Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2Cl)CC1
Yield: 73 %

Procedure:
To a suspension of 3-chloro-4-(piperidin-4-yloxy)nitrobenzene (1.00 g) obtained in reference example 8 in dichloromethane (20 ml) were added successively methanesulfonyl chloride (0.33 ml) and triethylamine (1.09 ml) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (0.96 g, yield: 73%) as a colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[C:25](C(O)=O)[CH:24]=[CH:23][N:22]4[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C([N:40](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>[Pd].CO.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[C:25]([NH2:40])[CH:24]=[CH:23][N:22]4[C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH2:12]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C(=O)O)ccn4c3-c3ccccc3)cc2)CCC1
Reactant: CCN(CC)CC
Agent: [Pd]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(N)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 129.9 %

Procedure:
A solution of 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid (1.20 g, 0.86 mmol) and 10% palladium on carbon (0.2 g) in MeOH (20 mL) in DMF (40 mL) and water (3.4 mL) was added triethylamine (0.38 mL, 2.73 mmol, 1.1 equiv) followed by diphenylphosphoryl azide (751 mg, 2.73 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature 10 minutes, at 100° C. for 6 h, at room temperature for 12 h. To the resulting mixture was added triethylamine (0.38 mL, 2.73 mmol, 1.1 equiv) followed by diphenylphosphoryl azide (751 mg, 2.73 mmol, 1.1 equiv). The resulting mixture was heated at 100° C. for 12 h. The resulting mixture was separated between EtOAc (100 mL) and water (50 mL). The organic phase was dried (Na2SO4 anh) and concentrated under reduced pressure. The remaining material (1.4 g) was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 3.5 min., gradient to 90% CH2Cl2: 10% MeOH over 1 min.; 90% CH2Cl2: 10% MeOH for 5.5 min., gradient to 80% CH2Cl2: 20% MeOH over 6 min., 80% CH2Cl2: 20% MeOH for 10.2 min.) to give {1-[4-(7-amino-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (508 mg, 45%):
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[Br:13]Br>CC(O)=O.O>[Br:13][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]([O:11][CH3:12])=[CH:4][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1Cl
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c(Br)cc1Cl
Temperature: 60 °C
Yield: 70.5 %

Procedure:
A solution of 4-chloro-3-methoxybenzoic acid (5.0 g, 26.7 mmol) in HOAc (25 mL) and water (25 mL) was treated slowly with Br2 (1.6 mL 32 mmol). After heating to 60° C. for 2 h, the reaction was stirred cooled to rt overnight. It was quenched with water (300 mL), and the precipitate was filtered and dried to yield 2-bromo-4-chloro-5-methoxybenzoic acid (5.0 g, 70%). (264.87 [M−H]) 1H NMR: (400 MHz, DMSO) δ: 3.90 (s, 3H), 7.46 (s, 1H), 7.82 (s, 1H), 13.63 (s, 1H).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:10]([OH:27])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[C:18]=1[CH3:26])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:40]([Si:44]([CH3:47])([CH3:46])Cl)([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:10]([O:27][Si:44]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:47])[CH3:46])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[C:18]=1[CH3:26])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Reaction time: 2.25 h

Procedure:
A solution of 1.153 g (2.445 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3-dimethyl-4-methoxyphenyl)methyl]hexanoic acid, 1.372 g (20.05 mmol) of imidazole and 1.709 g (11.0 mmol) of tert-butyldimethylchlorosilane in 8.7 ml of abs. DMF is stirred at RT for 18 h under argon. After that, the reaction mixture is poured onto ice-water and the whole is extracted with ethyl acetate. The organic phase is washed with cold 10% citric acid solution and saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated on a RE at approximately 30° C. The resulting product is dissolved in 28.8 ml of methanol and 11.2 ml of THF, and this solution is treated, at RT, with 1.962 g of potassium carbonate in 11.2 ml of water. After having been stirred for 2.25 h, the reaction mixture is concentrated down to half its volume at approximately 30° C. and the residue is treated with ethyl acetate and (cold) 10% citric acid solution, and the phases are separated. The organic phase is washed a further two times with saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The residue is purified by being chromatographed twice on silica gel (hexane:ethyl acetate, 1:1 and then 3:1), and the title compound is obtained. TLC Rf (hexane:ethyl acetate. 1:1)=0.42. FAB-MS (M+H)+ =586. IR (KBr) inter alia: 1711, 1485, 1260 and 1107 cm-1. 1H-NMR (CD3OD) inter alia: 7.30-7.06 (m, 5H); 6.91 and 6.65 (each d, each 1H); 6.00 and 5.41 (each d, in all 1 H from NH); 3.75 (s, 3H); 2.21 and 2.12 (each s, each 3H); 1.31 and 1.21 (each s, in all 9H from Boc); 0.89 (s, 9H); 0.12 and 0.08 (each s, each 3H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O>[N:13]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)=[N+:14]=[N-:15]
Reactant: CC(=O)c1ccc(CCBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(CCN=[N+]=[N-])cc1

