Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(C)C)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(N(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(4-dimethylaminophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (144 mg, 0.35 mmol, see step (b) Example 16) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol). Yield 70 mg (35%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[CH3:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18](Cl)=[O:19]>ClCCl>[OH:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:18](=[O:19])[CH2:17][C:16]([CH3:22])([CH3:21])[CH3:15])[CH2:2][CH2:3]1
Reactant: OCCC1CCNCC1
Reactant: CC(C)(C)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)CC(=O)N1CCC(CCO)CC1
Temperature: 0 °C
Yield: 45 %

Procedure:
To a solution of 2-(piperidin-4-yl)ethanol (0.30 g, 2.32 mmol) in anhydrous dichloromethane (10 mL), NaHCO3 (0.59 g, 6.97 mmol) was added. The suspension was cooled to 0° C. and then 3,3-dimethylbutanoyl chloride (0.38 g, 2.79 mmol) was added dropwise over a period of 15 min. The reaction was followed by TLC till the disappearance of the starting material (overnight) and was then filtered. The residue was then purified using column chromatography on a silica gel column eluting with a solution of ethyl acetate in hexane (50%) to produce the alcohol in a 45% yield.
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[CH:21]4)[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([C:36]([O:38][CH3:39])=[O:37])#N>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:1]1([C:7]2([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[C:36]([O:38][CH3:39])=[O:37])[CH2:18][CH2:19]3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C#N
Reactant: c1ccc(C2(N3CCC(n4cnc5ccccc54)CC3)CCCCCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a stirred solution of 1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazole (as prepared in WO 00/008013, 7.828 g, 20.957 mmol) in THF (200 ml) and HMPA (70 ml) was added dropwise a solution of n-BuLi (1.54 M solution in hexane, 20.4 ml, 31.435 mmol) at −78° C. After 1 hour stirring at −78° C., methyl cyanoformate was added to the reaction mixture at −78° C. After 2 hours stirring, the reaction mixture was quenched with NH4Cl solution and warmed to room temperature. The reaction mixture was extracted with ethyl acetate. The extracts combined were washed with NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated to give oil. This oil was purified by column chromatography (silica gel:200 g, ethyl acetate/n-hexane:1/2 as an eluent) to afford 1.53 g (17%) of title compound as colorless foam.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C:9]1[CH:16]=[N:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].[Cl:17][C:18]1[CH:23]=[C:22]([N+]([O-])=O)[CH:21]=[CH:20][N:19]=1>O>[Cl:17][C:18]1[CH:23]=[C:22]([O:8][C:9]2[CH:16]=[N:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:21]=[CH:20][N:19]=1
Reactant: N#Cc1ccncc1O
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccncc1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.8 %

Procedure:
A flask was charged with sodium hydride (3.99 g, 158 mmol) and DMF (50 mL), and 3-hydroxyisonicotinonitrile (15.8 g, 132 mmol) was added. The reaction was stirred for 2 hours at ambient temperature. 2-Chloro-4-nitropyridine (21.9 g, 138 mmol) was added and the reaction was and stirred overnight. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried and concentrated. The crude product was purified by silica gel chromatography, eluting with DCM, 5% ammoniated methanol in DCM to give the desired product (0.250 g, 0.820% yield) as yellow solid.
