Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][N:15]=2)[C@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CC(N(C)C)=O.[Br:44][C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][C:46]=1[F:52].C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:21])[NH:49][C:48]3[CH:50]=[CH:51][C:45]([Br:44])=[C:46]([F:52])[CH:47]=3)=[CH:16][N:15]=2)[C@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)O)cn1
Reactant: Nc1ccc(Br)c(F)c1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2ccc(Br)c(F)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
A solution of (R)-4-(5-carboxy-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.47 mmol, Preparation 33), EDC (130 mg, 0.70 mmol), and HOAt (95 mg, 0.70 mmol) dissolved in DMA (4.3 mL, 47 mmol) was stirred at RT for 30 min and then 4-bromo-3-fluoroaniline (89 mg, 0.47 mmol) was added, followed by N,N-diisopropylethylamine (0.2 mL, 1.2 mmol). The reaction mixture was stirred at RT overnight and extracted with ethyl acetate/water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted: 0-40% EtOAc:hexanes) to provide the title compound as a light yellow oil (100 mg, 40% yield). (m/z): [M+H]+ calcd for C22H26BrFN4O3 493.12 found 493.2.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]23[O:21][CH:20]2[CH:19]2[CH2:22][CH2:23][CH:16]3[CH2:17][CH2:18]2)=[O:14])=[CH:8][C:7]=1[C:24]([F:27])([F:26])[F:25])([O-:5])=[O:4].C1(P([NH:42]O)(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:13]([C:15]23[O:21][CH:20]2[CH:19]2[CH2:18][CH2:17][CH:16]3[CH2:23][CH2:22]2)=[O:14])[NH2:42])=[CH:8][C:7]=1[C:24]([F:27])([F:25])[F:26])([O-:5])=[O:4]
Reactant: O=P(NO)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)C12OC1C1CCC2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NN(C(=O)C12OC1C1CCC2CC1)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
NaH (60% in mineral oil, 7.9 mg, 0.20 mmol, 1.4 eq) was added to the solution of 11E (50 mg, 0.14 mmol, 1 eq) in DMF (3 mL). The reaction mixture was heated at 70° C. for 2 h. The reaction was cooled to rt and diphenylphosphinylhydroxylamine (52 mg, 0.22 mmol, 1.6 eq, made according to the procedure of Colvin, E. W. et. al. Tetrahedron Lett. 23, 3835-6 (1982)) was added. The reaction mixture was stirred at rt overnight and quenched by addition of water (3 mL) and extracted with EtOAc (2×20 mL). The combined organics were washed with H2O (25 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 10% EtOAc/CH2Cl2 gave 8.0 mg (0.022 mmol, 15.4%) of compound 11F as a yellow solid. HPLC conditions: 93% at 3.54 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2% H3PO4, detecting at 220 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH2:20]O)[CH:17]=[C:16]([Cl:22])[C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:24][CH2:20][C:18]1[CH:19]=[C:2]([Cl:1])[C:3]([O:4][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])=[C:16]([Cl:22])[CH:17]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)C(Oc1c(Cl)cc(CO)cc1Cl)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(Oc1c(Cl)cc(CBr)cc1Cl)c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred and cooled (0° C.) solution of 0.140 g (0.41 mmol) of the product of Step D dissolved in 2 mL of CH2Cl2 was added 0. 170 g (0.51 mmol) of carbon tetrabromide and 0.135 g (0.51 mmol) of triphenylphosphine. After the addition the reaction mixture was allowed to warm to room temperature and was stirred overnight. The mixture was then evaporated in vacuo and purified on a silica gel flash chromatography of the product of Step D dissolved in 2 mL of CH2Cl2 was added 0. 170 g the title compound.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH2:9]=[O:10]>C(N(CC)CC)C>[OH:10][CH2:9][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: C=O
Reactant: CCOP([O-])OCC
Solvent: CCN(CC)CC
Product: CCOP(=O)(CO)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a 2 liter, round bottomed flask fitted with a nitrogen inlet were added 500 grams (3.6 mole) of diethyl phosphite (Aldrich), 120 grams (3.8 mole) of paraformaldehyde (Baker) and approximately 6 milliliters of triethylamine. The mixture was stirred overnight at room temperature but no visible reaction had occurred so approximately 10 milliliters more of triethylamine was added and the mixture was slowly warmed to 90° C. The solution was heated for approximately an additional hour, filtered hot and distilled. 320 grams of liquid product corresponding to a 60% yield was obtained.
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1.C(Br)C1C=CC=CC=1.C(OC(=O)C(C)(C)CSC1SC(N)=NC=1)C>>[CH2:4]([O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1)[C:3]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:2]=1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: BrCc1ccccc1
Agent: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Product: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using benzyl bromide and 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1.[C:25]([C@:27]1([OH:34])[CH2:31][CH2:30][N:29]([CH3:32])[C:28]1=[O:33])#[CH:26]>>[OH:34][C@@:27]1([C:25]#[C:26][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:24]=2)[CH2:31][CH2:30][N:29]([CH3:32])[C:28]1=[O:33]
Reactant: CC(C)NC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CC(C)NC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Yield: 12.2 %

