Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH:10]([F:12])[F:11])=[CH:7][CH:6]=[CH:5][C:4]=1[S:13](Cl)(=[O:15])=[O:14])#[N:2].[CH3:17][NH:18][CH3:19].C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCCC1.O>[CH3:17][N:18]([CH3:19])[S:13]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C:1]#[N:2])(=[O:15])=[O:14]
Reactant: N#Cc1c(OC(F)F)cccc1S(=O)(=O)Cl
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)c1cccc(OC(F)F)c1C#N

Procedure:
To a solution of 0.65 g (2.4 mmol) of purified 2-cyano-3-difluoromethoxyphenylsulfonyl chloride in 20 ml of tetrahydrofuran a solution of 274 mg (2.4 mmol) of dimethylamine and 510 mg of sodium carbonate in 15 ml of water was added at room temperature. The reaction mixture was stirred at room temperature for 5 minutes before water was added. The aqueous phase was acidified to pH=1 using hydrochloric acid (10% strength by weight, aqueous solution). The aqueous phase was then extracted three times with dichloromethane. The combined organic extracts were dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting residue was triturated with methyl tert-butyl ether. Yield: 0.53 g (79% of theory) of the title compound having a melting point of 100-102° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1>CN(C=O)C.O>[Cl:15][C:16]1[N:17]=[N:18][C:19]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1ccc(Cl)nn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nn2)CC1
Temperature: 150 °C
Yield: 67.5 %

Procedure:
tert-Butyl piperidin-4-ylcarbamate (2 g, 10 mmol), 3,6-dichloropyridazine (1.79 g, 12 mmol) and TEA (2.1 ml, 15 mmol) was dissolved in dry DMF (30 ml) and the reaction mixture was heated in a microwave reactor at 150° C. for 20 mins. The reaction mixture was diluted with water (300 ml) and extracted with EtOAc (300 ml). The organic phase was dried (Na2SO4), filtrated and evaporated. The residue was purified by silica gel column chromatography using a 98:2 mixture of DCM:MeOH to give the title compound (2.11 g, 68%) as a solid. 1H-NMR (CDCl3, 500 MHz): δ 7.19 (d, 1H), 6.91 (d, 1H), 4.48 (bs, 1H), 4.29-4.20 (m, 2H), 3.73 (bs, 1H), 3.14-3.04 (m, 2H), 2.10-2.02 (m, 2H), 1.49-1.38 (m, 2H), 1.45 (s, 9H); 13C-NMR (CDCl3, 125 MHz): δ 158.9, 155.2, 146.7, 128.9, 115.5, 79.6, 47.9, 44.4, 31.9, 28.5.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O.C(=O)([O-])[O-].[K+].[K+].ClCCl>CO.O>[CH2:7]1[C:8]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)=[CH:12][C:9]=2[CH2:10][CH2:11][NH:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCNCC3)CC1
Temperature: 25 °C

Procedure:
400 mg tert-butyl 4-[3-(2,2,2-trifluoracetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy]-piperidine-1-carboxylate (see 38.2) are placed in 17 ml of methanol, then a mixture of 151.2 mg potassium carbonate in 3.3 ml of water is added. The reaction mixture is stirred at ambient temperature, until there is no further reaction. The methanol is then spun off. The residue is combined with dichloromethane and water. The organic phase is dried and evaporated to dryness. 310 mg are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH2:12]([OH:14])[CH3:13]>>[CH2:12]([O:14][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1)[CH3:13]
Reactant: CCO
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 42 g (0.2 mol) 3,4-dichlorobenzoyl chloride and 200 ml ethanol was heated to boiling for 2 hours, evaporated, the residue taken up in ether, the solution washed with NaHCO3 -solution and water, dried and evaporated. The distillation yielded 32 g (73% theor.) ethyl-3,4-dichlorobenzoate with a BP of 84° C./0.13 mbar and a mp of 33° to 35° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C@:13]([CH3:49])([CH2:47][OH:48])[C:14](=[O:46])[C@@H:15]([NH:23][C:24](=[O:45])[C@@H:25]([NH:29][C:30](=[O:44])[C@@H:31]([NH:35][C:36]([C:38]1[S:42][C:41]([CH3:43])=[N:40][CH:39]=1)=[O:37])[CH2:32][O:33][CH3:34])[CH2:26][O:27][CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:48][CH2:47][C@:13]([OH:12])([CH3:49])[C:14](=[O:46])[C@@H:15]([NH:23][C:24](=[O:45])[C@@H:25]([NH:29][C:30](=[O:44])[C@@H:31]([NH:35][C:36]([C:38]2[S:42][C:41]([CH3:43])=[N:40][CH:39]=2)=[O:37])[CH2:32][O:33][CH3:34])[CH2:26][O:27][CH3:28])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)c1ccc(C)cc1

