Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:9]2[NH:13][C@@:12]([CH2:15][OH:16])([CH3:14])[CH2:11][CH2:10]2)[CH:6]=[N:7][CH:8]=1.Cl[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]2[N:19]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[F:2][C:3]1[CH:4]=[C:5]([C@@H:9]2[N:13]([C:18]3[CH:23]=[CH:22][N:21]4[N:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]4[N:19]=3)[C@@:12]([CH2:15][OH:16])([CH3:14])[CH2:11][CH2:10]2)[CH:6]=[N:7][CH:8]=1
Reactant: C[C@@]1(CO)CC[C@H](c2cncc(F)c2)N1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1cnn2ccc(N3[C@@H](c4cncc(F)c4)CC[C@@]3(C)CO)nc12
Temperature: 190 °C
Yield: 25.2 %

Procedure:
A sealed reaction vessel was charged with ((2S,5R)-5-(5-fluoropyridin-3-yl)-2-methylpyrrolidin-2-yl)methanol hydrochloride (0.135 g, 0.547 mmol), ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 0.136 g, 0.602 mmol), DIEA (0.124 mL, 0.711 mmol) and isopropyl alcohol (1 mL). The vessel was sealed and the mixture was heated at 190° C. for 48 hours. The reaction was cooled to ambient temperature and concentrated. The residue was purified by reverse phase column chromatography (0-50% acetonitrile/water) to afford ethyl 5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (55 mg, 25% yield) as a viscous clear oil. MS (apci) m/z=400.1 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[N:7]1([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([C:28]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][CH2:3][C:4]([N:33]1[CH2:34][CH2:35][N:30]([C:28]([C:22]2([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][CH2:12][N:7]4[CH2:8][CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:18]=3)[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:29])[CH2:31][CH2:32]1)=[O:5]
Reactant: O=C(N1CCNCC1)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCN(C(=O)C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Methoxyacetyl chloride (55 μl, 0.6 mmol) was added dropwise at 0° C. to a solution of 1-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}carbonyl)piperazine of example 181 (200 mg, 0.5 mmol) and N,N-diisopropylethylamine (100 μl, 0.6 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (20 ml) and washed with 2N sodium hydroxide (20 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (20 ml). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 90:10:1 by volume) to provide the title compound (160 mg, 67%). HRMS ESI+ m/z 474.2952 [MH]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(OCC)(OCC)OCC.C[O-].[Na+].[CH3:25][O:26][C:27]([CH3:37])([CH3:36])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:35])[CH2:32][CH2:33]O>O.CN(C)C=O>[CH3:25][O:26][C:27]([CH3:36])([CH3:37])[CH2:28][CH2:29][CH2:30][CH:31]([CH3:35])[CH2:32][CH:33]=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(C)(C)CCCC(C)CCO
Agent: CCOP(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)CCCC(C)CC=Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A mixture consisting of 5.4 g (0.025 mol) of p-nitrobenzyl bromide and 4.15 g (0.025 mol) of triethyl phosphite is stirred at 90°, over the course of 1 hour and under nitrogen. The resulting ethyl bromide is distilled off from the reaction vessel. The obtained solution is then evacuated and stirred at a bath temperature of 110° for one further hour in a water jet vacuum. A suspension consisting of 1.68 g (0.030 mol) of sodium methylate and 10 cc of absolute dimethylformamide is carefully added at 0° to the residue. 4.65 g (0.025 mol) of 7-methoxy-3,7-dimethyloctanol in a small amount of dimethylformamide are subsequently added over the course of 5 minutes to the red reaction mixture which is stirred at 0° for 1 hour and at room temperature for 90 minutes. The ruby-coloured solution gradually turns dark brown. 60 cc of water are added and the reaction mixture is extracted with hexane. The extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated at 40° /20 mm Hg. After chromatography of the residue on silica gel with hexane/ethyl acetate (97:3) and (94:6), pure 1-(8-methoxy-4,8-dimethyl-1-nonenyl)-4-nitrobenzene is obtained as a slightly yellow oil. nD20 = 1.5473
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]([C:15]#[N:16])=[N:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH2:23]([C:25]([OH:30])([CH2:28][CH3:29])[C:26]#[CH:27])[CH3:24].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu](I)I>[CH2:26]([C:25]([C:23]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:10][C:11]([C:15]#[N:16])=[N:12]3)=[CH:7][CH:6]=2)[CH:24]=1)([OH:30])[CH2:28][CH3:29])[CH3:27]
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(CN=[N+]=[N-])cc2n1
Reactant: C#CC(O)(CC)CC
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)(CC)c1cn(Cc2ccc3c(-c4ccccc4)cc(C#N)nc3c2)nn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 7-(azidomethyl)-4-phenylquinoline-2-carbonitrile (100 mg, 0.35 mmol), 3-ethylpent-1-yn-3-ol (47 mg, 0.42 mmol), copper iodide (100 mg, 0.52 mmol) and diisopropylethylamine (305 μL, 1.75 mmol) in THF (4 mL) was stirred at rt for 6 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 398 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]([O:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])([CH3:27])[CH3:26]>>[CH:25]([O:28][C:29]1[CH:30]=[C:31]([NH:32][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:22])[CH:33]=[CH:34][CH:35]=1)([CH3:27])[CH3:26]
Reactant: CC(C)Oc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)Oc1cccc(NC(=O)c2cncc(N3C[C@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C3)c2)c1

