Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:43])[CH3:42])[C:34](Cl)=O.O>CN(C)C=O>[Cl:30][C:31]1[CH:32]=[C:33]([C:34]2[O:1][N:2]=[C:3]([C:4]3[C:14]4[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:9][C:8]=4[CH:7]=[CH:6][CH:5]=3)[N:22]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:42])[CH3:43]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=N)NO)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCN(C(=O)OC(C)(C)C)C4)no2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A mixture of 1,1-dimethylethyl 9-[(hydroxyamino)(imino)methyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 65) (32.9 g, 107 mmol) and triethylamine (17.9 ml, 128 mmol) in dry N,N-dimethylformamide (DMF) (200 ml) was cooled in ice/water under nitrogen. A solution of 3-chloro-4-[(1-methylethyl)oxy]benzoyl chloride (Preparation 102) (28.7 g, 123 mmol) in DMF (100 ml) was added over ca 20 minutes. When the addition was complete the mixture was allowed to warm to room temperature and stirred for 1 hour at room temperature, then at 120° C. for 3 hours. The mixture was allowed to cool and was poured into water (1 liter). The resulting solid was extracted into ethyl acetate (3×300 ml) and the extracts combined, washed with 1M hydrochloric acid (2×250 ml), then 1M sodium carbonate solution (3×250 ml), brine (250 ml), dried (sodium sulphate) and evaporated. The residue was purified by chromatography on silica. Eluting with a 10-40% gradient of ethyl acetate in isohexane to give the title compound as a crystalline solid (42.7 g) MS (ES): C25H2835ClN3O5 requires 485; found 486 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](Cl)=[N:8][CH:9]=1)([O-:3])=[O:2].[F-:11].[K+].C1CS(=O)(=O)CC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([F:11])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: [F-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-nitro-2-chloropyridine (2.0 g, 12.6 mmol) and anhydrous potassium fluoride (2.2 g, 38 mmol) in a combination of sulfalone (6 mL) and benzene (4 mL) was stirred at RT for 20 min. The benzene was then removed by distillation. The resulting mixture was heated at 150° C. for 12 h. The mixture was cooled to RT whereupon water (60 mL) was added. The desired product was separated from the solution via steam distillation. Extraction of the distillate with diethyl ether (2×10 mL) followed by drying (Na2SO4) and concentration gave 5-nitro-2-fluoropyridine as a water white oil (1.3 g, 73%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7](/[C:8](=[CH:14]/[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)/[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1.O>CO.CS(C)=O>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2C1Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Sodium borohydride (3.0 g, 79 mmol) (Aldrich) was added in small portions to a suspension of 6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one (19 g, 66 mmol) (from example 76a supra) in methanol (200 mL) and DMSO (50 mL) at such a rate that gas evolution was not too vigorous. When the addition was complete, mixture was stirred at room temperature for 0.5 h-1 h. After water (200 mL) was added, the resulting precipitate was collected and dried to give 18.3 g of rac-6-chloro-3-(4-chloro-benzyl)-1,3-dihydro-indol-2-one as a light yellow solid. MS: 293 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][O:20][CH3:21]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:6](=[O:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: O=c1cc(Cl)nc(Cl)[nH]1
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCn1c(Cl)nc(Cl)cc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
To a solution of 2,6-dichloro-3H-pyrimidin-4-one (600 mg, 3.65 mmol) in DMF (10 mL) was added K2CO3 (1.0 g, 7.3 mmol) and the mixture was stirred at RT for 10 min. 1-Bromo-3-methoxy-propane (101 mg, 7.3 mmol) was then added dropwise at 0° C., and the mixture was stirred at RT overnight. DMF was concentrated in vacuo, and the residue was purified by silica chromatography to give 400 mg of the title compound (47%). [M+H] Calc'd for; Calc'd for C8H10Cl2N2O2, 237. Found, 237.
