Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:7][CH2:6]1)=[O:4].[CH3:14][Mg]Br.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[F:13][C:2]([F:1])([F:12])[C:3]([C:5]1([S:8]([NH2:11])(=[O:9])=[O:10])[CH2:7][CH2:6]1)([OH:4])[CH3:14]
Reactant: NS(=O)(=O)C1(C(=O)C(F)(F)F)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(C(F)(F)F)C1(S(N)(=O)=O)CC1
Reaction time: 4 h

Procedure:
Under inert gas, 250 mg 1-(2,2,2-trifluoroacetyl)cyclopropanesulfonamide were initially charged in 6 ml of THF and then, at a temperature of −78° C., 1.15 ml of a 3.0 N methylmagnesium bromide solution in diethyl ether were added dropwise and the mixture was stirred at constant temperature for 4 hours. The reaction solution was admixed with 5 ml of a saturated aqueous ammonium chloride solution and allowed to come to room temperature while stirring. After adjustment to pH 5 with 2 N aqueous hydrochloric acid, the mixture was extracted with 10 ml of ethyl acetate, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (208 mg) with a molecular weight of 233.2 g/mol (C6H10F3NO3S); MS (ESI): m/e=234 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4].Br[C:15]1[C:28]2[C:19](=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=[N:21]3)[N:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].CO>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[C:28]3[C:19](=[C:20]4[C:25](=[CH:26][CH:27]=3)[C:24]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][CH:22]=[N:21]4)[N:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCc1ccc(B(O)O)cc1
Reactant: Brc1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CCCc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Temperature: 100 °C

Procedure:
4-(3-Butenyl)phenylboronic acid is made by the method of Nakashima and Irie (Nakashima, H.; Irie, M. Macromol. Chem. Phys. 200, 683-692). 4-(3-butenyl)phenylboronic acid (0.44 g) and a solution of Pd(Ph3)4 (58 mg) in 5 mL of degassed toluene is placed in a 50 mL Schlenk tube. The mixture is purged with nitrogen, after which a solution of 4-bromo-7-phenyl-1,10-phenanthroline (0.670 g) and Na2CO3 (428 mg, 4 mmol) in 5 mL of degassed 4:1H2O/CH3OH is added. The mixture is heated under nitrogen at 100° C. with rapid stirring until TLC monitoring shows the reaction to be complete (ca 24 hrs). The reaction mixture is then added to a separatory funnel and washed with ether (3×50 mL). The combined organic fractions are dried over MgSO4 and concentrated by roto-evaporation. The desired product is purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([F:16])[C:13](B(O)O)=[C:12]([F:20])[CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:22]1[S:23][C:24]([CH:27]=[CH2:28])=[CH:25][CH:26]=1>>[F:20][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)[CH:15]=[C:14]([F:16])[C:13]=1[C:22]1[S:23][C:24]([CH:27]=[CH2:28])=[CH:25][CH:26]=1
Reactant: CCCc1ccc(-c2cc(F)c(B(O)O)c(F)c2)cc1
Reactant: C=Cc1ccc(Br)s1
Product: C=Cc1ccc(-c2c(F)cc(-c3ccc(CCC)cc3)cc2F)s1