Procedure:
10-bromo-2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-3-carboxyl is acid was reacted with 2-aminopropane similarly to as described in example 2 with non-critical modifications to afford 112 mg (67%) 10-bromo-N3-isopropyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide. 10-bromo-N3-isopropyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 16 mg (12.2%) 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-N3-isopropyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.
Reaction SMILES: [C:1]([CH:5]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[C:24]3=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]3[N:22]=[C:21]2[CH2:31][CH3:32])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O:3]C)=[O:2].[OH-].[Na+]>CO>[C:1]([CH:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][N:20]2[C:24]3=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]3[N:22]=[C:21]2[CH2:31][CH3:32])=[CH:17][CH:18]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC(C(=O)OC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC(C(=O)O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 0.45 g of the product of Step A dissolved in 5.0 mL methanol, was added 3.0 mL of 3N NaOH solution, and the mixture was stirred for 30 minutes. The methanol was removed in vacuo and the water was removed by azeotropic distillation with toluene. The o toluene was removed in vacuo, then the product was redissolved in CHCl3 and excess NaOH was removed by filtration of the suspension through a celite pad. The filtrate was concentrated to a clear oil and purified on a silica gel flash chromatography column eluted with CHCl3 /MeOH/NH4OH (80:15:1). The product fractions were combined and concentrated. The resultant oil was triturated with ether to yield 396 mg (91%) of the title compound as a white powder.
Reaction SMILES: C([Li])CCC.[CH:6]([N:9]([CH:13]([CH3:15])[CH3:14])[CH2:10][C:11]#[CH:12])([CH3:8])[CH3:7].[C:16](=[O:18])=[O:17].O>CCCCCC.O1CCCC1.CO>[CH:6]([N:9]([CH:13]([CH3:15])[CH3:14])[CH2:10][C:11]#[C:12][C:16]([OH:18])=[O:17])([CH3:8])[CH3:7]
Reactant: O=C=O
Reactant: C#CCN(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)N(CC#CC(=O)O)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium in hexane (28.8 mL, 2.5 M in n-hexane) was slowly added to diisopropyl-prop-2-ynyl-amine (10.0 g, 72 mmol) in 70 mL of tetrahydrofuran under nitrogen. The mixture was stirred for 1 hr at −78° C., then dry carbon dioxide was passed through overnight. The resulting solution was poured into water and washed with ethyl acetate. The aqueous layer was evaporated under reduced pressure to give the crude acid. The dry acid was dissolved in methanol, and the insoluble salt was removed via filtration. The filtrate was collected and dried in vacuo to give 11 g of 4-diisopropylamino-but-2-ynoic acid: mass spectrum (m/e): M−H 182.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc([N+](=O)[O-])ccc21
Product: CC1c2ccc([N+](=O)[O-])cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C1COCC1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:28])[C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(OCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)OCCCCCCOC(=O)c2ccc(N)cc2)cc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
40.1 g 6-[(4-nitrobenzoyl)oxy]hexyl 4-nitrobenzoate (96.3 mM) were suspended in 300 ml of ethyl acetate and 300 ml of THF and 4.0 g of palladium on charcoal (10%) were added. The resulting mixture was hydrogenated at atmospheric pressure until the theoretical amount of hydrogen was consumed. The mixture was then filtered, the cake was washed with DMF and the filtrate was evaporated. The residue was suspended in 200 of cyclohexane. It was stirred for 30 min. and then the solids were filtered off, washed with cyclohexane and dried to give 33.2 g (93.1 mM, 97%) of 6-[(4-aminobenzoyl)oxy]hexyl 4-aminobenzoate as beige crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([OH:17])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)[CH:7]=1.C[O-].[Na+].[NH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C1(C)C=CC=CC=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([OH:17])=[C:6]([C:8](=[N:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: NCCC(=O)O
Reactant: Cc1cc(Cl)cc(C(=O)c2ccc(Cl)cc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(Cl)cc(C(=NCCC(=O)O)c2ccc(Cl)cc2)c1O