Procedure:
Prepared according to procedures described above, by reacting p-toluenesulfonyl chloride with N—((S)-1-(((S)-1-(((2 S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C32H40N4O10S2 m/z: 705 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:3]([NH:7]C(=O)OC(C)(C)C)[CH2:4][CH2:5][CH3:6].O.[ClH:22]>C(OCC)(=O)C>[ClH:22].[NH2:7][C@@H:3]([CH2:4][CH2:5][CH3:6])[C@@H:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:1]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCC[C@H](N)[C@H](O)c1ccccc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
The pure tert-butyl (1R,2S)-1-hydroxy-1-phenylpentan-2-ylcarbamate was dissolved in ethyl acetate (1.2 ml). Water (50 μl) and hydrochloric acid in ethyl acetate (1.0 ml, 1.5 M) were added. The solution was stirred at 50° C. for 90 min. A precipitation was formed. The volume was reduced to ⅔ by heavy stirring and a stream of argon gas. The stirring was continued for 1 h at r.t. The suspension was filtered and the solid was dried at 50° C. under reduced pressure for 2 h.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([CH:19]([CH2:25][CH3:26])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br:27][CH2:28][CH2:29][CH:30](Br)[CH3:31]>CCCCCC.O1CCCC1>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][C:19]([CH2:25][CH3:26])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: CCC(CC(=O)OC)c1ccccc1
Reactant: CC(Br)CCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC(CCCCBr)(CC(=O)OC)c1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
40 ml (0.1 mol) of n-butyl lithium as a 2.5 molar solution in hexane are added dropwise to a solution of 14 ml (0.1 mol) of diisopropylamine in 150 ml of anhydrous tetrahydrofuran at −30° C. and stirred for 10 minutes at −10° C. At −76° C., 16.4 g (0.1 mol) of methyl 2-phenylbutanecarboxylate are added dropwise and the mixture is stirred for 30 minutes at this temperature. Then 12.12 ml (0.101 mol) of 1,3-dibromobutane are added, when the addition has ended the cooling bath is removed and the mixture is stirred for 14 hours at ambient temperature. The reaction solution is poured onto 1.2 l water and extracted with diethylether. The organic phases are extracted with water, dried over sodium sulphate and the solvent is eliminated. The residue is distilled under high vacuum.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:10]([O:15][CH3:16])[C:11]([F:14])([F:13])[F:12])[C:7]1([CH3:18])[CH3:17])=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH3:17][C:7]1([CH3:18])[CH:8]([CH:9]=[C:10]([O:15][CH3:16])[C:11]([F:14])([F:13])[F:12])[CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(OC)C(F)(F)F)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=CC1C(C(=O)O)C1(C)C)C(F)(F)F
Yield: 60.5 %

