0.1 M HCl, 0.1 M NaOH, and brine and concentrated in vacuo. The crude material was purified by flash chromatography to give (S)-tert-butyl 3-(2,6-difluorophenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a colorless oil (90 mg), m/z=411 (M+Na).