Reaction SMILES: [C:1]([C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])#[N:2].C1(N=[CH:17][C:18]2[O:19][CH:20]=[CH:21][C:22]=2[CH3:23])C=CC=CC=1.ClC(OCCCC)=O>C1(C)C(C)=CC=CC=1>[CH2:6]([O:5][C:3]([C:1]1[CH:23]=[C:22]2[CH:21]=[CH:20][O:19][C:18]2=[CH:17][N:2]=1)=[O:4])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC(=O)C#N
Reactant: Cc1ccoc1C=Nc1ccccc1
Agent: CCCCOC(=O)Cl
Solvent: Cc1ccccc1C
Product: CCCCOC(=O)c1cc2ccoc2cn1
Temperature: 130 °C
Yield: 45.8 %

Procedure:
n-Butyl cyanoformate(13.7 g, 0.108 mol) and 3-methylfuran-2-carbaldehyde-N-phenylimine(5.0 g, 27.0 mmol) were mixed at room temperature in xylene (25 mL) then heated to reflux at 120 to 140° C. with stirring. A xylene (15 mL) solution of 7.40 g (54.2 mol) of n-butyl chloroformate was added dropwise for an hour to the resulting mixture. After all the solution had been added, the reaction mixture was heated to reflux for 2 hours, it was allowed to cool to room temperature, and the solvent was distilled off to give 7.10 g of crude product. This product was purified by column chromatography on silica gel, giving 2.71 g (45.8% yield) of 5-n-butoxycarbonylfuro[2,3-c]pyridine.
Reaction SMILES: [CH3:1][N+:2]([CH3:5])=[CH:3]Cl.[Cl-].P(Cl)(Cl)(Cl)=O.[Br:12][C:13]1[CH:14]=[C:15]([NH2:30])[C:16]([CH3:29])=[N:17][C:18]=1[O:19][C@H:20]1[CH2:25][CH2:24][C@@H:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1.Cl[CH2:32]Cl>>[Br:12][C:13]1[CH:14]=[C:15]([N:30]=[CH:1][N:2]([CH2:3][CH3:32])[CH3:5])[C:16]([CH3:29])=[N:17][C:18]=1[O:19][C@H:20]1[CH2:21][CH2:22][C@@H:23]([CH:26]([CH3:27])[CH3:28])[CH2:24][CH2:25]1
Reactant: Cc1nc(O[C@H]2CC[C@@H](C(C)C)CC2)c(Br)cc1N
Reactant: C[N+](C)=CCl
Reactant: ClCCl
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(C)C=Nc1cc(Br)c(O[C@H]2CC[C@@H](C(C)C)CC2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
The Vilsmeier reagent was freshly prepared by the slow addition of phosphorus oxychloride (7.09 mL, 75.89 mmol, 1.2 eq) to a solution of N,N-ethylmethylformamide (6.61 g, 75.89 mmol, 1.2 eq) in dichloromethane (75 mL) at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The Vilsmeier reagent was then added drop wise over 40 min to a solution of 5-bromo-6-(cis-4-isopropylcyclohexoxy)-2-methyl-pyridin-3-amine (20.70 g, 63.24 mmol) in dichloromethane (225 mL) at room temperature under inert atmosphere (Ar). Stirring was continued for 1.5 h at room temperature. The reaction mixture was then quenched by the addition of water (100 mL) and the pH was adjusted to 14 by the addition of a 2.0 molar aqueous NaOH solution (80 mL). The phases were separated and the aqueous phase extracted with dichloromethane (2×100 mL). The organic layer was washed with brine (250 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give a residue, which was purified by column chromatography (silica gel, heptane/ethyl acetate, v/v=1/0-4/1). Fractions containing the pure compound were collected and concentrated in vacuo to give the title compound (20.23 g, 81%) as a yellow oil.