Reaction SMILES: P(=O)([O-])O[C:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:4]#N.[H-].[Na+].C(C1C=C(C(C)C)[C:19]([O:25][S:26](=[O:47])(=[O:46])[NH:27][C:28](=[O:45])[CH2:29][C:30]2[C:35](C(C)C)=[CH:34][C:33]([CH:39]([CH3:41])[CH3:40])=[CH:32][C:31]=2[CH:42]([CH3:44])[CH3:43])=C(C(C)C)C=1)=O>O1CCCC1>[C:28]([CH:29]=[CH:4][C:3]1[CH:8]=[C:9]([CH:30]([CH3:31])[CH3:35])[C:19]([O:25][S:26](=[O:47])(=[O:46])[NH:27][C:28](=[O:45])[CH2:29][C:30]2[C:35]([CH:39]([CH3:41])[CH3:40])=[CH:34][C:33]([CH:39]([CH3:41])[CH3:40])=[CH:32][C:31]=2[CH:42]([CH3:44])[CH3:43])=[C:7]([CH:33]([CH3:34])[CH3:32])[CH:6]=1)#[N:27]
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(C=O)cc2C(C)C)c(C(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(C=CC#N)cc2C(C)C)c(C(C)C)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
Diethylcyanomethyl phosphonate (1.49 mL, 9.2 mmol) was added dropwise to a suspension of sodium hydride (0.37 g, 9.2 mmol) in 20 mL tetrahydrofuran at 0° C. After 15 minutes, the reaction was cooled to -78° C. and a solution of [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 4-formyl-2,6-diisopropyl-phenyl ester (2.32 g, 4.4 mmol) in 75 mL tetrahydrofuran was added dropwise. The reaction was allowed to warm to room temperature overnight and then concentrated in vacuo and partitioned the residue between 1 M HCl and dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give an oily solid. Chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.16 g of the title compound as a white solid; mp 157-160° C.
Reaction SMILES: O.[C:2]([O-:5])([O-])=O.[Ca+2].[Br:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1CBr>O1CCOCC1>[Br:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH2:2][OH:5]
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccc2ccccc2c1Br
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: OCc1ccc2ccccc2c1Br
Yield: 84.3 %

Procedure:
Water (100 ml) and CaCO3 (18 g, 180 mmole) were added to a solution of 13 in dioxane (100 ml) and the mixture was refluxed for 10 hr. The solution was cooled and the dioxane was removed under reduced pressure and the mixture was acidified with 1N HCl and extracted with methylene chloride. The combined methylene chloride fractions were washed with saturated solution of NaHCO3, H2O, brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a white solid which when crystallized from hexane afforded 7 g of 24 (84.3%). A single component was detected by TLC (100% hexane, Rf, 0; hexane/ethyl acetate 80:20, Rf, 0.5); NMR (CDCl3) d 2.1 (m, 1H, H--O), d 5.0 (s, 2H, CH2 --OH), d 7.4-8.4 (m, 6H, naphthyl); MS (HRFAB) calcd for C11H9BrO (M+Li)+ 243.0003 found 243.0003.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5]Cl)[CH3:2].[S:9]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=[C:10]1[C:17]([C:19]1[CH:20]=[C:21]([CH:25]([CH3:29])[C:26]([O-:28])=[O:27])[CH:22]=[CH:23][CH:24]=1)=[O:18].[Na+]>CN(C)C=O.Cl>[S:9]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=[C:10]1[C:17]([C:19]1[CH:20]=[C:21]([CH:25]([CH3:29])[C:26]([O:28][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:7][CH3:8])=[O:27])[CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: CCN(CC)CCCl
Reactant: CC(C(=O)[O-])c1cccc(C(=O)c2cc3ccsc3s2)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOC(=O)C(C)c1cccc(C(=O)c2cc3ccsc3s2)c1
Reaction time: 16 h
Yield: 108.1 %

Procedure:
A solution of 2-diethylamino-chloroethane (1.6 g) in dimethylformamide (16 cc) is added dropwise to a suspension of sodium 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionate (4 g) [prepared as described in Example 1] in dimethylformamide (16 cc). After 16 hours at 25° C., the reaction mixture is poured into distilled water (400 cc) and extracted three times with diethyl ether (total 300 cc). The combined ether phases are washed with a saturated aqueous sodium bicarbonate solution (75 cc), then three times with distilled water (total 300 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (0.5 g), filtered and evaporated. The residue obtained (4.75 g), to which is added some product (3.1 g) prepared in the same way, is dissolved in 1N aqueous hydrochloric acid (50 cc). The solution is washed three times with diethyl ether (total 175 cc) and then rendered alkaline to pH 11 by the addition of 1N aqueous sodium hydroxide solution (55 cc). The resulting precipitate is extracted three times with diethyl ether (175 cc). The combined ether solutions are washed three times with distilled water (total 175 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (0.5 g), filtered and evaporated. 2-Diethylaminoethyl 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionate (5.3 g), in the form of an oil, is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:3]=1.[CH:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CC(N(C)C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:4]1[CH:3]=[C:2]([NH:1][C:31]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:32])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:9]2
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2)C1CCCCC1
Reaction time: 8 h
Yield: 10.2 %

Procedure:
1-[7-amino-5-(2-chloro-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (71 mgs, 0.2 mmoles) was dissolved in anhydrous dimethylacetamide (1 ml) to which was added cyclohexyl carbonyl chloride (40 ul, 0.3 mmoles) followed by triethylamine (41.6 ul, 0.3 mmoles) and the solution flushed with nitrogen and left stirring overnight. The product was purified by semi-preparative C18 HPLC (9.4 mgs, 10.2% yield, 100% pure, CO-AAW00031).