Procedure:
The compound 2-(3,5-difluoro-4′-propylbiphenyl-4-yl)-5-vinylthiophene (PUS-3-V) is prepared analogously to Example 3 from 4′-propyl-3,5-difluoro-4-biphenylboronic acid and 2-bromo-5-vinylthiophene.
Reaction SMILES: [OH-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([NH:19][C:20]3[CH:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[O:18])=[C:15]([OH:38])[CH:14]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]>CO.O1CCOCC1>[C:3]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:37]=[CH:36][C:16]([C:17]([NH:19][C:20]3[CH:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[O:18])=[C:15]([OH:38])[CH:14]=2)[CH2:10][CH2:11]1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCN(C(C)=O)CC2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)N1CCC(Oc2ccc(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c(O)c2)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.082 mL) was added to a solution mixture of the obtained methyl 2-(4-((1-acetylpiperidin-4-yl)oxy)-2-hydroxybenzamido)-4-phenylbenzoate (0.016 g) in methanol (0.5 mL) and dioxane (0.5 mL), followed by stirring at 60° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then methanol (1 mL), dioxane (1 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.082 mL) were added to the reaction mixture, followed by stirring at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. Water was added to the obtained residue, followed by adjusting the pH to 3 with 6 mol/L hydrochloric acid. The solid substance was collected from the reaction mixture by filtration to obtain 0.014 g of 2-(4-((1-acetylpiperidin-4-yl)oxy)-2-hydroxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([C:29]2[S:30][C:31]([CH3:34])=[CH:32][N:33]=2)[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:18][CH:17]=1.[CH3:35][NH:36][C:37]1[N:42]=[C:41]([CH:43](O)[CH3:44])[CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(OC)(C)C>[CH3:35][NH:36][C:37]1[N:42]=[C:41]([CH2:43][CH2:44][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][N:33]=3)[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:18][CH:17]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CNc1cccc(C(C)O)n1
Reactant: COC(=O)CC(Cc1ccc(O)cc1)c1ncc(C)s1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Product: CNc1cccc(CCOc2ccc(CC(CC(=O)OC)c3ncc(C)s3)cc2)n1
Temperature: 25 °C
Yield: 106.4 %

Procedure:
Diisopropyl azodicarboxylate (0.25 mL, 1.28 mmole) was added to a suspension of methyl (±)-4-(4-hydroxyphenyl)-3-(5-methylthiazol-2-yl)butanoate (249 mg, 0.85 mmole), 6-(methylamino)-2-pyridylethanol (194 mg, 1.28 mmole), and triphenylphosphine (336 mg, 1.28 mmole) in TBME (5 mL) at 0° C. The mixture was allowed to warm to RT as the bath warmed. After 72 hr the mixture was concentrated and the residue was chromatographed on silica gel (30% EtOAc/CHCl3). Fractions containing the product were concentrated to give the title compound (385 mg, contaminated with triphenylphosphine oxide): MS (ES) m/e 426 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:35]=[CH:36][CH:37]=3)[C:21]([N:23]3[CH2:34][CH2:33][CH2:32][C@H:24]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:22])=[CH:12][CH:11]=2)[CH:5]=[C:6]([OH:9])[C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][C:46](=[O:48])[CH3:47]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:35]=[CH:36][CH:37]=3)[C:21]([N:23]3[CH2:34][CH2:33][CH2:32][C@H:24]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:22])=[CH:12][CH:11]=2)[CH:5]=[C:6]([O:9][CH2:45][C:46](=[O:48])[CH3:47])[C:7]=1[F:8]
Reactant: CC(=O)CBr
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1cccc(COc2ccc(-c3cc(O)c(F)c(F)c3)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1cc(-c2ccc(OCc3cccc(C(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)c3)cc2)cc(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
The compound (106 mg, 0.208 mmol) of Step 1 of Example 47 was dissolved in DMF (2 mL), and potassium carbonate (57.5 mg, 0.416 mmol) and bromoacetone (0.0192 mL, 0.229 mmol) were added thereto, and stirred at room temperature for 5 hours. The solvent was distilled away under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The resultant was purified by silica gel chromatography to thus obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.Br[C:26]1[C:27]([C:32]#[N:33])=[N:28][CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CO.ClCCl.O.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:26]3[C:27](=[C:32]([NH2:33])[N:8]=[C:6]2[CH:7]=1)[N:28]=[CH:29][CH:30]=[CH:31]3
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: N#Cc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Nc1nc2cc(Cl)ccc2c2cccnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-carbamate (from step 2) (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% methanol in dichloromethane to give a semipure solid, which was then stirred in hot 10% ethyl acetate in hexane, filtered, and dried to give a pure solid. 1H NMR (acetone d-6): δ 9.03 (d, 1H), 8.93 (d, 1H), 8.46 (d, 1H), 7.85-7.88 (dd, 1H), 7.57 (s, 1H), 7.32 (d, 1H), 6.94 (br, 2H). LRMS [M+H]=230.1
Reaction SMILES: COC1C=C(N2CCC(=O)CC2)C=CC=1[N+]([O-])=O.Cl.F[C@@H]1CCNC1.[F:26][C:27]1(F)[CH2:32]C[CH2:30][N:29]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[C:41]([O:48][CH3:49])[CH:40]=3)[CH2:35][CH2:34]2)[CH2:28]1>>[F:26][C@@H:27]1[CH2:32][CH2:30][N:29]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[C:41]([O:48][CH3:49])[CH:40]=3)[CH2:35][CH2:34]2)[CH2:28]1
Reactant: COc1cc(N2CCC(N3CCCC(F)(F)C3)CC2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: F[C@@H]1CCNC1
Product: COc1cc(N2CCC(N3CC[C@@H](F)C3)CC2)ccc1[N+](=O)[O-]
Yield: 100 %

