Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.C(N1C=CN=C1)(N1C=CN=C1)=[O:16].CC(C)CCC(O)=O.NC1C(C)=CC=CC=1>ClCCl>[CH3:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:6][C:5](=[O:16])[CH2:4][CH2:3][CH:2]([CH3:14])[CH3:1]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)CCc1cc2ccccc2[nH]1
Agent: CC(C)CCC(=O)O
Solvent: ClCCl
Solvent: Cc1ccccc1N
Product: Cc1ccccc1NC(=O)CCC(C)C

Procedure:
Preparation of 2-(3-methyl-n-butyl)-indole. Carbonyldiimidazole (65 g) was mixed with 500 ml of dry dichloromethane in a 2-L round bottom flask and stirred magnetically. A solution of 4-methylvaleric acid in 200 ml of dichloromethane was added dropwise over 45 minutes and the mixture was stirred for another 1.25 hours. o-Toluidine (45 g) in 100 ml of dichloromethane was then added over about 20 minutes. After stirring for 2 hours the mixture was washed with water and then the solvent was stripped on a rotary evaporator. The residue was mixed with 150 ml of methanol and 75 ml of water and put in the freezer. Filtration of the precipitate, dilution of the filtrate with water and refiltration of the precipitate gave 75 g (94%) of vacuum dried N-(2-methylphenyl)-4-methylvaleramide which was used without further treatment in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([CH3:25])=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:26])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1>C(Cl)Cl.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([CH3:25])=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:26])[CH:11]=2)=[O:9])=[CH:27][CH:28]=1
Reactant: Cc1nc2c(cc1C#CCO)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2c(cc1CCCO)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1,7-dimethyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide (0.12 g, 0.30 mmol) in CH2Cl2 (20 mL) and MeOH (3 mL) is added 10% Pd/C (21 mg). The reaction is subjected to hydrogenation at 18 psi for 30 min. The reaction is filtered over Celite and monitored to determine the extent of the reaction. Fresh catalyst is added and the reaction is placed under hydrogen at 18 psi again. After another 30 minutes, the reaction is complete. The reaction is filtered over Celite. The filter cake is rinsed thoroughly with CH2Cl2 and MeOH. The filtrate is concentrated in vacuo and the residue is then dissolved in CH2Cl2 and adsorbed onto silica. Purification by chromatography (eluent 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 4% MeOH/CH2Cl2 (1L)) affords the desired product as a white solid (0.079 g, 0.20 mmol, 66%). Physical characteristics are as follows: m.p. 176-177° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.30, 8.98, 8.35, 7.41, 7.36, 4.59, 4.56, 4.01, 3.47, 2.82, 2.67, 1.75; IR (drift) 1658, 1609, 1556, 1531, 1503, 1458, 1420, 1357, 1333, 1260, 1095, 1056, 1017, 811, 701 cm−1; MS (ESI) m/z 400.1 (M+H)+, 398.1 (M—H)−; HRMS (FAB) calcd for C21H22ClN3O3+H1 400.1428, found 400.1434.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:22]3[S:26][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:24][CH:23]=3)[CH:13]=[C:14]([C:16]#[C:17][Si](C)(C)C)[CH:15]=2)[N:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:16]([C:14]1[CH:13]=[C:12]([C:22]2[S:26][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:24][CH:23]=2)[CH:11]=[C:10]([NH:9][C:5]2[N:4]=[C:3]([C:2]([F:32])([F:31])[F:1])[CH:8]=[CH:7][N:6]=2)[CH:15]=1)#[CH:17]
Reactant: CC(C)(O)c1ncc(-c2cc(C#C[Si](C)(C)C)cc(Nc3nccc(C(F)(F)F)n3)c2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)O)s2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
To a solution of the product of Step 2 (35 mg, 0.073 mmol) in THF (1.0 mL) was added TBAF (1.0 M in THF, 0.44 mL, 0.44 mmol) and the mixture was stirred at room temperature for 90 minutes. The mixture was concentrated in vacuo, then purified by chromatography on silica gel (80:20 to 30:70, hexanes:ethyl acetate) to provide 22 mg (0.054 mmol, 74%) of 2-[5-(3-ethynyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propan-2-ol as a white solid. MS ESI: [M+H]+ m/z 405.1. 1H NMR (400 MHz, CDCl3): δ 8.68 (d, J=4.9 Hz, 1H); 8.06 (s, 1H); 7.88 (s, 1H); 7.69-7.59 (m, 2H); 7.38 (s, 1H); 7.09 (d, J=4.9 Hz, 1H); 3.20 (s, 1H); 2.05 (s, 1H); 1.73 (s, 6H). rhSYK activity=+++
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][CH2:14][C:15]([F:18])([F:17])[F:16].[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:30]=1)[C:25](O)=[O:26]>>[C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N:13]([CH2:14][C:15]([F:16])([F:17])[F:18])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[N:30]=[C:22]([C:21]([F:36])([F:20])[F:35])[CH:23]=1
Reactant: Cc1ccccc1-c1ccncc1NCC(F)(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (4-o-tolyl-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 23 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (26%). MS (ESI): m/z=508.11 [M+H]+.
Reaction SMILES: [C:1]([CH2:6][CH:7]1[C:12](=[O:13])[CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)([O:3][CH2:4][CH3:5])=[O:2]>[Pd].C(OCC)(=O)C>[C:1]([CH2:6][CH:7]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CC1CCC(c2ccccc2)=CC1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCC(c2ccccc2)CC1=O
Yield: 70.5 %