Procedure:
16.6 g (0.0624 mol) of 2,2-dimethyl-3-(3,3,3-trifluoro-2-methoxy-prop-1-enyl)-cyclopropanecarboxylic acid ethyl ester were dissolved in 100 ml of ethanol, a solution of 2.9 g (0.073 mol) of sodium hydroxide in 75 ml of water was then added and the mixture was heated to the reflux temperature for 4 hours, while stirring. The ethanol was then distilled off under a waterpump vacuum, the residue was taken up in 300 ml of water and the aqueous mixture was extracted once with 300 ml of methylene chloride. The aqueous phase was separated off, acidified with concentrated hydrochloric acid and then extracted twice with 300 ml of methylene chloride. The organic phase was then separated off over magnesium sulphate, dried and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 50° C. under 2 mbar. 9 g (60.6% of theory) of 2,2-dimethyl-3-(3,3,3-trifluoro-2-methoxy-prop-1-enyl)-cyclopropanecarboxylic acid were then obtained as a yellow viscous oil.
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]2[N:6]([CH2:31][CH:32]3[CH2:34][CH2:33]3)[C:7]([CH2:9][O:10][CH2:11][C:12]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:8][C:4]=2[CH:3]=1.[C:37]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)#[N:38].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Pd]>[C:37]([C:39]1[CH:44]=[CH:43][C:42]([C:2]2[CH:36]=[CH:35][C:5]3[N:6]([CH2:31][CH:32]4[CH2:33][CH2:34]4)[C:7]([CH2:9][O:10][CH2:11][C:12]4([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14][CH2:13]4)=[N:8][C:4]=3[CH:3]=2)=[CH:41][CH:40]=1)#[N:38]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2nc3cc(Br)ccc3n2CC2CC2)(c2ccccc2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(COCc2nc3cc(-c4ccc(C#N)cc4)ccc3n2CC2CC2)(c2ccccc2)CC1
Reaction time: 0.83 h

Procedure:
Following the procedure is described in the literature (Lee, S. H. et. al. J. Org. Chem. 2004, 69, 8829-8835). tert-Butyl 4-(((5-bromo-1-(cyclopropylmethyl)-1H-benzo-[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (48 mg, 0.087 mmol) was subjected to Suzuki coupling reaction in toluene (1.0 mL) at 110° C. with p-cyanophenylboronic acid (3 equiv) and cesium carbonate (3 equiv) using Pd (dppf) (0.08 equiv) as catalyst. The crude product was purified by silica gel chromatography using a 50 min linear gradient of 12% -100% ethyl acetate in hexane. Fractions containing the required product were combined and evaporated in vacuo to give 23 mg (46%) as a gum. 1H-NMR (CD3OD, 500 MHz) δ 7.91 (s, 1H), 7.85 (d, JAB=8.5 Hz, 2H), 7.80 (d, JAB=8.5 Hz, 2H), 7.65-7.60 (m, 2H), 7.36-7.29 (m, 4H), 7.21 (m, 1H), 4.71 (s, 2H), 3.82, (d, J=7.0 Hz, 2H), 3.72 (m, 2H), 3.58 (s, 2H), 3.04 (m, 2H), 2.20 (m, 2H), 1.84 (m, 2H), 1.42 (s, 9H), 1.04 (m, 1H), 0.50-0.47 (m, 2H), 0.33-0.30 (m, 2H); 13C NMR (CD3OD, 126 MHz,) δ 155.7, 151.9, 146.5, 143.1, 142.2, 136.2, 134.3, 132.8, 128.5, 128.0, 127.3, 126.4, 122.9, 118.9, 117.6, 111.6, 110.4, 80.0, 79.9, 65.6, 41.6, 32.1, 27.7, 11.0, 3.6. Mass Spec.: 577(MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].O.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH2:36][CH2:37][C:38]3=[O:43])O1>CN(C)C=O>[CH:12]1([CH2:11][O:10][C:4]2[C:3]([O:15][CH2:16][O:17][CH3:18])=[C:2]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH2:36][CH2:37][C:38]4=[O:43])[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[CH2:14][CH2:13]1
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
Reactant: COCOc1c(Br)ccc(OC)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OCC1CC1
Temperature: 80 °C
Yield: 51.6 %

Procedure:
A stirring solution of 1-bromo-3-(cyclopropylmethoxy)-4-methoxy-2-(methoxymethoxy)benzene (3 g, 9.46 mmol) in dimethylformamide (50 mL) was purged with argon for 1 h, to this cesium carbonate (9.23 g, 28.39 mmol), water (3 mL), tetrakis triphenylphosphine palladium (546 mg, 0.472 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (2.93 g, 11.35 mmol) were added and the resultant reaction mixture was heated to 80° C. for 5 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 4-(3-(Cyclopropylmethoxy)-4-methoxy-2-(methoxymethoxy)phenyl)-2,3-dihydro-1H-inden-1-one as a solid (1.8 g, 51%).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5](N)[CH2:4][CH2:3]1.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:9][CH2:8][C:7]2=[C:6]3[C:13](=[CH:12][CH:11]=[CH:10]2)[C:16]2[CH2:17][CH2:18][CH2:19][C:15]=2[N:5]3[CH2:4][CH2:3]1
Reactant: CN1CCc2ccccc2N(N)CC1
Reactant: O=C1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCO
Product: CN1CCc2cccc3c4c(n(c23)CC1)CCC4
Temperature: 25 °C
Yield: 25.7 %