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[NH:28][N:27]=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].[C:43](OC)(OC)(OC)[CH3:44]>CN(C=O)C>[CH3:43][C:44]1[N:12]2[C:3]([C:4]3[CH:5]=[C:6]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:7]([C:13]4[CH:18]=[CH:17][C:16]([CH2:19][N:20]5[CH2:21][CH2:22][CH:23]([C:26]6[N:30]=[C:29]([C:31]7[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=7)[NH:28][N:27]=6)[CH2:24][CH2:25]5)=[CH:15][CH:14]=4)=[N:8][C:9]=3[CH:10]=[CH:11]2)=[N:1][N:2]=1
Reactant: NNc1nccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: COC(C)(OC)OC
Solvent: CN(C)C=O
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(CN5CCC(c6n[nH]c(-c7ccccn7)n6)CC5)cc4)nc3ccn12
Temperature: 100 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To 5-hydrazino-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridine (2-1) (55 mg, 0.101 mmol) in DMF (1.0 mL) was added trimethyl orthoacetate (0.63 mL, 5.04 mmol). The reaction mixture was stirred at 100° C. for 3 hours, and then concentrated in vacuo, and chromatographed to furnish the desired 3-methyl-9-phenyl-8-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridine (2-2) (28 mg) as its trifluoroacetic acid salt. 1H NMR: (500 MHz, CDCl3) δ 8.87 (s, 1H), 8.65 (d, J=6.4 Hz, 1H), 8.33 (d, J=7.5 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.49-7.41 (m, 3H), 7.36-7.30 (m, 8H), 3.61 (s, 2H), 3.02-3.00 (m, 2H), 3.00-2.84 (m, 1H), 2.25-2.21 (m, 2H), 2.10-1.83 (m, 4H), 1.97 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:29]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 75 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (25.0 g), dimethylformamide (200 ml), potassium carbonate (44.5 g) and ethyl 4-bromobutyrate (36.9 ml) were mixed at room temperature and stirred at 75° C. for 6 hr. The reaction mixture was cooled to room temperature, and the insoluble material was filtered off through celite. To the filtrate was added water (150 ml) and the mixture was extracted twice with ethyl acetate (100 ml, 50 ml). To the aqueous layer was added water (100 ml) again and the mixture was extracted twice with ethyl acetate (50 ml). To the combined organic layer was added n-hexane (100 ml), and the mixture was washed 3 times with water (100 ml) and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate-5/1 to 1/1) to give the title compound (33.4 g, 84%).