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[C:4](=[O:11])[NH:3][C:2]1=[O:12].C(O)(=O)C.C(N(C(C)C)C(C)C)C.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH:32]=O)[CH3:27].C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH2:32][N:8]1[CH2:9][CH2:10][C:5]2([NH:1][C:2](=[O:12])[NH:3][C:4]2=[O:11])[CH2:6][CH2:7]1)[CH3:27]
Reactant: O=C1NC(=O)C2(CCNCC2)N1
Reactant: CCOc1cc(C=O)ccc1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC3(CC2)NC(=O)NC3=O)ccc1C
Temperature: 55 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
To a solution of 1,3,8-triaza-spiro[4.5]decane-2,4-dione (25.4 mg, 0.15 mmol, 1.0 equiv; intermediate A1) in ethanol (1 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) was added 3-ethoxy-4-methyl-benzaldehyde (29.6 mg, 0.18 mmol, 1.2 equiv; intermediate B10, vide infra) and the mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 8.6 mg (17%) of the title compound. MS (ISP): 338.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:10]([SH:13])[NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:21][CH2:22][CH2:23]Br.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:10]3[S:13][CH2:21][CH2:22][CH2:23][N:11]3[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1[nH]nc(-c2cccc(Br)c2)c1-c1ccncc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Yield: 50 %

Procedure:
5-(3-Bromo-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (60 mg, 0.22 mmol), 1,3-dibromopropane (22 ul, 0.22 mmol), K2CO3 (152 mg, 1.1 mmol) and dry DMF (5 ml) were reacted at room temperature for 16 hours. Water was added and the reaction extracted with ethyl acetate. The pooled organic extracts were washed with brine, dried over sodium sulphate and evaporated down. The crude material was purified by flash column chromatography eluting with ethyl acetate:hexane (1:1) to give a white solid (50% yield over two steps).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.[CH2:21]([O:28][CH2:29][CH2:30][OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:38]1OCCOCCOCCOCCOCCO[CH2:39]1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:21]([O:28][CH2:29][CH2:30][O:31][C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:38][CH3:39])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: OCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1CC[C@@H](Nc2cc(OCCOCc3ccccc3)ncc2[N+](=O)[O-])CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a suspension of cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acid (5 g, 16.68 mmol) in toluene (111 mL) was added 2-(benzyloxy)ethanol (7.62 g, 50.0 mmol), cesium carbonate (16.31 g, 50.0 mmol), and 18-crown-6 (6.61 g, 25.02 mmol). The resulting mixture was purged with argon and stirred at 75° C. overnight. The mixture was allowed to cool to RT and diluted with EtOAc to about 150 mL total volume and washed sequentially with brine (2-150 mL), aqueous NH4Cl (2-150 mL) and water (150 mL). The organic phase was collected, dried over sodium sulfate and concentrated under reduced pressure. The residue was suspended in EtOH (111 mL) and thionyl chloride (36.5 mL, 500 mmol) was added dropwise via syringe. The reaction mixture was stirred at RT for 16 hours. The mixture was concentrated to ⅓ volume and diluted with DCM (150 mL). The organic portion was washed with aqueous NaHCO3 (100 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (10-50% EtOAc/Hexanes) to afford cis-ethyl 4-(2-(2-(benzyloxy)ethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxylate (5.6 g, 76% yield). MS m/z=444.2 [M+H]. Calc'd for C23H29N3O6: 443.2.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:8]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]3)=[CH:4][CH:3]=1.C(OCC)(=O)C.[C:40]1([CH3:50])[CH:45]=[CH:44][C:43]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:42][CH:41]=1>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[C:8]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]3)=[CH:4][CH:3]=1.[CH3:50][C:40]1[CH:41]=[CH:42][C:43]([S:46]([O-:49])(=[O:48])=[O:47])=[CH:44][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Place 6-(5-methylthiophen-2-yl)-5-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-ol (103.4 mg, 0.22 mmol) in a vial. Add ethyl acetate (4 mL) and p-toluenesulfonic acid (52 mg, 0.30 mmol) and stir at ˜60° C. Add tetrahydrofuran to clarify the solution and sonicate for 15 minutes. Carefully decant the suspension from gum that forms on the flask. Filter the suspension to obtain a cake of very light pink solids. Wash the cake with pentane (2×2 mL) and dry in a 40° C. vacuum oven overnight to obtain the title compound. MP (DSC)=136.24° C.