Procedure:
6-(Carbethoxymethyl)-3-phenyl-2-cyclohexen-1-one (2.11 g) was added to a mixture of 0.2 g of 10% palladium on carbon in 30 ml of ethyl acetate. The reaction mixture was hydrogenated under a hydrogen atmosphere (maximum pressure 45 psi) for 41 hours. The mixture was filtered through celite, and the solvent was removed under reduced pressure. The recovered crude oil product was purified by chromatography on silica gel eluted with 5% ethyl acetate in hexane to provide 1.5 g (71%) of 6-(carbethoxymethyl)-3-phenylcyclohexanone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:29][CH:30]1[O:35][C:34](=[O:36])[CH2:33][C:32](=[O:37])[CH2:31]1.OC1C=C(C)OC(=O)C=1>CN(C)C1C=CN=CC=1.ClCCl>[OH:37][C:32]1[CH2:31][CH:30]([CH3:29])[O:35][C:34](=[O:36])[C:33]=1[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC1CC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1cc(O)cc(=O)o1
Solvent: ClCCl
Product: CC1CC(O)=C(C(=O)Cc2ccc([N+](=O)[O-])cc2)C(=O)O1
Reaction time: 1 h
Yield: 54.9 %

Procedure:
4-Nitrophenylacetic acid (6.7 g, 37 mmol) and then dicyclohexylcarbodiimide (8.0 g, 39 mmol) were added, at room temperature, to a dichloromethane (100 ml) suspension of 6-methyl-dihydro-2,4-pyrandione (4.73 g, 36.9 mmol) which was synthesized by the hydrogenation of 4-hydroxy-6-methyl-2-pyrone, after which 4-dimethylaminopyridine (0.23 g, 1.9 mmol) was added and stirring carried out for 1 hour and then further 4-dimethylaminopyridine (0.46 g, 3.8 mmol) added and stirring carried out for 23 hours at room temperature. The dicyclohexylurea was filtered off while the solution was still warm, then the reaction solution washed with dilute hydrochloric acid (50 ml), after which the aqueous layer was extracted with dichloromethane. After drying with anhydrous sodium sulphate, the solvent was distilled off and separation and purification performed by column chromatography. When recrystallization was performed from ethanol, 4-hydroxy-6-methyl-3-(4-nitrophenylacetyl)-5,6-dihydro-2-pyrone (5.9 g, 55%) was obtained as yellow crystals. Tetrahydrofuran (100 ml), methanol (35 ml) and concentrated hydrochloric acid (10 ml) were added to the compound (2.00 g, 6.9 mmol) obtained, then Pd-C (5%, containing 100% of water, 300 mg) added and the atmosphere replaced by hydrogen. The raw material was consumed in 4 hours and then the hydrogen replaced by argon. The precipitate was filtered off, washed with hot methanol, and the filtrate concentrated. When the solid obtained was recrystallized from ethanol, 3-(4-aminophenylacetyl)-4-hydroxy-6-methyl-5,6-dihydro-2-pyrone hydrochloride (1.43 g, 70%) was obtained. A chloroform (15 ml) solution of the compound obtained (500 mg, 1.68 mmol) was ice-cooled and 2-thiopheneacetyl chloride (0.25 ml, 2.1 mmol) added. Next, pyridine (0.41 ml, 5.4 mmol) was added and stirring carried out for 3 hours. After returning