Procedure:
(5-Chloro-2-hydroxy-3-methylphenyl)-(4-chlorophenyl)-methanone (98.4 g, 0.35 mol), sodium methoxide (19 g, 0.35 mol) and β-alanine (31.2 g, 0.35 mol) are added to 2 liters of toluene and 0.5 liters of methanol. The mixture is heated gradually and the ternary azeotrope (62° C.) is distilled. After a Dean-Stark apparatus has been fitted, the residue is heated at the reflux temperature of toluene for 6 hours. The mixture is then evaporated to dryness in vacuo. The solid residue is triturated with diethyl ether and filtered off. The solid is dissolved in 1.5 liters of water. The aqueous solution is acidified by the addition of citric acid to pH 4. The solid obtained is filtered off and then dissolved in CHCl3. The chloroform solution is dried (MgSO4) and then evaporated in vacuo. The solid obtained is triturated in petroleum ether, filtered off and dried. This gives the desired acid product, melting at 137.5°-138° C.
Reaction SMILES: ClC1C=CC=CC=1C(C1C=CC(F)=CC=1)O[CH2:6][CH2:7][NH:8]C(=O)C.FC1C=CC(C(C2C=CC(F)=CC=2)OCCNC(=O)C)=CC=1.[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49].Cl>>[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49].[CH2:7]([NH2:8])[CH3:6]
Reactant: CC(=O)NCCOC(c1ccc(F)cc1)c1ccccc1Cl
Agent: CC(=O)NCCOC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Product: CCN

Procedure:
Using the procedure described in Example IV but substituting an equivalent amount of N-{-2-[0-chloro-α-(p-fluorophenyl)benzyloxy]ethyl}acetamide for the N-{2-[bis(p-fluorophenyl)methoxy]ethyl}acetamide and maleic acid for the hydrogen chloride, there is obtained 2-[ 0 -chloro-α-(p-fluorophenyl)benzyloxy]ethylamine hydrogen maleate, which is crystallised from ethanol. Its melting point is 123°-123.5° C.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:14])[CH:4]=1)=O.[CH:15](C1C=CC(C(O)=O)=C(C)C=1)=O.OS(O)(=O)=O>CCO>[CH3:14][C:5]1[CH:4]=[C:3]([CH:1]=[CH2:15])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Cc1cc(C=O)ccc1C(=O)O
Reactant: CCOC(=O)c1ccc(C=O)cc1C
Agent: O=S(=O)(O)O
Solvent: CCO
Product: C=Cc1ccc(C(=O)OCC)c(C)c1
Temperature: 80 °C
Yield: 80 %

Procedure:
Ethyl 4-formyl-2-methylbenzoate (AI16) To a stirred solution of 4-formyl -2-methylbenzoic acid (3 g, 18.2 mmol) in EtOH (30 mL) was added H2SO4 and the reaction mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water. The combined EtOAc extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a solid (2.8 g, 80%): 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.04 (m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])[CH3:10])=[CH:4][N:3]=1.[C:21]([C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1)#[N:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:9]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])[C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:21]#[N:22])[CH:24]=2)=[O:31])[CH3:10])=[CH:4][N:3]=1
Reactant: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)c(F)c1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)Nc2cccc(C#N)c2)C(C)c2cnc(Cl)nc2)c(F)c1
Temperature: 25 °C