Procedure:
1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (1.0 g, 4.0 mmol) and commercially available (R)-(−)-3-fluoropyrrolidine hydrochloride were subjected to a reductive amination analogous to the procedure for 3,3-difluoro-1′-[3-(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine (Intermediate B41) to give 4-[(3R)-3-fluoro-1-pyrrolidinyl]-1-[3-(methyloxy)-4-nitrophenyl]piperidine (1.3 g, 100% yield). 1H NMR (400 MHz, d6-DMSO) δ 7.84 (d, J=9.6 Hz, 1H), 6.56 (dd, J=9.6 and 2.0 Hz, 1H), 6.47 (d, J=2.0 Hz, 1H), 5.24-5.07 (m, 1H), 3.91-3.87 (m, 5H), 3.05-2.99 (m, 2H), 2.88-2.77 (m, 2H), 2.70-2.58 (m, 1H), 2.38-2.27 (m, 2H), 2.13-2.00 (m,1H), 1.88-1.75 (m, 3H), 1.46-1.36 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.[NH2:25][N:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](/[C:22](=[N:25]/[N:26]3[CH2:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])/[CH3:23])[N:20]=2)[N:15]=[N:14]1
Reactant: NN1CC(=O)NC1=O
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Product: C/C(=N\N1CC(=O)NC1=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 71.5 %

Procedure:
The title compound (18.0 mg, 66%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (20.0 mg, 0.06 mmol) and 1-amino-imidazolidine-2,4-dione (28.2 mg, 0.19 mmol) using the same procedure as described in the synthesis of example 72. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.45 (bs, 1H), 9.41 (s, 1H), 8.93 (dd, 1H), 8.42 (d, 1H), 8.21 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.26 (s, 2H), 4.56 (s, 2H), 2.45 (s, 3H). LCMS (method B): [MH]+=420, tR=1.95 min.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[N:12]([CH:5]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:4][OH:3])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Reaction time: 2 h

Procedure:
The solution of 5.0 g (12.6 mmol) [2-(4-chloro-phenyl)-benzoimidazol-1-yl]-cyclohexyl-acetic acid ethyl ester in 75 mL dry tetrahydrofuran was cooled to 0° C. and 0.5 g (13.3 mmol) lithium aluminium hydride were added. The cooling bath was removed and stirring was continued for 2 h at room temperature. The reaction was poured on 300 mL 10% aqueous sodium-potassium-tartrate solution and 300 mL ethyl acetate. The phases were separated and the aqueous layer extracted with 300 mL ethyl acetate. The combined organic layers were washed with 300 mL brine, dried over magnesium sulfate, filtered and evaporated to give the desired compound as a white foam which was pure enough for the next step. MS (Turbo Spray): m/z=355.2 [M+H].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:9][C:10](=[O:45])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:28]3[C:27](=[O:29])[N:26]([CH2:30][CH2:31][C:32](O)=[O:33])[CH2:25][C:24]([CH3:36])([CH3:35])[O:23][C:22]=3[N:21]=[C:20]([N:37]3[CH2:43][CH:42]4[O:44][CH:39]([CH2:40][CH2:41]4)[CH2:38]3)[N:19]=2)=[CH:14][CH:13]=1)[CH3:8].[O-]S([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[CH2:7]([NH:9][C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:28]3[C:27](=[O:29])[N:26]([CH2:30][CH2:31][CH2:32][OH:33])[CH2:25][C:24]([CH3:36])([CH3:35])[O:23][C:22]=3[N:21]=[C:20]([N:37]3[CH2:43][CH:42]4[O:44][CH:39]([CH2:40][CH2:41]4)[CH2:38]3)[N:19]=2)=[CH:16][CH:17]=1)=[O:45])[CH3:8]
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)nc3c2C(=O)N(CCC(=O)O)CC(C)(C)O3)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)nc3c2C(=O)N(CCCO)CC(C)(C)O3)cc1
Temperature: 66 °C
Yield: 24.7 %