to room temperature, stirring was carried out for 15 hours, then dilute hydrochloric acid added and extraction performed with dichloromethane. The organic layer was dried with anhydrous sodium sulphate, and the solvent distilled off. When recrystallization was performed from ethanol, Compound 6 (317 mg, 49%) was obtained as pale yellow crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](=O)[C:19](O)=[O:20]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][C:19](=[O:20])[C:18]([C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)=[N:12]2)(=[O:3])=[O:4]
Reactant: O=C(O)C(=O)c1cccs1
Reactant: CS(=O)(=O)c1ccc(N)c(N)c1
Product: CS(=O)(=O)c1ccc2[nH]c(=O)c(-c3cccs3)nc2c1

Procedure:
The quinoxalin-2-one of the present example is prepared with 4-Methanesulfonyl-benzene-1,2-diamine and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-Methanesulfonyl-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[C:7](O)=[N:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[C:10]([Cl:11])[C:5]2=[N:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[N:6]2[C:7]([Cl:23])=[N:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[C:10]([Cl:11])[C:5]2=[N:4][CH:3]=1
Reactant: Oc1nc(-c2ccc(Cl)cc2Cl)c(Cl)c2ncc(Cl)n12
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2nc(Cl)n3c(Cl)cnc3c2Cl)c(Cl)c1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
200 mg (0.4 mmol) of 3,8-dichloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-ol (Example 124A) are introduced into phosphoryl chloride (2 ml), 300 mg (1.3 mmol) of benzyltriethylammonium chloride are added, and the reaction mixture is stirred at 120° C. for 12 h. The reaction mixture is slowly added, with vigorous stirring, to saturated sodium bicarbonate solution, and solid sodium bicarbonate (approx. 1.5 g) is added until a pH of 10 is reached. The mixture is stirred for 10 min, ethyl acetate (100 ml) is added and shaken, and the organic phase is separated off, washed with water and dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is purified by silica gel chromatography (cyclohexane/ethyl acetate 10:1). 150 mg (94% of theory) of the product are obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4](NC1CC1)=[O:5].[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4]([NH:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: NCCc1ccccc1
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CC[C@H](N)[C@H](O)C(=O)NCCc1ccccc1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using 2-phenylethanamine in the seventh step (step B7).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2]1.[O-:14][C:15]#[N:16].[K+].CN(C=O)C>[Br-].C([N+](CC)(CC)CC)C.O>[CH2:4]([CH:3]1[O:1][C:15](=[O:14])[NH:16][CH2:2]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: N#C[O-]
Reactant: CCCCCCCCCCC1CO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCC1CNC(=O)O1
Yield: 65.2 %

