Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][N:3]=1.[C:20]1([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:8]([C:5]1[CH:4]=[N:3][C:2]([C:29]2[CH:30]=[CH:31][C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:27][CH:28]=2)=[N:7][CH:6]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: OB(O)c1ccc(-c2ccccc2)nc1
Reactant: CCCCCCCCCCCCc1cnc(Br)nc1
Product: CCCCCCCCCCCCc1cnc(-c2ccc(-c3ccccc3)nc2)nc1

Procedure:
The synthesis was carried out analogously to Example 27 from 2-bromo-5-dodecylpyrimidine and 2-phenylpyridine-5-boronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:15]([S:19](Cl)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]>C(Cl)Cl>[CH2:15]([S:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]
Reactant: Nc1ccccc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)Nc1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
9.9 ml of aniline (10.1 g, 108.4 mmol) and 15 ml of triethylamine (11.0 g, 108.4 mmol) were dissolved at 50° C. in 108 ml of methylene chloride. Again at 50° C. 14.1 ml of n-butanesulfonyl chloride (17.0 g, 108.4 mmol) were added dropwise to this solution over the course of 1 h. After 15 minutes of stirring at 50° C. the reaction mixture was extracted twice with 100 ml of water. The resultant crude product in solution in 150 ml of methylene chloride was extracted with 150 ml of 1 N NaOH. The aqueous phase was adjusted to a pH of 1–2 using concentrated HCl and was extracted twice with 100 ml of methylene chloride. Drying over magnesium sulphate and removal of the methylene chloride by distillation gave 17.0 g of the target compound, whose constitution was verified by NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2([NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[C:14]([O:22][CH3:23])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc1C1(NC(=O)c2ccccc2)C(=O)c2ccccc2C1=O
Yield: 100.8 %

Procedure:
A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (200 mg, 0.60 mmol) in dichloromethane (10 ml) was stirred overnight together with benzoyl chloride (0.09 mL, 0.77 mmol) and triethylamine (0.27 mL, 1.9 mmol) at room temperature. The reaction mixture was extracted with dichloromethane, and purified by silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (250 mg, 97%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[C:15]([CH3:16])[C:10]3=[CH:9][N:8]=2)[CH2:4][C:3]1=[O:17].CN(C)C=O.[Br:23]N1C(=O)CCC1=O>O>[Br:23][C:9]1[N:8]=[C:7]([CH:5]2[CH2:6][N:2]([CH3:1])[C:3](=[O:17])[CH2:4]2)[N:11]2[CH:12]=[CH:13][N:14]=[C:15]([CH3:16])[C:10]=12
Reactant: Cc1nccn2c(C3CC(=O)N(C)C3)ncc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn2c(C3CC(=O)N(C)C3)nc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
1-Methyl-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-2-one (293 mg, 1.27 mmol) was dissolved N,N-dimethylformamide (12 ml) and N-bromosuccinimide (227 mg, 1.27 mmol) was added and reation mixture was stirred at room temperature overnight. Then water was added to the reaction mixture and extracted with chloroform/iso-propanol (9/1) three times. The combined organic layers were dried (Na2SO4) and concentrated in vacuo and a brown oil was obtained. The residue was purified by column chromatography (silica gel; dichloromethane/methanol/heptane=9/1/4) to give 4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)-1-methylpyrrolidin-2-one (200 mg).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[CH:7][N:6]=1.O>CO>[Cl:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[N:8]=[CH:7][N:6]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(Cl)ncn1
Temperature: 25 °C
Yield: 100 %

Procedure:
5.8 g sodium methanolate was added to 10 g 4,6-dichloropyrimidine in 150 mL MeOH at 0° C. The reaction was warmed up to RT and stirred over night at RT. Then 3.63 g sodium methanolate was added and the reaction was stirred for 3 h. The mixture was treated with water and extracted with EtOAc. The organic layer was dried over magesiumsulfate and evaporated to give 9.7 g 4-chloro-6-methoxy-pyrimidine.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl.CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][O:25]1
Reactant: OCCCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: BrCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 5-bromopentanol (10 g) in DCM (150 mL) was added pyridinium p-toluenesulfonate (1.5 g) followed by 3,4-dihydro-2H-pyran (8.1 mL) and the reaction mixture was stirred at room temperature under nitrogen for 21 hours. The solution was diluted with ether then washed with diluted brine (1:1 brine:water, 140 mL) before the organics were dried over sodium sulfate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0 to 50% ethyl acetate in cyclohexane to afford the subtitled compound as a colourless liquid. Yield 14.14 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][CH2:12][CH3:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]=[C:21]=[O:22])[CH:15]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:21](=[O:22])[NH:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[CH2:11][CH2:12][CH3:13]
Reactant: O=C=Nc1cccnc1
Reactant: CCCc1cc2c(cc1Cl)NCC2
Product: CCCc1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2