Procedure:
For the preparation of the starting material of Example 10a, p-(2-bromoethyl)-acetophenone was reacted with sodium azide in dimethylsulfoxide to give p-(2-azidoethyl)acetophenone. Oxidation with sodium hypobromite gave p-(2-azidoethyl)benzoic acid (m.p. 130°-131°, from acetone-hexane), which was converted with thionyl chloride into the corresponding acid chloride and subsequently with ammonia into p-(2-azidoethyl)benzamide. Treatment with triphenylphosphine and hydrolysis gave p-(2-aminoethyl)benzamide, m.p. 132°-133° (from ethanol).
Reaction SMILES: [C:1]([OH:11])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>ClCCl>[C:1]([Cl:20])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 15.80 g (0.10 mol) of nonanoic acid in 150 mL of dichloromethane at 0° C. was added 0.1 mL of N,N-dimethylformamide and 9.59 mL (0.11 mol) of oxalyl chloride. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then concentrated in vacuo, diluted with hexanes and filtered. The filtrate was concentrated in vacuo to provide 17.67g (100%) of nonanoyl chloride which was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:17]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:17]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cccc(CCN(C)C)c1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cccc(CCN(C)C)c1
Yield: 77.5 %

Procedure:
Following general procedure F, 1-{6-bromo-4-[3-(2-(dimethylamino)ethyl)phenylamino]quinolin-3-yl}ethanone (50 mg, 0.120 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.180 mmol) to afford the desired product (46 mg, 77%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.31 (s, 1H), 8.20 (dd, J=8.8, 2.0 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.70-7.56 (m, 2H), 7.51 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.10 (s, 2H), 3.40-3.30 (m, 2H), 3.21-3.11 (m, 2H), 2.94 (s, 6H), 2.82 (s, 3H); ESI MS m/z 494 [C27H25Cl2N3O2+H]+; HPLC 96.8% (AUC), tR=8.94 min.
Reaction SMILES: [P:1]([O-:21])([O:12][CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])([O:3][CH2:4][CH:5]([CH2:10][CH3:11])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:2].[NH3:22]>CCCCCC>[P:1]([O-:21])([O:3][CH2:4][CH:5]([CH2:10][CH3:11])[CH2:6][CH2:7][CH2:8][CH3:9])([O:12][CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:2].[NH4+:22]
Reactant: N
Agent: CCCCC(CC)COP(=O)([O-])OCC(CC)CCCC
Solvent: CCCCCC
Product: [NH4+]
Temperature: 50 °C

Procedure:
To a four neck flask of 200 ml are added 19.94 g (60 mmol) of di(2-ethylhexyl) phosphate [Starting Material A] and 40.0 g of hexane at 20° C., which are gradually heated to 50° C. and thereafter 3.46 g (60 mmol) of a 29.6% aqueous solution of ammonia is added dropwise to obtain a solution of ammonium di(2-ethylhexyl) phosphate. Then, 11.8 g (20 mmol) of a 55.04% aqueous solution of lanthanum nitrate is added to this solution at a dropping rate of 1 ml/min and further the reaction is continued at the same temperature for 60 minutes. The reaction solution is left at rest to remove the separated water layer and the resulting organic phase is washed with 25 ml of water three times, and then a reflux dehydrator is mounted onto the vessel to remove water and the solvent in the reaction solution through azeotropy, and subsequently the same procedure as in [Example 1] is conducted to obtain 55.2 g of a solution of lanthanum di(2-ethylhexyl) phosphate in cyclohexane having a concentration of about 40%. The analytical results are shown in Table 1.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10]C)=[C:8]([F:12])[C:7]([Br:13])=[C:6]([CH3:14])[C:3]=1[C:4]#[N:5].B(Br)(Br)Br.O.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:12])[C:7]([Br:13])=[C:6]([CH3:14])[C:3]=1[C:4]#[N:5]
Reactant: COc1c(N)c(C#N)c(C)c(Br)c1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1c(Br)c(F)c(O)c(N)c1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.3 %

Procedure:
2-Amino-5-bromo-4-fluoro-3-methoxy-6-methylbenzonitrile (I-45) (8.63 g, 33.30 mmol) was dissolved in methylene chloride (270 ml), and at −20° C., boron tribromide (1 M methylene chloride solution, 100 ml, 100.00 mmol) was gradually dropwise added. With gradually heating, this was stirred at room temperature for 15 hours. After the reaction, water with ice was added, followed by neutralization to pH of 7 with an aqueous saturated sodium hydrogencarbonate solution. Adding methylene chloride for fractionation was tried, but resulted in suspension, and therefore, this was dissolved in ethyl acetate, washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was recrystallized and purified with n-hexane/methylene chloride to obtain the entitled compound (7.86 g, 96%) as a pale brown solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:3]1.[H-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](F)[CH:31]=1.O>CN(C)C=O>[Cl:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[O:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:3]1
Reactant: Fc1cccc(Cl)c1
Reactant: Cc1ccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2Oc2cccc(Cl)c2)cc1C
Reaction time: 2 h

