Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:45]=[C:46]([N+:48]([O-])=O)[CH:47]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:44])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:43])([F:42])[O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8])([O-])=O>CN(C)C=O.O.[Zn]>[NH2:48][C:46]1[CH:45]=[C:6]([CH:5]=[C:4]([NH2:1])[CH:47]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:44])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:42])([F:43])[O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8]
Reactant: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(N)cc(C(=O)OCCCCCCOC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 83.1 %

Procedure:
5.95 g (8.38 mmol) of 6-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)-prop-2-enoyl]oxy}hexyl 3,5-dinitrobenzoate are dissolved in a mixture of 54 mL of N,N-di-methylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 4.53 g of 6-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)-phenoxy]-methyl}phenyl)prop-2-enoyl]oxy}hexyl 3,5-diaminobenzoate as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:15])[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=1.Cl.[CH3:17][CH:18]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20][O:19]1.C(N(CC)CC)C>>[CH3:15][N:3]1[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=[C:2]1[N:23]1[CH2:22][CH2:21][CH2:20][O:19][CH:18]([CH3:17])[CH2:24]1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: CC1CNCCCO1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC1CN(c2nc(-c3ccncn3)cc(=O)n2C)CCCO1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a slurry of 2-Chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (126 mg, 0.565 mmol) and 2-methyl-[1,4]oxazepane hydrochloride (100 mg, 0.660 mmol) was added triethylamine (172 mg, 1.70 mmol) at room temperature. The resulting mixture was stirred at room temperature for 10 hours and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant; ethyl acetate) to afford 1-methyl-2-(2-methyl-[1,4]oxazepan-4-yl)-1H-[4,4′]bipyrimidinyl-6-one as white solid (A051) (103 mg, 61%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C@H:18]([CH2:20]O)[O:17][C:16]2=[O:22])=[CH:11][C:10]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:36]=[N+:37]=[N-:38].[Na+]>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>[N:36]([CH2:20][C@H:18]1[O:17][C:16](=[O:22])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([F:23])[CH:11]=2)[CH2:19]1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(OCc2ccccc2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(OCc3ccccc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 10 g (5R)-3-(4-benzyloxy-3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (MW: 317.32, 31.51 mmol) and 4.78 g triethylamine (MW: 101.19, 47.26 mmol) in 300 ml dichloromethane was treated under stirring at 10° C. with 4.32 g of methane sulfonyl chloride (MW: 114.55, 37.82 mmol). The reaction was stirred at room temperature for one hour and monitored by TLC (ethyl acetate:hexane 1:1). The reaction mixture was quenched with 100 ml water and the organic layer washed with 100 ml brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in 100 ml dimethylformamide, 5.12 g sodium azide (MW: 65.01, 78.7 mmol) and a catalytic amount of tetrabutyl ammonium iodide were added. The suspension was stirred at 90° C. over night. The reaction was monitored by HPLC. The dimethylformamide was evaporated under reduced pressure, the residue dissolved in 200 ml dichloromethane and the organic layer washed successively with 100 ml water and 100 ml brine. The dichloromethane solution was dried over magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure. The residue was crystallized from 150 ml of a 1/1 mixture of ethyl acetate:hexane. The crystals were collected to afford an off white solid. Yield: 10.4-g, 97%. MS: 343.1 (M+H)+−. Method: ESI+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[S:13](=NC1C=CC=CC=1)=[O:14]>CO.C(O)(=O)C>[S:13](=[N:10][NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=1)=[O:14]
Reactant: O=S=Nc1ccccc1
Reactant: NNc1cccc(C(F)(F)F)c1
Solvent: CO
Solvent: CC(=O)O
Product: O=S=NNc1cccc(C(F)(F)F)c1
Yield: 63.7 %