Reaction SMILES: [OH-].[K+].C([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:23]2[CH2:22][CH2:21][C@@:17]2([CH:18]([F:20])[F:19])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[O:28]C(=O)C)[CH2:8]1)(=O)C>CO.C(OCC)(=O)C>[F:19][CH:18]([F:20])[C@:17]12[CH2:21][CH2:22][C@H:23]3[C@@H:12]([CH2:11][CH2:10][C:9]4[C@:24]3([CH3:27])[CH2:25][CH2:26][C:7](=[O:6])[CH:8]=4)[C@@H:13]1[CH2:14][CH2:15][C:16]2=[O:28]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C(F)F)CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C(F)F)C(=O)CC[C@@H]12

Procedure:
After adding 22 ml of a 10% strength potassium hydroxide solution, a solution of 2.3 g of 18,18-difluoro-androst-5-ene-3β,17β-diol diacetate (crude product) in 130 ml of methanol is stirred for 1 hour at room temperature, whilst passing nitrogen through the solution. The reaction mixture is then concentrated to about 60 ml in an aspirator vacuum and taken up in ethyl acetate and the mixture is washed with 1 N hydrochloric acid and with water until neutral, dried and evaporated in an aspirator vacuum. The crude 18,18-difluoro-androst-5-ene-3β,17β-diol is suspended, without purification, in 80 ml of toluene, the suspension is treated with 8 ml of cyclohexanone and 2.2 g of aluminium isopropylate and the mixture is refluxed for 45 minutes with stirring. The cooled reaction mixture is worked up by diluting it with ethyl acetate and washing it successively with saturated Seignette salt solution (potassium sodium tartrate solution) and with water. The washings are further extracted with ethyl acetate and the organic phases are dried and evaporated in an aspirator vacuum. The amorphous residue is then chromatographed over 100 times the amount by weight of silica gel. Elution with a mixture of hexane/ethyl acetate (3:1) gives successively, in approximately equal amounts by weight, 18,18-difluoro-androst-4-ene-3,17-dione, which after recrystallisation from acetone/hexane melts at 161°-163° C, and 18,18-difluoro-17β-hydroxy-androst-4-en-3-one of melting point 183°-184° C (recrystallised from acetone/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.I[CH2:40][CH2:41][OH:42].CCN(CC)CC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[N:23]4[CH2:28][CH2:27][N:26]([CH2:40][CH2:41][OH:42])[CH2:25][CH2:24]4)[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: OCCI
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2N2CCNCC2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2N2CCN(CCO)CC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 48.3 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(piperazin-1-yl)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.09 mmol), 2-Iodo-ethanol (155 mg, 0.9 mmol) and Et3N (18 mg, 0.18 mmol) in acetone (1 mL) was heated at 80° C. for 1 h. Then the mixture was concentrated and the residue was purified by Prep-HPLC to give the title compound as a white solid (26 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8](Cl)=[C:7]([C:21](=O)[CH3:22])[N:6]=1)=[O:4].[K].CC(=[N:28][NH2:29])C.CC(=NO)C>>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]2[C:7](=[C:21]([CH3:22])[NH:28][N:29]=2)[N:6]=1)=[O:4]
Reactant: CC(C)=NN
Reactant: COC(=O)c1nc(C(C)=O)c(Cl)c(F)c1Nc1ccccc1F
Agent: CC(C)=NO
Agent: [K]
Product: COC(=O)c1nc2c(C)[nH]nc2c(F)c1Nc1ccccc1F

Procedure:
The title compound is prepared from 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (prepared in Example 8) and the potassium salt of acetone hydrazone in place of the potassium salt of acetone oxime by the method previously described in step H of Example 8.
Reaction SMILES: [OH-:1].[Na+:2].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]4[CH2:28][O:27][C:26](=[O:29])[C:14]=4[CH:15]=[C:16]4[C:24]=3[C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=[C:17]4[Cl:25])=[CH:11][C:6]=2[O:5][CH2:4]1>CO>[Na+:2].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([CH2:28][OH:1])=[C:14]([C:26]([O-:27])=[O:29])[CH:15]=[C:16]4[C:24]=3[C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=[C:17]4[Cl:25])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: [OH-]
Reactant: O=C1OCc2c1cc1c(Cl)cc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Agent: [Na+]
Solvent: CO
Product: O=C([O-])c1cc2c(Cl)cc3c(c2c(-c2ccc4c(c2)OCO4)c1CO)OCO3
Temperature: 70 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