Reaction SMILES: [OH:1][C:2]1[C:12](I)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.CN(C=O)C.[CH:19](B(O)O)=[CH2:20].C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][C:2]1[C:12]([CH:19]=[CH2:20])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1
Reactant: C=CB(O)O
Reactant: CCOC(=O)c1cnc(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cc(C(=O)OCC)cnc1O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
Ethyl 6-hydroxy-5-iodonicotinate (200 mg, 0.682 mmol) was added with N,N′-dimethylformamide (4.1 mL) and water (1.4 mL). The resultant mixture was then added with tetrakis triphenylphosphine palladium (79 mg, 0.0682 mmol), vinylboronic acid (417 μL, 2.46 mmol) and sodium carbonate (433 mg, 4.09 mmol), and stirred at 80° C. for 20 minutes. Subsequently, the resultant mixture was further added with tetrakis triphenylphosphine palladium (79 mg, 0.0682 mmol) and vinylboronic acid (417 μL, 2.46 mmol), and stirred at 80° C. for 20 minutes. The reaction solution was filtered using celite and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (chloroform/acetone) and concentrated in vacuo. Ethyl 6-hydroxy-5-vinylnicotinate (95 mg, yield 72%) was obtained as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[K+]>CO.O>[CH3:6][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])[C:3]([OH:13])=[O:2]
Reactant: COC(=O)C(C)(C)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 87 %

Procedure:
A solution of 0.10 mole (1 eq.) of α,α-dimethylphenylacetic acid methyl ester 2 in 150 mL of MeOH and 50 mL of water was added 1.02 mole (10. 1 eq.) of KOH pellets. After stirring at room temperature for 3.5 days, the methanol was stripped off by rotary evaporation. To the residual liquid was added 100 mL of water and enough concentrated HCl to bring to ˜pH 3. The aqueous solution was extracted with Et2O (3×100 mL). The combined organic layers were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and dried under vacuum to give a white solid as α,α-dimethylphenylacetic acid 3 (87-89%). Method D
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1([Cl:17])C=O.[C:21](=O)([O-])[O-].[K+].[K+].[C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])#[N:28].O>C(O)C>[C:27]([C:29](=[CH:21][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[C:2]([Cl:1])[CH:3]=2)[C:7]=1[Cl:17])[C:30]([O:32][CH2:33][CH3:34])=[O:31])#[N:28]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC#N
Reactant: O=CC1(Cl)Cc2ccccc2N1Cc1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1c(Cl)n(Cc2cccc(Cl)c2)c2ccccc12

Procedure:
To 500 mg of 1-(3-chlorobenzyl)-2-chloroindole-carbaldehyde, slurried in 10 ml of ethanol, was added 500 mg of potassium carbonate and 0.19 ml of ethyl cyanoacetate. After overnight stirring 10 ml of water was added, and the product collected by filtration, washed with water, and dried to give (10a). Yield 510 mg of (10a). M.p. 130.5°-132° C. (sample recryst. from EtOH).
Reaction SMILES: [NH3:1].C([O:4][C:5]([C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:18]4[CH2:27][CH2:28][CH2:29][C:17]=34)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)=O)C.ClCCl.CO>CO>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]3[N:11]([C:7]([C:5]([NH2:1])=[O:4])=[CH:8][N:9]=3)[CH:12]=2)=[C:17]2[CH2:29][CH2:28][CH2:27][N:18]2[N:19]=1
Reactant: N
Reactant: CCOC(=O)c1cnc2ccc(-c3c(-c4ccccn4)nn4c3CCC4)cn12
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cnc2ccc(-c3c(-c4ccccn4)nn4c3CCC4)cn12
Temperature: 110 °C
Yield: 82 %

Procedure:
Add 7N ammonia in methanol (10 mL) to a sealed tube containing 6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (Example 35; 0.105 g, 0.28 mmol). Heat at 110° C. for 48 h. Flash chromatograph using dichloromethane/methanol mixtures to give the title compound (0.08 g, 82%) as a white solid. MS ES+ m/e 344.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.4-8.37 (m, 1H), 8.28 (s, 1H), 7.82-7.77 (m, 3H), 7.59 (d, J=9 Hz, 1H), 7.4 (dd, J=9.0, 2.0 Hz, 1H), 7.25 (m, 1H), 4.21 (t, J=7 Hz, 2H), 2.99 (t, J=7, 2H), 2.62 (quintet, 2H, 8 Hz).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.C([Li])CCC.[CH:40]1([CH2:43][OH:44])[CH2:42][CH2:41]1>>[CH:40]1([CH2:43][O:44][C:5]2[N:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:8]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:7]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:6]=2)[CH2:42][CH2:41]1