Procedure:
To a solution of 4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (1.55 g, 8.1 mmole) in 1-propanol (100 mL) was added cyclopentanone (5.23 g, 62.3 mmole), followed by p-toluenesulfonic acid monohydrate (3.2 g, 16.8 mmole), and the resulting reaction mixture was refluxed for 40 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate (150 mL), saturated aqueous sodium chloride (150 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 0.50 g of the title compound as a white solid, mp 128-130° C. MS (ESI) m/z 241 ([M+H]+).
Reaction SMILES: [C:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH3:28]I>C1COCC1>[CH3:28][CH:2]([CH2:3][CH2:4][CH2:5][CH3:6])[C:1]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)=[O:7]
Reactant: CI
Reactant: CCCCCC(=O)c1cccc(OCc2ccc3ccccc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(C)C(=O)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C

Procedure:
A solution of the ketone, 2-(3-hexanoylphenoxymethyl)quinoline (prepared from 3-hexanoylphenol and 2-chloromethyl quinoline)(6 g, 0.018 mol) in dry THF (25 ml) was added slowly to a mildly refluxing suspension of sodium hydride (1.3 g, 0.054 mol) in dry THF (75 ml) containing excess methyl iodide (10.3 g, 0.073 mol) After the addition of the ketone was complete (30 min.), the reaction mixture was refluxed for 4 hours. After cooling the mixture to room temperature, excess NaH was destroyed by adding methanol. All volatiles were removed at the rotary evaporator and the residue was taken up in ethyl acetate. The organic extract was washed with water and brine, and dried over anhydrous magnesium sulfate. Upon removal of all solvent, the mono-methylated eetone (2-[3-(2-methylhexanoyl) phenoxymethyl]quinoline, was obtained as a yellow oil weighing 8 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1)#[N:2].[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:38][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2/[CH:22]=[CH:21]/[CH:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:40][CH:41]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1O)CCc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)CCc1ccc(C#N)cc1
Yield: 88.8 %

Procedure:
A solution of 2300 mg (5.87 mmol) of ethyl E-6-[2-(4-cyanophenyl)ethyl]-8-(2-hydroxyphenyl)oct-7-enoate from Example 87A in 160 ml of dry acetonitrile is mixed with 1600 mg (7.05 mmol) of 4-(tert-butyl)benzyl bromide and 1220 mg (8.81 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography an silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 2800 mg (5.21 mmol, 88% yield) of a solid are obtained.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[NH3:40]>O1CCOCC1>[C:20]([C@@H:17]1[CH2:18][CH2:19][C@H:14]([N:13]2[C:12]3[CH:23]=[C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]4)[CH:25]=[CH:26][C:11]=3[NH:10]/[C:9]/2=[N:8]\[C:6](=[O:7])[C:5]2[CH:38]=[CH:39][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:15][CH2:16]1)(=[O:21])[NH2:40].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:29][CH2:30][CH:31]([C:34]([OH:37])([CH3:35])[CH3:36])[CH2:32][CH2:33]4)=[CH:23][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20]([N:40]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[O:22])[CH2:16][CH2:15]2)=[O:7])=[CH:38][CH:39]=1
Reactant: N
Reactant: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)O)CC4)c3c2)CC1
Solvent: C1COCCO1
Product: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)N5CCNCC5)CC4)c3c2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(N)=O)CC4)c3c2)CC1