Procedure:
A solution of 15.0 g (0.04 mol) of the trans-3-hydroxy-4-(3,4-dimethyl-phenoxy)-1-carbobenzyloxy-piperidine described in Example 19 in 100 ml of dimethylformamide is introduced in the course of 30 minutes, at 30°-35°, into a suspension of 2.8 g (0.062 mol) of a 55% strength oily dispersion of sodium hydride in 50 ml of dimethylformamide. The mixture is then warmed to 50° and treated dropwise with 7.16 g (0.055 mol) of 1-chloro-3-fluorobenzene. The reaction mixture is subsequently stirred for 41/2 hours at 60°-70° and then for 15 hours at room temperature, cooled in an ice-water bath and treated with 250 ml of water. The mixture is extracted by shaking with 3 times 250 ml of ethyl acetate and the combined organic phases are washed twice with water, dried over magnesium sulphate and evaporated to dryness, first under a water pump vacuum and then under a high vacuum. The oil which remains behind is dissolved in 100 ml of toluene and the solution is filtered through a layer of silica gel. Elution with a toluene/ethyl acetate mixture (4:1) gives trans-3-(3-chloro-phenoxy)-4-(3,4-dimethylphenoxy)-1-carbobenzyloxy-piperidine in the form of a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][O:16][CH2:17][CH3:18].[I-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:14][CH2:15][O:16][CH2:17][CH3:18])=[C:4]([CH3:10])[CH:3]=1
Reactant: CCOCCBr
Reactant: Cc1cc(Br)cc(C)c1O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1c(C)cc(Br)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2,6-dimethylphenol (20 g) in DMF (10 ml) was added dropwise to a suspension of 60% sodium hydride (4.4 g) in DMF (50 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. To the mixture were added bromoethylethyl ether (12.3 ml) and sodium iodide (16.4 g), and the mixture was stirred at 75° C. overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was distilled under reduced pressure to give 5-bromo-2-(2-ethoxyethoxy)-1,3-dimethylbenzene (24.1 g) as colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N:5]/[O:6][CH3:7].[Cl-].[Al+3].[Cl-].[Cl-].[C:26](Cl)([CH3:29])([CH3:28])[CH3:27]>[N+](C)([O-])=O.O>[CH3:1][NH:2][C:3](=[O:21])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[CH:17][C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:20]=1)=[N:5]/[O:6][CH3:7]
Reactant: CC(C)(C)Cl
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
To a solution of (E)-N-methyl-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (300 mg) in nitromethane (3 ml), aluminium chloride (423 mg) and t-butyl chloride (147 mg) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with diethyl ether. The solvent was dried and evaporated, and the residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate to give 375 mg of the objective compound.
Reaction SMILES: [Li]CCCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[C:31]2=[O:38])[CH:27]=[CH:28][CH:29]=1.[CH3:39][O:40][CH2:41]I>C1COCC1>[CH3:39][O:40][CH2:41][C:30]1([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=2)[CH2:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[C:31]1=[O:38]
Reactant: COCI
Reactant: COc1cccc(C2CCCCN(C)C2=O)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCC1(c2cccc(OC)c2)CCCCN(C)C1=O
Reaction time: 1 h