Procedure:
13 mg of lithium aluminium hydride (0.34 mmol) are placed in 5 ml of anhydrous THF. A solution containing 90 mg (0.17 mmol) of 3-[4-[4-(3-ethylureido)phenyl]-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-7,8-dihydro-5H-9-oxa-1,3,6-triazabenzocyclohepten-6-yl]propionic acid in 10 ml of THF is added dropwise. The reaction mixture is heated at 66° C. for 18 hours. 72 mg of lithium aluminium hydride (1.89 mmol) are added and the mixture is heated for a further 24 hours at 66° C. The medium is then cooled in an ice-water bath to 4° C. and basified with saturated aqueous Na2SO4 solution. Ethyl acetate is added and the mixture is filtered through Celite, rinsed with ethyl acetate and concentrated. The residue is chromatographed on silica gel with a gradient of MeOH containing 10% aqueous ammonia DCM ranging from 0% to 10%. The solid is rinsed with acetonitrile and then with pentane to give 22 mg of 1-ethyl-3-{4-[6-(3-hydroxypropyl)-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]phenyl}urea.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[C:3]1=[O:21].F[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][C:24]=1[F:34].C([O-])([O-])=O.[Na+].[Na+].O>CS(C)=O>[CH2:19]([C:16]1[CH:15]=[N:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:34])[C:3]3=[O:21])[CH2:8][CH2:9]2)=[N:18][CH:17]=1)[CH3:20]
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Reactant: CCc1cnc(N2CCC(N3CC[C@H](N)C3=O)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1cnc(N2CCC(N3CC[C@H](Nc4ccc(S(=O)(=O)CC)cc4F)C3=O)CC2)nc1
Yield: 31.4 %

Procedure:
A solution of ((S)-3-amino-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (100 mg, 0.35 mmol), 1,2-difluoro-4-(ethylsulfonyl)benzene (0.2 g, 1.0 mmol), and Na2CO3 (110 mg, 1.0 mmol) in DMSO (2 mL) was stirred at 130° C. for 18 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified over silica gel (10% methanol in EtOAc) to yield (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(4-(ethylsulfonyl)-2-fluorophenylamino)pyrrolidin-2-one (50 mg, 0.11 mmol, 30%). Mass spectrum (apci) m/z=476.3 (M+H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11]([OH:20])=[CH:12][C:13]([OH:19])=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:19][C:13]1[CH:12]=[C:11]([O:20][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([Cl:9])=[CH:15][C:14]=1[C:16](=[O:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(Cl)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 8 h
Yield: 90 %

Procedure:
Benzyl bromide (30 mL) was added to a mixture of 1-(5-chloro-2,4-dihydroxy-phenyl)-ethanone (20 g, 0.107 moles) and potassium carbonate (37 g, 2.5 equiv) in acetonitrile (350 mL). The mixture was heated at reflux for 6 hours then allowed to cool and stirred overnight. The mixture was filtered and the solids were washed with dichloromethane (3×100 mL). The combined organic extracts were evaporated in vacuo to leave a pale yellow solid which was triturated with a mixture of hexane (350 mL)/ethyl acetate (15 mL) and filtered to give an off-white solid, 1-(2,4-bis-benzyloxy-5-chloro-phenyl)-ethanone (35.4 g, 90%). 1H NMR (400 MHz) consistent with structure.
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[CH:12]=[CH:11][C:8](C#N)=[C:7]([CH3:13])[CH:6]=1.Cl.C([O:17][CH2:18][CH3:19])C>>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([C:18](=[O:17])[CH3:19])=[C:7]([CH3:13])[CH:6]=1
Reactant: Cc1cc(Cl)ccc1C#N
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Product: CC(=O)c1ccc(Cl)cc1C
Temperature: 40 °C