Procedure:
The title compound was prepared from cis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid and 0.5-M ammonia in dioxane using a method analogous to that used in the preparation of (E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (68 mg, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 6H), 1.20-1.35 (m, 3H), 1.55-1.78 (m, 6H), 1.78-1.90 (m, 2H), 2.16-2.24 (m, 2H), 2.55 (br. s., 1H), 2.71-2.94 (m, 4H), 3.50 (br. s., 2H), 4.01 (s, 1H), 4.76 (br. s., 1H), 6.91 (br. s., 1H), 7.16 (d, J=7.6 Hz, 1H), 7.29 (dd, J=8.9 Hz, 8.9 Hz, 2H), 7.35 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 8.29 (dd, J=8.7, 6.1 Hz, 2H), 12.73 (br. s., 1H). MS, m/z (C30H38FN5O3): calcd, 535.3. found, 536.1 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([CH:10]([CH3:12])[CH3:11])[N:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[C:8]([C:7]1[C:2]([N:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[N:3][C:4]([CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=1)#[N:9]
Reactant: CC(C)c1ncc(C#N)c(N)n1
Reactant: COC(OC)N(C)C
Product: CC(C)c1ncc(C#N)c(N=CN(C)C)n1

Procedure:
The title compound was prepared from the reaction of 4-Amino-2-isopropyl-pyrimidine-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH:28]([CH3:32])[C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.FC(F)C(OC(=O)C(F)F)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:8][C:9]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:2](=[O:1])[CH:4]([F:7])[F:5])[CH:28]([CH3:32])[C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2C
Agent: O=C(OC(=O)C(F)F)C(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)C(F)F)C2C

Procedure:
A solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.028 mmol), 2,2-difluoroacetic anhydride (7.4 mg, 0.042 mmol), and DIPEA (10.94 mg, 0.085 mmol) in DCM (141 μL) was stirred at room temperature for 1 h. Purification by HPLC Method A gave the title compound as a TFA salt (8.2 mg) as an off-white film. 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.27 (dd, J=7.6, 6.6 Hz, 6H), 1.51 (d, J=6.8 Hz, 2.1H), 1.62 (d, J=6.8 Hz, 0.9H), 1.90-2.00 (m, 2H), 2.09-2.17 (m, 2H), 2.65-2.75 (m, 1H), 2.80-3.03 (m, 3H), 3.25 (td, J=12.9, 3.9 Hz, 0.3H), 3.34-3.42 (m, 2H), 3.52-3.61 (m, 0.7H), 4.11-4.21 (m, 1.7H), 4.46 (dt, J=7.3, 3.7 Hz, 1H), 4.66 (dd, J=13.4, 5.6 Hz, 0.3H), 4.91-4.98 (m, 0.3H), 5.25 (q, J=6.7 Hz, 0.7H), 6.44-6.69 (m, 1H), 6.84-6.92 (m, 1H), 6.99 (ddd, J=11.3, 8.4, 3.2 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 496.90.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9](OC3C=CC=CC=3)[C:8]=2[N:22]=1)[CH3:2].C([O-])(=O)C.[NH4+:35].[NH4+].[OH-]>O>[NH4+:6].[OH-:3].[NH2:35][C:9]1[C:8]2[N:22]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:25])[CH3:26])[C:7]=2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=1
Reactant: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CC(C)(C)NC(C)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CC(C)(C)NC(C)=O
Temperature: 160 °C
Reaction time: 24 h
Yield: 146.6 %

Procedure:
A pressure flask was charged with N-{2-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]-1,1-dimethylethyl}acetamide (980 mg, 2.39 mmol) and ammonium acetate (1.25 g). The flask was sealed and heated to 160° C. The solids soon melted to give a viscous oil and heating was continued for 24 h. The reaction mixture was cooled and treated with H2O and NH4OH solution until pH reached ˜12. The mixture was then extracted with CHCl3 (3×). The combined organic portions were washed with brine, dried with Na2SO4 and concentrated. Column chromatography (SiO2, 5% MeOH/CHCl3 saturated with NH4OH) gave N-{2-[4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]-1,1-dimethylethyl}acetamide (584 mg) as a tan foam. MS m/z 334 (M+H). 1H NMR (300 MHz, CDCl3) δ 5.57 (s, 1H), 4.92 (s, 2H), 4.77 (s, 2 H), 4.71 (br s, 2 H), 3.62 (q, J=7.0 Hz, 2H), 2.44 (s, 6H), 1.96 (s, 3H), 1.30 (s, 6 H), 1.24 (t, J=7.0 Hz, 3H).