Procedure:
The product from Example 33B and 3-isopropoxyaniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 467 (M+H)+.
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41].N1C=CC=CC=1>ClCCCl>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Temperature: 25 °C
Yield: 113.9 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (500 mg) obtained from Step 1 of Example 93 was suspended in 1,2-dichloroethane (10 ml), isobutyryl chloride (114 mg) and pyridine (86 μl) were added thereto at room temperature, and the mixture was refluxed for 2 hours and 30 minutes. The reaction mixture was allowed to cool, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 647 mg of the titled compound (Yield: 100%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[O:8][CH:7]=[CH:6][C:5]=1O)=[O:3].P(Cl)(Cl)(Cl)(Cl)[Cl:11].O>C(Cl)Cl>[C:2]([C:4]1[O:8][CH:7]=[CH:6][C:5]=1[Cl:11])(=[O:3])[CH3:1]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)c1occc1O
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1occc1Cl
Reaction time: 1 h

Procedure:
Isomaltol (6.3 g, 0.05 moles) in 60 ml of CH2Cl2 was added dropwise over 10 minutes to a solution of PCl5 (10.4 g, 0.05 moles) in 125 ml of CH2Cl2 at 4° C. After stirring at 4°-5° C. for 1 hour, the reaction was allowed to come to room temperature, poured into 350 ml of water and the CH2Cl2 layer separated. The aqueous layer was then extracted with CH2Cl2, the CH2Cl2 layers combined and then concentrated to yield a dark oil, 7.0 g. Pure 2-acetyl-3-chloro-furan was obtained by chromatography from silica gel, NMR (CDCl3, δ) 7.5 (1H, d, J=2Hz), 6.56 (1H, d, J=2Hz), 2.53 (3H, s).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][CH:8]1[C:15]2[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=2[CH2:10][CH2:9]1)(=[O:3])[CH3:2].[OH-].[Li+].CO>C1COCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][CH:8]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=2[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(C(C)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1cccc(CC2CCc3[nH]c(C(=O)O)cc32)c1
Yield: 9 %