Procedure:
4.6 g of 1,2-epoxydodecane, 12.2 g of potassium cyanate, 25 ml of DMF, 0.2 g of tetraethylammonium bromide and 1.8 ml of water were stirred and heated at 120°-130° C. for 5 hours. The disappearance of the epoxide was followed by thin layer chromatography (tlc). The cooled reaction mixtre was poured into 200 ml of water and this was extracted with ethyl acetate. The combined organic extracts were washed with water, followed by brine, dried and concentrated to give a solid. Recrystallization from methylene chloride/hexane gave 3.7 g (65.2%) of product, m.p. 86°-87° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([N:15]2[N:19]=[C:18]3[C:20](Br)=[CH:21][CH:22]=[C:23](Br)[C:17]3=[N:16]2)[C:6]=1[OH:26])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([N:15]2[N:19]=[C:18]3[C:20]([C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:18]=4)=[CH:21][CH:22]=[C:23]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:17]3=[N:16]2)[C:6]=1[OH:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(-n2nc3c(Br)ccc(Br)c3n2)c(O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-n2nc3c(-c4ccccc4)ccc(-c4ccccc4)c3n2)c(O)c(C(C)(C)C)c1
Temperature: 95 °C

Procedure:
To a 40 mL glass vial, was added 4-phenylboronic acid (0.127 g, 1.04 mmol), 2,4-di-tert-butyl-6-(4,7-dibromo-benzotriazol-2-yl)-phenol (0.25 g, 0.52 mmol), toluene (0.65 mL), phase transfer catalyst (Aliquat 366®, 60% in toluene, 0.35 mL), tetrakis (triphenylphosphine) palladium in toluene (0.0104 M, 1.0 ml), and 0.8 mL of 2M degassed aqueous potassium carbonate. The vial was heated on an orbital shaker at 95° C. for 20 hours. After cooling to room temperature, methanol was added to the reaction mixture. Pale yellow crystals of product were collected after filtration and washed with DI water. Photoluminescence spectrometry of a dilute solution of the product in dichloromethane showed no visible emission.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]([C:41]#[N:42])([C:38]([OH:40])=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([C@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([C@H:50]([NH:52][C:38]([C:35]2([C:41]#[N:42])[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:37][CH2:36]2)=[O:40])[CH3:51])=[CH:46][CH:45]=1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1(C#N)CCN(C(=O)OC(C)(C)C)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.255 g, 3.30 mmol) was added in one portion to 1-(tert-butoxycarbonyl)-4-cyanopiperidine-4-carboxylic acid (Intermediate 43) (0.763 g, 3 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.462 mL, 3.00 mmol) and DIPEA (1.572 mL, 9.00 mmol) in DMA (20 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (150 mL), and washed sequentially with 1M aqueous citric acid (50 mL), water (50 mL), and saturated sodium hydrogen carbonate (100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product thus obtained was concentrated, then purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to afford (R)-tert-butyl 4-(1-(4-chlorophenyl)ethylcarbamoyl)-4-cyanopiperidine-1-carboxylate (1.100 g, 94%) as a colourless gum which solidified on drying under high vacuum. This material was then redissolved in DCM (20.00 mL), and trifluoroacetic acid (2.311 mL, 30.00 mmol) was added. The solution was stirred at room temperature for 3 hours, after which the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford (R)—N-(1-(4-chlorophenyl)ethyl)-4-cyanopiperidine-4-carboxamide (0.720 g, 82%) as a colourless gum. This material was used directly in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][C:10]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18](=[O:26])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>>[C:20]1([N:19]2[C:18](=[O:26])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:9]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccccc1
Product: O=c1c2ccccc2nc(C=Cc2ccccn2)n1-c1ccccc1
Yield: 52 %

Procedure:
The title compound was synthesized according to General Procedure B using picolinaldehyde and compound 27. After cooling, the precipitate formed was filtered off, washed with water, dried and recrystallized from ethanol to yield compound 43 (0.49 g, 52%). M. Wt. 325. LCMS [M+H]+=326.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH3:9])[N:5]=[C:4]([CH2:20][NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CC#N.C(O)(C(F)(F)F)=O>O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][N:8]([CH3:9])[C:6]2[N:7]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[N:3]=[C:4]([CH2:20][NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: CN(CCCc1ccc(F)cc1)c1nc(Cl)nc(CNCCc2ccc(O)cc2)n1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2nc(CNCCc3ccc(O)cc3)nc(N(C)CCCc3ccc(F)cc3)n2)CC1
Yield: 97 %