Procedure:
6-Chloro-5-propylindoline (D54) (57 mg, 0.3 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was recrystallised from ethanol/diethyl ether to give the title compound as a white crystalline solid m.p. =218°-220° C.
Reaction SMILES: [F:1][CH:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])P(=O)(OCC)OCC.[Li+].CC([N-]C(C)C)C.[NH2:27][C:28]1[C:37]2[N:36]=[CH:35][C:34]([CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[CH3:48])=[CH:33][C:32]=2[C:31]2[CH:49]=[CH:50][C:51]([CH:53]=O)=[CH:52][C:30]=2[N:29]=1>C1COCC1>[NH2:27][C:28]1[C:37]2[N:36]=[CH:35][C:34]([CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[CH3:48])=[CH:33][C:32]=2[C:31]2[CH:49]=[CH:50][C:51](/[CH:53]=[C:2](/[P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])\[F:1])=[CH:52][C:30]=2[N:29]=1
Reactant: CCOP(=O)(OCC)C(F)P(=O)(OCC)OCC
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(C=O)ccc4c3c2)c(C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)/C(F)=C/c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tetraethyl fluoromethylenediphosphonate (2.5 equiv.) in THF (0.27 M) cooled at −78° C. was added LDA solution (1.8 M in ethylbenzene/pentane/hexane, 2.0 equiv.). The resulting reaction mixture was warmed up to room temperature and stirred for 30 minutes, before it was cooled back down to −78° C. A solution of 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde (2-2) (Example 9−Step 1) (1.0 equiv.) in THF (0.18 M) was added, and the reaction mixture was allowed to warm up to room temperature slowly. The reaction was quenched with saturated NH4Cl solution. Aqueous phase was extracted with DCM (3×). The combined organic phases were combined and concentrated in vacuo. The residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide (E)-Diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1-fluorovinylphosphonate (3-2) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:21][N:20]=[C:8]2[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)cc1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Yield: 90.6 %

Procedure:
Prepared according to Method D Step A from (3-chloro-2-fluoro-phenyl)-(4-methoxyphenyl)-methanone (0.84 g, 3.2 mmol), hydrazine hydrate (1.0 mL, 32 mmol) and DMAP (0.39 g, 3.2 mmol) to give the product (0.75 g) as a white solid.
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.C(=O)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)=O>C(N(CC)CC)C>[C:14]1([CH:13]=[CH:12][CH2:4][CH2:6][C:7]([OH:9])=[O:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=CC=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=C(O)CCC=Cc1ccccc1
Temperature: 95 °C

Procedure:
7.2 g (0.05 mol) of Meldrum's acid and 6.6 g (6.3 ml, 0.05 mol) of cinnamaldehyde were weighed in to 50 ml of the mixture of formic acid and triethylamine prepared as described in Example 1. The reaction mixture was heated to 95° C. during 1 hour and maintained at the same temperature for 2 hours. The product was separated according to Example 1.
Reaction SMILES: Cl.NO.C([N:7](CC)C(C)C)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23]C(OCC)=O)=S)=[N:18][CH:19]=1>CCO.CO>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:7]=[C:21]([NH2:23])[N:20]=2)[CH:19]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Br)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2ccc(Br)cn2n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a suspension of hydroxylamine hydrochloride (409.2 g, 5.888 mol) in EtOH/MeOH (1:1, 2.5 L) was added N,N-diisopropylethylamine (606.1 mL, 3.480 mol), the mixture was stirred at room temperature (20° C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (352.8 g, 1.160 mol) was then added and the mixture slowly heated to reflux (Note: bleach scrubber required to quench H2S evolved). After 2 h at reflux the mixture was allowed to cool and filtered to collect the precipitated solid. The collected solid was washed successively with water (1.0 L), EtOH/MeOH (1:1, 1.0 L) and diethyl ether (500 mL) then air-dried to afford the title compound as a white solid (169.2 g, 69%). No further purification was required.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:15]1([CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: Cc1ccccc1B(O)O
Reactant: FC(F)(F)CNc1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1NCC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-amine and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (91%). MS (ESI): m/z=267.11 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=O)#[N:2].C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O>[C:1]([C:3]1[CH:4]=[C:5]([C:6](=[S:38])[NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)#[N:2]
Reactant: C[Si](C)(C)CNC(=O)c1ccc(-n2cncn2)c(C#N)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)CNC(=S)c1ccc(-n2cncn2)c(C#N)c1
Yield: 129.4 %