Procedure:
The title compound was synthesized from methyl 4-(3-acetylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.006 g, 0.020 mmol) and lithium hydroxide (0.010 g, 0.24 mmol in 0.5 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (1 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-50% EtOAc/heptane affording the title compound: 0.5 mg, 9% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.56-2.61 (m, 7H), 2.79-2.91 (m, 2H), 6.29 (s, 1H), 7.39-7.44 (m, 1H), 7.44-7.46 (m, 1H), 7.78 (s, 1H), 7.82-7.86 (m, 1H); LCMS-MS (ESI−) 282.2 (M−H); HPLC (UV=100%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][CH3:18])=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[CH2:29]([O:31][C:32]([CH:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1)=[O:33])[CH3:30].Cl>C1(C)C=CC=CC=1>[CH2:29]([O:31][C:32]([CH:34]1[CH2:39][CH2:38][C:37]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH2:17][CH3:18])=[N:7][N:8]3[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=2)([OH:40])[CH2:36][CH2:35]1)=[O:33])[CH3:30]
Reactant: CCc1nn(C2CCCCC2)c2cc(Br)ccc12
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(O)(c2ccc3c(CC)nn(C4CCCCC4)c3c2)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a solution of 6bromo-1-cyclohexyl-3-ethyl-1H-indazole (12.7 g, 41.3 mmol) in toluene (64 mL) was added tetrahydrofuran (6.70 mL, 82.6 mmol). The solution was cooled to -78° C. and n-butyllithium (17.3 mL of a 2.5M solution in hexanes, 43.4 mmol) was added dropwise. The solution was stirred 10 minutes and added to a solution of 4-oxo-cyclohexanecarboxylic acid ethyl ester (8.80 g, 51.7 mmol) in toluene (127 mL) at -78° C. The reaction mixture was stirred for 15 minutes and poured into 1N aqueous hydrochloric acid (200 mL). The layers were separated and the aqueous layer was reextracted with toluene (60 mL). The organic extracts were combined and dried over magnesium sulfate, filtered, and concentrated to an oil which was purified by filtration through a pad of silica gel eluting with 4:1 hexanes/ethyl acetate. The product-rich fractions were concentrated to yield 4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cyclohexanecarboxylic acid ethyl ester (13.5 g, 82%) as a mixture of diastereoisomers. Upon standing, one of the diastereoisomers crystallized and was isolated by trituration with hexanes. 1H NMR (400 MHz, CDCl3) δ 1.25-1.40 (m, 4), 1.27 (t, 3, J=7.1), 1.35 (t, 3, J=7.7), 1.65-2.07 (m, 15), 2.37-2.44 (m, 1), 2.96 (q, 2, J=7.7), 4.15 (q, 2, J=7.1), 4.30-4.38 (m, 1), 7.13 (d, 1, J=8.5), 7.58 (s, 1), 7.63 (d, 1, J=8.5). 13C NMR (100 MHz, CDCl3) δ 14.16, 14.26, 20.69, 24.60, 25.39, 25.91, 32.54, 38.22, 42.57, 57.59, 60.34, 72.80, 104.49, 116.80, 120.28, 121.26, 139.84, 146.09, 146.93, 175.63. Analysis calculated for C24H34N2O3 : C, 72.33; H, 8.60; N, 7.03. Found: C, 72.11; H, 8.55; N, 6.92.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([C:29]([Cl:32])([F:31])[F:30])=[N:27][N:28]=2)[N:25]=1>>[Cl:32][C:29]([F:30])([F:31])[C:26]1[N:24]2[N:25]=[C:20]([N:15]3[CH2:16][CH2:17][CH2:18][N:12]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=4)[CH2:13][CH2:14]3)[CH:21]=[CH:22][C:23]2=[N:28][N:27]=1
Reactant: FC(F)(F)c1cnc(N2CCCNCC2)c(Cl)c1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Product: FC(F)(F)c1cnc(N2CCCN(c3ccc4nnc(C(F)(F)Cl)n4n3)CC2)c(Cl)c1
Yield: 62 %

Procedure:
A mixture of 1-(3-chloro-5-trifluoromethyl-2-pyridyl)-1,4-diazepane and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 339 to give 3-[chloro(difluoro)methyl]-6-[4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1,4-diazepan-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 62% yield.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[N:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:38][N:37]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[N:40]=[C:39]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:38][N:37]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1noc(-c2ccccc2)n1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2noc(-c3ccccc3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.24 g), potassium carbonate (0.94 g), 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole (0.68 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.79 g, 45%).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:31][Mg]Br>C1COCC1.C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]([OH:26])[CH3:31])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C[Mg]Br
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)O)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of 399 g (899 mmol) of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (Example 151, Step B) in THF (9 L) was added 1.93 L (2.70 mol) of a 1.4 M solution of methylmagnesium bromide 75:25 in toluene/tetrahydrofuran slowly over a 30 min period so as to maintain an internal reaction temperature below 6° C. The yellow solution was warmed to room temperature and stirred for 1.5 h. At this time the reaction was cooled to 0° C. and quenched by cautious, slow addition of saturated aqueous ammonium chloride (4.6 L) so as to maintain an internal reaction temperature below 15° C. The mixture was warmed to room temperature, ethyl acetate was added, and the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water (1×) and then saturated aqueous sodium chloride (1×), dried over Na2SO4, filtered and the filtrate was concentrated to afford a yellow oil. Purification of the residue by chromatography on silica (Biotage® Snap™ column; Biotage, LLC, Charlotte, N.C.), 5% acetone/5% EtOAc/90% hexanes grading to 5% acetone/29% EtOAc/66% hexanes) provided the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:21])[N:10]=[N:11][C:12]=2[C:13]2[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](Cl)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:25][CH2:24][CH2:23]1>>[N:22]1([C:15]2[CH:14]=[C:13]([C:12]3[N:11]=[N:10][C:9]([NH2:21])=[N:8][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:18]=[C:17]([CH3:19])[N:16]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: Cc1cc(-c2nnc(N)nc2-c2ccccc2)cc(Cl)n1
Reactant: C1CNC1
Product: Cc1cc(-c2nnc(N)nc2-c2ccccc2)cc(N2CCC2)n1