Procedure:
(±)-[1-(2,4-Dichloro-pyrimidin-5-yl)-ethyl]-(2-fluoro-4-methoxy-phenyl)-amine (1.15 g; 3.63 mmol) (from Example 8b supra) was combined with 3-cyanophenyl isocyanate (0.55 g; 3.81 mmol) (Aldrich) in toluene (10 mL) and heated in an oil bath at 110–115° C. for 2 hours and then up to 128° C. over the next 3 hours. Upon cooling to room temperature, the reaction was concentrated and triturated with hexanes. The crude material was purified by flash chromatography (Biotage, 40M; 50:50 ethyl acetate-hexanes) to give the intermediate (±)-1-[1-(2-chloro-pyrimidin-5-yl)-ethyl]-3-(3-cyano-pheny)-1-(2-fluoro-4-methoxy-phenyl)-urea. (Yield 1.20 g; 71.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH2:10][NH2:11].[CH2:20]1[C:22]2([CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]2)[CH2:21]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([O:12][Si:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:18][CH3:19])[CH2:10][NH:11][CH2:28][CH:25]1[CH2:26][CH2:27][C:22]2([CH2:20][CH2:21]2)[CH2:23][CH2:24]1
Reactant: CC[Si](CC)(CC)OC(CN)c1c(Cl)cccc1Cl
Reactant: O=CC1CCC2(CC1)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(CNCC1CCC2(CC1)CC2)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2,6-dichlorophenyl)-2-((triethylsilyl)oxy)ethanamine (248 mg, 0.774 mmol) in DCM (2581 μl) was added spiro[2.5]octane-6-carbaldehyde (107 mg, 0.774 mmol), AcOH (35.5 μl, 0.619 mmol) and NaBH(OAc)3 (246 mg, 1.161 mmol). The slurry mixture was stirred at room temperature for overnight. The mixture was quenched with 0.5 M NaOH and mixture was stirred at rt for 30 min. Evolution of gas was observed. The layers were separated. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in hexane to give 2-(2,6-dichlorophenyl)-N-(spiro[2.5]octan-6-ylmethyl)-2-((triethylsilyl)oxy)ethanamine
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[F:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:25]([F:24])[CH:26]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1cccc(F)c1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3cccc(F)c3)(CC1)CC2
Yield: 37 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (80.0 mg) and 3-fluoroaniline (63.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(3-fluorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (38.1 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH:12]=[CH2:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].Cl[CH2:17][CH2:18][CH:19]([CH3:23])[C:20](=[O:22])[CH3:21]>>[O:22]=[C:20]([CH3:21])[CH:19]([CH3:23])[CH2:18][CH2:17][N:4]1[C:5](=[O:14])[C:6]2[N:7]([CH2:11][CH:12]=[CH2:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:15]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(=O)C(C)CCCl
Product: C=CCn1cnc2c1c(=O)n(CCC(C)C(C)=O)c(=O)n2C

Procedure:
1-(4-Oxo-3-methylpentyl)-3-methyl-7-allylxanthine (melting point 73-74° C.) is prepared from 3-methyl-7-allylxanthine and 1-chloro-3-methylpentan-4-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8](CC2C=CC=CC=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH:10]([OH:15])[C:11]([F:13])([F:12])[F:14])[CH:5]=[CH:6][CH:7]=1
Reactant: OC(CN(Cc1ccccc1)c1cccc(F)c1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: OC(CNc1cccc(F)c1)C(F)(F)F
Yield: 98.4 %

Procedure:
EX-662A) 3-[(3-fluorophenyl)[phenylmethyl]amino]-1,1,1-trifluoro-2-propanol (2.56 g, 8.2 mmol) was dissolved in methanol (30 mL) and hydrogenated over 5% palladium on charcoal for 3 h. The mixture was filtered through celite, and the solvent was removed in vacuo to give 1.8 g (98%) of the desired 3-[(3-fluorophenyl)amino]-1,1,1-trifluoro-2-propanol product as an oil, 99% pure by HPLC analysis. MS m/z=224 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2].[NH:33]1[CH2:37][CH2:36][CH2:35][C:34]1=[O:38].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>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].O.C(O)(C)(C)C>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:33]3[CH2:37][CH2:36][CH2:35][C:34]3=[O:38])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2]
Reactant: O=C1CCCN1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)(C)O
Product: CC(=O)N1CCN(c2cc(N3CCCC3=O)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O

Procedure:
To a mixture of 1-acetyl-3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (228 mg) described in Preparation Example 234, pyrrolidin-2-one (64 mg), tripotassium phosphate (149 mg), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (52 mg) and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (24 mg) was added tert-butanol (1.5 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated and methanol (1.6 mL), 1N aqueous sodium hydroxide solution (0.75 mL) were added to the obtained crude product of 1-acetyl-3-[2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)phenyl}imidazolidin-2-one, and the mixture was stirred at 40° C. for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (69 mg).