Procedure:
3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzamide (1.1 g) was dissolved with toluene. To the mixture was added Lawesson reagent (1.5 g) and heated to reflux for 5 hours. The reaction mixture was returned to room temperature, water was added thereto, and the aqueous layer was extracted with ethyl acetate. The combined organic layers, were washed with a saturated aqueous sodium hydrogen carbonate solution, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzenecarbothioamide (1.5 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:20])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+]>O.CO>[CH3:20][N:7]1[C:8]2[C:13](=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc2c(c1)cc(C(=O)OCC)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(C(=O)O)cc2cc(C(=O)O)ccc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
Solution of 1-methyl-indole-2,5-dicarboxylic acid diethyl ester 17 (675 mg, 2.5 mmole) and NaOH (5.00 mmole) in a mixture of water/MeOH (1/4) (20 ml) was stirred at 50° C. for 4 h and then overnight at ambient temperature. The reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in water (20 ml) and acidified with 1M HCl up to pH=3. The precipitate was collected on the filter and washed with water (3×5 ml) and dried over phosphorus pentoxide in dessicator to give 488 mg (89%) of 1-methyl-indole-2,5-dicarboxylic acid 18 as white crystalline material. MS: 218.2 (M−H). 1H-NMR (DMSO-d6): δ 8.35 (m, 1H, H-4, indole); 7.90 (m, 1H, H-6, indole); 7.41 (d, 1H, H-7, indole); 7.32 (s, 1H, H-3, indole); 4.05 (s, 3H, NCH3, indole).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9]([NH:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18]Cl)[N:17]=1)(=[O:11])[CH3:10]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C)C=O>[C:9]([NH:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][N:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]2=[O:8])[N:17]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(Cn2cc(Cl)cnc2=O)cs1
Temperature: 90 °C
Yield: 11.9 %

Procedure:
A stirred suspension of 5-chloropyrimidin-2-one (653 mg), 2-acetylamino-4-chloromethylthiazole (1.430 g) anhydrous sodium carbonate (1.060 g) and benzyltrimethylammonium chloride (20 mg) in dry N,N-dimethylformamide (25 ml) was heated at 90° C. After 11/2 h the reaction mixture was evaporated to dryness and then the residue was suspended in ethyl acetate (250 ml) and washed with water (3×70 ml), dried (MgSO4) and evaporated to a yellow foam. The foam was subjected to p.l.c. on silica developing with chloroform-ethanol, 19:1 (three runs). The major band was eluted with ethyl acetate to give a foam which was crystallised from acetone to give off white crystals of the title pyrimidinone (170 mg), m.p. 209°-211° C., λmax (EtOH) 227 nm (ε 11,960), 267 nm (ε 8,540), 334 nm (ε 3,420).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].O>C1COCC1>[F:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:11]/[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.65 g (16.3 mmol) of sodium hydride (as a 60% suspension in mineral oil) was initially charged in 25 ml of THF and cooled to 0° C. 4.29 g (17 mmol) of tert-butyl diethylphosphonoacetate were then slowly added dropwise. After 30 min, 2.5 g (14.8 mmol) of 4-fluoro-3-nitrobenzaldehyde were added. The reaction mixture was stirred at RT for 3 h and then poured into 100 ml of water and extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography (silica gel, mobile phase cyclohexane/ethyl acetate 50:1). This gave 3.37 g (85% of theory) of the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]1([C:51]2[S:52][CH:53]=[C:54]([C:56](O)=[O:57])[N:55]=2)[CH2:50][CH2:49][CH2:48]1.C(N(CC)CC)C>CN(C=O)C>[CH:47]1([C:51]2[S:52][CH:53]=[C:54]([C:56]([N:28]3[CH2:29][C:30]4([CH2:35][CH2:34][N:33]([CH2:36][C:37]5[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[C:41]([F:43])[CH:42]=5)[CH2:32][CH2:31]4)[O:25][CH2:26][CH2:27]3)=[O:57])[N:55]=2)[CH2:48][CH2:49][CH2:50]1
Reactant: O=C(O)c1csc(C2CCC2)n1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1csc(C2CCC2)n1)N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1
Reaction time: 0.5 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.32 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.2 g), 2-cyclobutylthiazole-4-carboxylic acid (example 58, step c) (0.12 g) and triethylamine (0.36 mL) in DMF (7 mL) and the resulting yellow solution was stirred for 30 min. The mixture was partitioned between ethyl acetate and brine (100 mL) and the layers separated. The organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and the solvent evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added and the solvent evaporated to give the subtitled compound as a clear oil. Yield 0.18 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH:11]([OH:17])[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11](=[O:17])[CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCC(O)CN(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)CCC(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of 1-(N-t-butoxycarbonyl-N-methylamino)2-hydroxy-5-methylhexane (2.45 g) and triethylamine (3.03 g) in dimethyl sulfoxide (20 ml) was added sulfur trioxide pyridine complex (4.77 g) under ice-bath cooling. After the mixture was stirred at ambient temperature overnight, the reaction mixture was poured into ice-water (100 ml). The mixture was extracted with diethyl ether (100 ml×2). The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (20% ethyl acetate in n-hexane as eluent) to give 1-(N-t-butoxycarbonyl-N-methylamino)-2-oxo-5-methylhexane (2.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:14]([CH3:17])(O)[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+].C([O-])(O)=O.[Na+].N1C=CC=CC=1.[FH:46]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]2[CH2:12][CH:11]([C@@H:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[C:14]([F:46])([CH3:17])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 42 °C
Reaction time: 9 h