Procedure:
Methylmagnesium bromide (6.29 g, 52.8 mmol) was added to a stirred solution of 4-chloro-2-methyl-benzonitrile (5.00 g, 33.0 mmol) in diethyl ether (44 mL). The mixture was heated to 40° C. After 72 h the mixture was cooled to room temperature and poured into a stirred mixture of anhydrous diethyl ether (120 mL), ice water (100 mL), and 10% aqueous HCl (100 mL). The aqueous layer was separated, stirred at reflux for 1 h, then was cooled to room temperature and was extracted into diethyl ether (4×50 mL). The organic layers were combined, washed with saturated NaHCO3 and brine, dried (Na2SO4) and concentrated in vacuo. 1-(4-Chloro-2-methylphenyl)ethanone was obtained as an oil. 1H NMR (CDCl3, 400 MHz) δ 2.52 (s, 3H), 2.56 (d, J=0.7 Hz, 3H), 7.24 (m, 2H), 7.65 (d, J=8.8 Hz, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH3:10])[C:5](=O)[N:6]([CH3:8])[CH3:7])[CH:2]=[CH2:3].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:4]([CH3:10])[C:5]([N:6]([CH3:8])[CH3:7])=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: Nc1ccccc1N1CCOCC1
Reactant: C=CCN(C)C(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: C=CCN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of 3-allyl-1,1,3-trimethylurea (7.17 g) in benzene (50 ml) with 4-(2-aminophenyl)morpholine (6 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.71 ml) for 45 hours at 70° C. gave 1-allyl-2-(2-morpholinophenyl)-1,3,3-trimethylguanidine (bp. 148°-150° C. at 0.2 mm Hg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:21]1[C:22]([C:32]#[N:33])=[N:23][N:24]([CH3:31])[C:25]=1[CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]1[N:24]([CH3:31])[N:23]=[C:22]2[C:21]=1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:2]=[C:32]2[NH2:33]
Reactant: Cn1nc(C#N)c(Br)c1CCCCCl
Reactant: Nc1ccccc1B(O)O
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cn1nc2c(N)nc3ccccc3c2c1CCCCCl
Temperature: 110 °C
Yield: 13.1 %

Procedure:
2-Aminophenylboronic acid hydrochloride (9.20 g, 53.0 mmol), potassium phosphate (28.0 g, 133 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (685 mg, 0.662 mmol), and bis[(2-diphenylphosphino)phenyl]ether (428 mg, 0.795 mmol) were added to a mixture of 4-bromo-5-(4-chlorobutyl)-1-methyl-1H-pyrazole-3-carbonitrile (7.30 g, 26.5 mmol) and powdered molecular sieves (1 g) in toluene (165 mL). Nitrogen was bubbled through the reaction mixture, and then the reaction was heated at 110° C. for 24 hours. The mixture was filtered through a layer of silica gel (eluting with 3:2 chloroform/methanol). The filtrate was concentrated under reduced pressure and dissolved in ethanol (130 mL). Hydrogen chloride (20 mL of a 4 M solution in ethanol) was added to the solution and the reaction was heated at reflux for two hours and allowed to cool to ambient temperature. The reaction was worked up as described in Part F of Example 19. After purification by chromatography on a HORIZON HPFC system, the solid was stirred in acetonitrile and filtered to provide 1.0 g of 1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine that was used in the next step. The filtrate was concentrated to provide an additional 4.0 g of product.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:7]([NH:17][C@H:18]([C:21](O)=[O:22])[CH2:19][OH:20])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C=O>[C:11]1([CH2:10][O:9][C:7](=[O:8])[NH:17][C@@H:18]([CH2:21][OH:22])[C:19](=[O:20])[NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nn1cccc1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(N[C@@H](CO)C(=O)Nn1cccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of 1-aminopyrrole (3.28 g) and carbobenzyloxy-L-serine (9.57 g) in 100 ml of dry DCM and 10 ml of dry dimethylformamide was added DCC (10.0 g) at 0° C. After 10 minutes the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The precipitate was filtered and stirred in boiling ethyl acetate. The mixture was filtered and the filtrate was combined with the filtrate of the reaction mixture and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, DCM/methanol 20:1). The appropriate fractions were concentrated and the residue recrystallized from ethyl acetate to afford 7.48 g of the product as crystals, m.p. 163°-164° C.