Procedure:
The title compound was prepared in 97% yield via the procedure outlined for Example 14 using 4-{2-[(4-chloro-6-{[3-(4-fluorophenyl)propyl]methylamino}-1,3,5-triazin-2-yl)methylamino]ethyl}phenol and 1-methypiperazine to give a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.12 (s, br, 2H), 7.06 (d, 2H, J=8.0), 6.94 (m, 2H); 6.72 (d, 2H, J=8.0), 4.88 (s, br, 1H) 3.79-3.58 (m, 9H), 3.08 (s, 3H), 3.02 (s, br, 3H), 2.78 (m, 2H), 2.60 (t, 2H, J=7.0), 2.45 (s, br, 4H), 2.34 (s, 3H), 1.88 (m, 2H); low-resolution MS (ES+) m/e 495 (MH+); RP-HPLC (Capcell Pak C-18 25 cm×4.6 mm; 0-95% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=12.04 min, 99% purity.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=4)[N:14](S(C4C=CC=CC=4)(=O)=O)[C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ncnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of Example 3D (2.6 g, 4.60 mmol) in dioxane was added 6M sodium hydroxide (7.67 mL, 46 mmol). The mixture was stirred at 100° C. for 2 hours, cooled and diluted with 50 mL ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, filtered, and concentrated to give the title compound, which was used without further purification. MS (ESI+) m/z 425.43 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:38]1[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:38]4[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-chloro-6-methylpyridazine following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 2 tR=1.163 min, m/z=464; 1H NMR (CDCl3) 1.12 (d, 6H), 1.55 (d, 3H), 2.18 (s, 2H), 2.19-2.28 (m, 2H), 2.40 (m, 1H), 2.74 (s, 3H), 2.90 (m, 1H), 5.71 (m, 1H), 6.96-7.05 (t, 2H), 7.10 (d, 2H), 7.29 (m, 2H), 7.38 (d, 2H), 7.69 (d, 1H), 7.82 (d, 2H).
Reaction SMILES: [CH:1]1([C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[CH2:9]([N:12]=[C:13]=[O:14])[CH:10]=[CH2:11]>>[CH2:9]([NH:12][C:13]([CH:5]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:8])[C:6]#[N:7])=[O:14])[CH:10]=[CH2:11]
Reactant: C=CCN=C=O
Reactant: N#CCC(=O)C1CC1
Product: C=CCNC(=O)C(C#N)C(=O)C1CC1
Yield: 79.6 %

Procedure:
When β-cyclopropyl-β-oxopropionitrile (2,.00 g, 18.3 mmoles) [prepared in Example 1, Step A]was reacted with allylisocyanate (1.60 g, 19.2 mmoles) according to the general procedure of Example 1, Sep B, the title compound (2.8 g) was obtained as a white solid after recrystallization from 30% aqueous ethanol, m.p. 72°-73.5° C.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:8])=[CH:6][CH:7]=1)=O.[CH2:9]([O:16][C:17]1[CH2:21][NH:20][C:19](=[O:22])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O>[CH2:9]([O:16][C:17]1[C:21](=[CH:1][C:3]2[NH:4][C:5]([CH3:8])=[CH:6][CH:7]=2)[NH:20][C:19](=[O:22])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc(C=O)[nH]1
Reactant: O=C1C=C(OCc2ccccc2)CN1
Solvent: CS(C)=O
Product: Cc1ccc(C=C2NC(=O)C=C2OCc2ccccc2)[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2-formyl-5-methylpyrrole (4 g; 36.65 mmols) and 4-benzyloxy-3-pyrrolin-2-one (8.24 g; 43.78 mmols) in DMSO (65 ml) 2N sodium hydroxyde (45 ml) was added under nitrogen atmosphere and the mixture was stirred at 60° C. for 8 hours. After dilution with water (200 ml) the yellow suspension was filtered. The crude material was taken up in ethyl acetate, stirred and filtered to give 4-benzyloxy-5-(5-methyl-1H-pyrrol-2-yl-methylene)-1,5-dihydro-pyrrol-2-one (7.7 g; 27.49 mmols) as a 4:1 Z:E mixture. Yield: 75%