Procedure:
To a solution of 175 mg (0.368 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol in 3 mL of CH2Cl2, 1 mL of hydrogen fluoride-pyridine was added and the reaction was stirred for 9 h at 42° C. Then the reaction mixture was poured to 7 mL of 5N NaOH, 7 mL of ag NaHCO3 and 30 mL of CH2Cl2. Adjusted pH to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with 10% methyl tert-butyl ether-hexane to afford the title compound as a white solid. 1H NMR(CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.20 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.33 (m, 8H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH2:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:19](Cl)([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20]>C1C=CC=CC=1>[C:19]([O:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH2:9])=[CH:6][CH:5]=1)([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20]
Reactant: C=Cc1ccc(CCO)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=Cc1ccc(CCOC(=O)C(=O)OCC)cc1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A 200 ml flask equipped with a stirrer, a thermometer and a dropping funnel was charged with 14.8 g (0.1 mol) of p-hydroxyethylstyrene, 150 ml of benzene and 10.1 g (0.1 mol) of triethylamine and cooled to 10° C. To the mixture was added dropwise with stirring 13.7 g (0.1 mol) of ethoxalyl chloride for one hour at 10° C. to precipitate a hydrochloride of triethylamine (white solid). After mixting at room temperature for 2 hours, 80 g of hexane was added to complete precipitation of the hydrochloride. The hydrochloride is removed by filteration and the resultant filtrate was condensed to obtain the aimed compound. The compound was identified by 1H NMR (360 Mz) and IR. ##STR6##
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl.[NH2:25][O:26][CH2:27][CH2:28][OH:29]>C1COCC1>[OH:29][CH2:28][CH2:27][O:26]/[N:25]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[N:3]=[CH:4]4)=[CH:13][N:14]=2)[N:17]=1)\[CH3:22]
Reactant: CC(=O)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Reactant: NOCCO
Agent: Cl
Solvent: C1CCOC1
Product: C/C(=N\OCCO)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Yield: 58.8 %

Procedure:
A solution of 1-(3-((1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (20.0 mg, 0.07 mmol) and 2-(aminooxy)ethanol hydrochloride (14.87 mg, 0.13 mmol) in 10 mL THF was stirred at 40° C. overnight. Solvent was removed in vacuo. The crude product was purified on flash chromatography (DCM:MeOH=50:1) to give the title compound as a yellow solid (15.0 mg, 57%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.04 (d, 1H), 7.94 (s, 1H), 7.68˜7.61 (m, 3H), 7.54 (d, 1H), 7.39 (d, 1H), 4.41 (s, 2H), 4.23 (s, 2H), 3.98 (s, 3H), 3.68 (s, 2H), 2.29 (s, 3H). LCMS (method A): [MH]+=365, tR=4.70 min.