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCC1CC1
Agent: [Li]CCCC
Product: Fc1ccc(Oc2nc(OCC3CC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cc1F

Procedure:
2-Methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 20 (65 mg, 0.12 mmol) was reacted with 2 equivalents each of n-butyl lithium and cyclopropylmethanol by the procedure described in Reference Example 6 and 7 to afford the title compound: HPLC/MS: m/e=533 (M++1); Rt=5.12 min. 1H-NMR 400 MHz (CDCl3): 0.56-0.61 (m, 2H), 1.23-1.30 (m, 2H), 1.57 (s, 1H), 4.01 (d, J=7 Hz, 2H), 6.90-6.94 (m, 1H), 7.04-7.10 (m, 1H), 7.12-7.28 (m, 7H), 7.35 (d, J=2 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[C:21]3Cl)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:27]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[C:21]3[NH2:27])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2cccc3c(Cl)nccc23)CC1
Reactant: N
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2cccc3c(N)nccc23)CC1
Temperature: 150 °C
Reaction time: 20 h

Procedure:
A solution of Intermediate 130 (500 mg) in dioxane (2.5 ml) was added with 28% aqueous ammonia solution (2.5 ml) and stirred at 150° C. for 20 hours in a sealed tube. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with dioxane (6 ml), 2 N aqueous sodium hydroxide (2 ml) and di-t-butyl dicarbonate (655 mg) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=30:1) to obtain the title compound (95.0 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19].[BH3-]C#N.[Na+].CC(O)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[C:5]([CH3:10])=[C:6]([CH:9]=1)[CH2:7][NH:19][CH2:18][CH:17]([O:20][CH3:21])[O:16][CH3:15]
Reactant: COC(CN)OC
Reactant: Cc1c(C=O)cc(Br)cc1OC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(CNCc1cc(Br)cc(OC(C)C)c1C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a solution of 5-bromo-2-methyl-3-(propan-2-yloxy)benzaldehyde (108b, 4.5 g, 18 mmol) and 2,2-dimethoxyethanamine (2.2 g, 21 mmol) in MeOH (50 mL) was added NaBH3CN (1.4 g, 22 mmol) and HOAc (1 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (50 mL). The reaction mixture was concentrated under vacuum. The residue was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=5:1) to obtain N-[5-bromo-2-methyl-3-(propan-2-yloxy)benzyl]-2,2-dimethoxyethanamine (108c, 3.5 g, 58%) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][C:6]([CH3:9])([OH:8])[CH3:7].[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>C(#N)C>[OH:8][C:6]([CH3:9])([CH3:7])[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][CH2:12][CH2:11][CH2:17][S:14]([OH:16])(=[O:15])=[O:13])[CH3:10]
Reactant: CC(N)CCCC(C)(C)O
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: CC(CCCC(C)(C)O)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 70.2 %

Procedure:
To a solution of 6-amino-2-methyl-2-heptanol (2.5 g, 17.2 mmol) in acetonitrile (22 mL) was added 1,3-propane sultone (2.0 g, 16.4 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was filtered and washed with acetonitrile (2×20 mL). The solid was dissolved in 20% MeOH (75 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (150 mL), and then the solid material was filtered and dried in vacuo, affording the title compound (3.08 g, 70%). 1H NMR (D2O, 500 MHz) δ ppm 3.19 (m, 1H), 3.08 (m, 2H), 2.88 (t, 2H, J=7.3 Hz), 1.99 (m, 2H), 1.60 (m, 2H), 1.36 (m, 4H), 1.18 (d, 3H, J=6.8 Hz), 1.07 (s, 6H). 13C (D2O, 125 MHz) δ ppm 71.63, 54.73, 48.08, 43.46, 42.27, 32.97, 27.78, 27.73, 21.64, 19.67, 15.43. ES-MS 268 (M+1).