1 N aqueous NaOH solution (1.56 mL) was added to the solution of 37 (57 mg, 0.15 mmol) in MeOH (25 mL). The mixture was stirred at 70° C. for 1 h. The solvent was evaporated to give a crude product, which was purified by silica gel column chromatography using CH2Cl2/MeOH (3:1, v/v) to afford 44 (55 mg, 87%) as a white powder. mp 220° C. (decomp.); 1H NMR (DMSO-d6) δ 8.39 (s, 1H, H4), 7.54 (s, 1H, H6), 6.89 (d, 1H, H5′, J=8.7 Hz), 6.73 (d, 1H, H2′, J=1.5 Hz), 6.63 (dd, 1H, H6′, J=1.5, 8.7 Hz), 6.05 (AB, 2H, 3′,4′-OCH2O—, Δδ=18.9 Hz), 5.81 (AB, 2H, 7,8-OCH2O—, A5=8.1 Hz), 4.12 (s, 2H, 2-CH2OH); MS (FAB, positive) m/z 425 [M+H+2]+, 423 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.CN1C[CH2:24][CH2:23][C:22]1=O.C(N(CC)CC)C.C([Sn](CCCC)(CCCC)/C=C/C)CCC>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]1([C@@H:12]([N:8]2[C:6]3=[N:7][C:2](/[CH:22]=[CH:23]/[CH3:24])=[CH:3][N:4]=[C:5]3[N:10]=[C:9]2[OH:11])[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN1CCCC1=O
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C/C=C/[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C/C=C/c1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 120 °C
Yield: 54 %

Procedure:
A thick-walled microwave bottle equipped with a stirbar was charged with (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), and (Ph3P)4Pd (0.12 equiv). The bottle was covered with a sheet of Parafilm and purged with nitrogen for 5 min, and N-methylpyrrolidone (14 volume equivalents), triethyl amine (2.0 equiv), and (E)-tributyl(prop-1-enyl)stannane (3.0 equiv) were added by syringe. The resulting mixture was immediately fitted with a septum and cap and heated to 120° C. in a microwave for 20 min. The reaction was then diluted with EtOAc, washed four times with saturated aq. NaHCO3 and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse-phase preparative HPLC provided the title compound (54%) as a foam. LCMS m/z (APCI)=281.1 (M+H).
Reaction SMILES: [CH3:1][Mg]I.[F:4][C:5]([F:19])([F:18])[CH2:6][CH:7]([CH3:17])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=O.Cl>C(OCC)C>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([CH:7]([CH3:17])[CH2:6][C:5]([F:19])([F:18])[F:4])=[CH2:1])=[CH:11][CH:12]=1
Reactant: C[Mg]I
Reactant: Cc1ccc(C(=O)C(C)CC(F)(F)F)cc1
Agent: Cl
Solvent: CCOCC
Product: C=C(c1ccc(C)cc1)C(C)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 1.45 ml (4.34 mmol) of a 3 M solution of methylmagnesium iodide in diethyl ether were initially charged in 10 ml of diethyl ether, and 1000 mg (4.34 mmol) of 4,4,4-trifluoro-2-methyl-1-(4-methylphenyl)butan-1-one, dissolved in 5 ml of diethyl ether, were added slowly at 0 C. The reaction mixture was then slowly warmed to room temperature and stirred overnight. The reaction solution was then slowly added to 15 ml of 1 M hydrochloric acid and diluted with diethyl ether. After removal of the organic phase, the aqueous phase was extracted three more times with diethyl ether. The combined organic phases were dried over magnesium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 50:1). This gave 710 mg (3.11 mmol, 71% of theory) of the title compound as a colorless oil.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32][C:33]1[CH:34]=[N:35][NH:36][CH:37]=1.[C:38]([O:42][C:43](=[O:49])[N:44]([CH2:46][CH2:47]O)[CH3:45])([CH3:41])([CH3:40])[CH3:39]>C1COCC1>[C:38]([O:42][C:43](=[O:49])[N:44]([CH2:46][CH2:47][N:35]1[CH:34]=[C:33]([Br:32])[CH:37]=[N:36]1)[CH3:45])([CH3:41])([CH3:40])[CH3:39]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: Brc1cn[nH]c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCn1cc(Br)cn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
Diethylazodicarboxylate (0.48 mL, 3.1 mmol) was added to a 0° C. solution of triphenylphosphine (0.80 g, 3.1 mmol) in THF (20 mL). After stirring for 5 minutes, 4-bromo-pyrazole (0.30 mg, 2.0 mmol) was added. After another 5 minutes of stirring, (2-hydroxyethyl)-methyl-carbamic acid tert-butyl ester (0.45 g, 2.6 mmol) was added. The reaction was allowed to warm to room temperature and stir overnight. The reaction was cooled to 0° C. and filtered. The filtrate was concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, ethyl acetate to afford [2-(4-bromo-pyrazol-1-yl)-ethyl]-methyl-carbamic acid tert-butyl ester (541 mg, 87%).