Procedure:
To 1.6 M n-BuLi in hexane (3.38 mL, 5.42 mmol) at 0° C. was added a solution of 2,2,6,6-tetramethyl piperidine (0.91 mL, 5.42 mmol) in anh. THF (10 mL) over 5 min. A solution of 3-(3-methoxy-phenyl)-1-methyl-azepan-2-one (as described in Example 4, Step A) (0.632 g, 2.71 mmol) in anhydrous THF (10 mL) was added and stirred OC for 1 h. Iodomethyl methyl ether (0.275 mL, 3.25 mmol) was added. After stirring for 30 min, the reaction was quenched with H2O, concentrated in vacuo, diluted with EtOAc, washed with 5N HCl (100 mL), water and brine. The organic layer was dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([O-:18])=[O:17])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[Li+].[OH-].O>C1COCC1.CO>[N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1ccc(C(=O)[O-])cc1NC(=O)c1cnc2ccccn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoate (3) (5.43 g, 17.6 mmol) in THF (225 ml) and MeOH (150 mL) was added LiOH 3 M (17.5 mL) and water (50 mL). The reaction was stirred at room temperature for 12 hours then reduced in volume on roto-vap to remove THF and MeOH. The mixture was diluted with water (75 mL) and neutralized with HCl (17.5 mL of a 3M solution). The resulting precipitate was filtered, washed with water and dried under vacuum to afford 3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylbenzoic acid (4) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 10.0 (s, 1H), 9.45 (dt, J=6.8, 1.2 Hz, 1H), 8.58 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.79 (dt, J=9.2, 1.2 Hz, 1H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 7.52 (ddd, J=9.2, 9.2, 1.2 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.17 (td, J=6.8, 1.2 Hz, 1H), 2.35 (s, 3H). MS m/z 296.1 (M+1)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([C:41]4[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=4)[CH2:36][CH2:37]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][S:15][CH2:16][C@@H:8]12
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (80.0 mg, 0.318 mmol) was suspended in propionitrile (0.8 mL) and (cyanomethyl)trimethylphosphonium iodide (93.0 mg, 0.382 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (167 ul, 0.955 mmol). To the stirred mixture was then added 6-(piperazin-1-yl)nicotinonitrile (59.9 mg, 0.318 mmol). The reaction was heated to 90° C. with stirring for 16 h. The reaction was cooled to room temperature and left to sit 48 h. The precipitate was filtered off, washed with ethanol (5 mL) and dried in vacuum to afford the title compound (53.9 mg, 40.2%) as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 8.41 (d, J=1.8 Hz, 1H), 7.78 (d, J=1.8 Hz, 2H), 7.62 (dd, J=8.8, 2.3 Hz, 1H), 6.95 (br. s., 1H), 6.60 (d, J=8.8 Hz, 1H), 5.06 (dt, J=13.6, 2.8 Hz, 1H), 4.43 (dd, J=10.4, 3.3 Hz, 1H), 3.70 (br. s., 4H), 3.45 (br. s., 2H), 3.15 (td, J=12.9, 2.3 Hz, 1H), 3.00 (td, J=12.8, 2.8 Hz, 1H), 2.78-2.94 (m, 2H), 2.54 (br. s., 4H), 2.40 (dd, J=13.6, 1.5 Hz, 1H). [M+H] calc'd for C21H23N7OS, 422. found, 422.
Reaction SMILES: ClC(C1C(CC2CC2)=C(C(OC)=O)C(C(F)F)=NC=1C(F)(F)F)=O.[CH:25]1([CH2:28][C:29]2[C:34]([C:35]#[N:36])=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=[C:31]([CH:41]([F:43])[F:42])[C:30]=2[C:44]([O:46][CH3:47])=[O:45])[CH2:27][CH2:26]1.C(NCC)C.[SH2:53]>CN(C=O)C>[NH2:36][C:35](=[S:53])[C:34]1[C:29]([CH2:28][CH:25]2[CH2:27][CH2:26]2)=[C:30]([C:44]([O:46][CH3:47])=[O:45])[C:31]([CH:41]([F:43])[F:42])=[N:32][C:33]=1[C:37]([F:40])([F:38])[F:39]
Reactant: S
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C#N)c1CC1CC1
Agent: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)Cl)c1CC1CC1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(N)=S)c1CC1CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Methyl 5-chlorocarbonyl-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (example B3 of U.S. Pat. No. 5,156,670) was converted to methyl 4-(cyclopropylmethyl)-5-cyano-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridine-carboxylate by the procedure similar to example 88 and 92 of U.S. Pat. No. 4,692,184. A solution of 20 g (60 mmol) of this cyano compound and 0.62 g (6 mmol) of diethylamine in 60 ml of DMF was heated to 50° C. Hydrogen sulfide gas was introduced into this solution. When absorption of hydrogen sulfide was complete the reaction mixture was stirred at 50° C. for 1 h and poured into water and extracted with ether. The ether extract was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was kugelrohr distilled to give 17.7 g (80% yield) of yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[CH:9]=[C:8]([C:10](OC)=[O:11])[N:7]=[C:4]2[S:5][CH:6]=1.O>C1C=CC=CC=1.C1COCC1>[CH3:1][C:2]1[N:3]2[CH:9]=[C:8]([CH2:10][OH:11])[N:7]=[C:4]2[S:5][CH:6]=1
Reactant: COC(=O)c1cn2c(C)csc2n1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc2nc(CO)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
100 ml of a 70% solution of NaAlH2 (CH3OCH2CH2O)2 in benzene are dropped at 25° into a suspension of 25 g of 3-methyl-6-carbomethoxy-imidazo-(2,1-b)thiazole, prepared as described in Example 8, in 250 ml of dry THF. The suspension is stirred for 2 hours at room temperature and thereafter 25 ml of water are slowly added. The suspension is then filtered and the filtrate concentrated to yield 21 g of 3-methyl-6-hydroxymethyl-imidazo-(2,1-b)thiazole; m.p. 155°-156° (methyl-ethyl-ketone).