Procedure:
6-[2-(Azetidin-1-yl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine was prepared from 5-phenyl-6-(2-chloro-6-methyl-pyridin-4-yl)-1,2,4-triazin-3-amine (100 mg, 0.34 mmol) and azetidine (96 mg, 0.11 ml, 1.69 mmol) according to the general procedure for Preparation 4a.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.Cl[P:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.O1CCCC1>[C:22]1([P:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Brc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 1.0 mole of n-butyllithium in hexane at -78° C under an inert atmosphere is added dropwise and with efficient stirring 236g of p-dibromobenzene in dry tetrahydrofuran (total volume 500 ml). The resulting solution is stirred at -78° C for 1 hour, then treated dropwise at this temperature with 220.5g of chlorodiphenylphosphine. When this addition is complete, the mixture is allowed to warm to room temperature, then solvent is removed under vacuum. The residue is triturated with two 400-ml portions of methanol, then distilled through a Vigreux column. The cut with bp 165°-170° C (0.15 mm) is recrystallized from ethanol to give 100.5g of p-diphenylphosphinobromobenzene, mp 78°-80° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:21][C:22]1[C:29]([F:30])=[CH:28][C:25]([C:26]#[N:27])=[C:24](F)[CH:23]=1>O1CCCC1>[Cl:21][C:22]1[C:29]([F:30])=[CH:28][C:25]([C:26]#[N:27])=[C:24]([CH:23]=1)[O:3][CH:4]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(Oc1cc(Cl)c(F)cc1C#N)c1cccnc1
Yield: 87.4 %

Procedure:
Sodium hydride (141 mg, 60% dispersion in oil) was added to a solution of the product from step (b) (785 mg, 2.96 mmol) and 4-chloro-2,5-difluorobenzonitrile (546 mg, 3.75 mmol) in tetrahydrofuran (9 ml) and the resultant suspension was stirred for 0.5 h. The mixture was quenched with saturated aqueous ammonium chloride, basified to pH 8 and extracted with ethyl acetate (three times). The combined organic extracts were dried (sodium sulphate), evaporated and purified by chromatography on silica eluting with petrol—acetone to give 1.05 g (88%) of the sub-title compound as a colourless oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10]3([CH2:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][CH:16]=[C:17](Br)[CH:18]=4)[O:13]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26].COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCN(C(OC(C)(C)C)=O)CC1)CC2=O>>[CH3:29][O:28][C:24](=[O:27])/[CH:25]=[CH:26]/[C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[O:13][C:10]1([CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]1)[CH2:21][C:20]2=[O:22]
Reactant: C=CC(=O)OC
Reactant: O=C1CC2(CCN(c3ccccc3)CC2)Oc2ccc(Br)cc21
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(c3ccccc3)CC1)O2

Procedure:
(E)-3-{1′-Phenyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester was synthesized starting from 1′-phenyl-6-bromo-spiro[chromane-2,4′-piperidine]-4-one (650 mg, 1.75 mmol) and methyl acrylate (541 mg, 6.2 mmol) according to the procedure described for Intermediate 1, Step B, giving 541 mg of the product.
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([C:26]4[S:30](=[O:32])(=[O:31])[N:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:28](=[O:37])[CH:27]=4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:40]1([CH2:46][O:47][C:48]2[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[C:33]([N:29]1[C:28](=[O:37])[CH:27]=[C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([N:8]3[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=[C:7]3[CH2:6][C:5]3[CH:4]=[CH:3][C:2]([C:51]4[CH:52]=[CH:53][C:48]([O:47][CH2:46][CH:40]5[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]5)=[CH:49][CH:50]=4)=[CH:39][CH:38]=3)[CH:21]=2)[S:30]1(=[O:32])=[O:31])([CH3:35])([CH3:36])[CH3:34]
Reactant: CC(C)(C)N1C(=O)C=C(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S1(=O)=O
Reactant: OB(O)c1ccc(OCC2CCCCC2)cc1
Product: CC(C)(C)N1C(=O)C=C(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OCC5CCCCC5)cc4)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-2-tert-butyl-isothiazol-3-one-1,1-dioxide (7 mg, 0.01 mmol) was treated as described in general procedure G using 4-(cyclohexylmethoxy)-phenylboronic acid (5 mg, 0.02 mmol, prepared according to general procedure H) to give 2-tert-Butyl-5-{3-[2-(4′-cyclohexylmethoxy-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-isothiazol-3-one-1,1-dioxide.