Procedure:
20 g (0.113 mole) of 3-trifluoromethyl-phenylhydrazine were dissolved in 50 ml of methanol with addition of 5 ml of acetic acid; 16 g (0.115 mole) of sulfinylaniline were added dropwise at a temperature of 22°C. The product crystallized out while the temperature rose to about 30°C. After filtration and drying, 16 g of N-sulfinyl-N-' -(3-trifluoromethylphenyl)-hydrazine of melting point 100°C were obtained. The yield was 64% of theory.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[C:8]2=[CH:17]OC)=[O:4].[N:21]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[CH3:20][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]\[NH:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:33][CH:32]=1)=[O:4]
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: COC=C1C(=O)NC(=O)c2ccc(C(=O)N(C)C)cc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc2c(c1)/C(=C/Nc1ccc(CN3CCCCC3)cc1)C(=O)NC2=O
Yield: 74.7 %

Procedure:
Prepared from a solution of 70 mg (0.255 mmol) of 4-methoxymethylene-1,3-dioxo-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid dimethylamide and 48.5 mg (0.255 mmol) of 4-piperidin-1-ylmethyl-phenylamine in 1.6 mL of N,N-dimethylformamide (DMF) at 110° C. under N2 as described for example 21. After heating for 0.25 h, the reaction is chilled in ice. The solid product is collected, washed with N,N-dimethylformamide (DMF) and Et2O and dried to give 82.4 mg (74%) of bright yellow crystals: mp 266-267° C. (dec); 1H NMR (DMSO-d6) δ 12.45 (d, 1H, J=9 Hz), 11.40 (s, 1H), 8.95 (d, 1H, J=9 Hz), 8.17 (s, 1H), 8.06 (d, 1H, J=6 Hz), 7.53 (d, 2H, J=9 Hz), 7.32 (d, 2H, J=9 Hz), 7.20 (d, 1H, J=6 Hz), 3.42 (s, 2H), 3.04 (s, 3H), 2.90 (s, 3H), 2.32 (s, 4H), 1.48 (m, 4H), 1.38 (s, 2H); HRMS (ESI) m/e calcd for C25H28N4O3 431.20886, fond 431.20820 (M−H)−1.
Reaction SMILES: O[C:2]([C:5]1[C:14]([O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)([CH3:4])[CH3:3].C([O-])(O)=O.[Na+]>C(O)=O.[Zn]>[CH:2]([C:5]1[C:14]([O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:17])=[O:18])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)([CH3:4])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Oc2cc3ccccc3nc2C(C)(C)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: O=CO
Product: Cc1ccc(S(=O)(=O)Oc2cc3ccccc3nc2C(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 37.7 %

Procedure:
Toluene-4-sulfonic acid 2-(1-hydroxy-1-methyl-ethyl)-quinolin-3-yl ester (3.75 g, 10.5 mmol) was stirred in 50 mL of formic acid for 10 minutes, and zinc dust (3.43 g, 5.25 mmol) was added. The reaction mixture was stirred for four hours and then was added cautiously to a mixture of 100 mL aqueous saturated NaHCO3 and 100 g of ice. The resulting aqueous mixture was neutralized to pH7 by addition of aqueous saturated NaHCO3, and was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography using silica eluting with 10% ethyl acetate in hexanes to afford 1.35 g of toluene-4-sulfonic acid 2-isopropyl-quinolin-3-yl ester.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].[NH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C@H:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=2)=[CH:19][CH:18]=1)[NH2:16]>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:16][NH:15][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C@H:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=3)=[CH:19][CH:18]=2)=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14]
Reactant: C[C@@H]1CC(=O)NN=C1c1ccc(NN)cc1
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Solvent: CCO
Product: COc1c(O)ccc(C=NNc2ccc(C3=NNC(=O)C[C@H]3C)cc2)c1[N+](=O)[O-]

Procedure:
A solution of 4-hydroxy-3-methoxy-2-nitro-benzaldehyde (1.6 g) in ethanol (15 ml) was added to a suspension of (R)-6-(4-hydrazino-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one (1.75 g) in ethanol (20 ml) and the resulting mixture refluxed for two hours. The resulting crystals were filtered at room temperature and washed with ethanol. Yield 2.37 g. HPLC: purity 99.4%, optical purity 99.8%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]1[C:19]2[CH:28]=[CH:27][NH:26][C:20]=2[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([C:18]2[C:19]3[CH:28]=[CH:27][NH:26][C:20]=3[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=2)[CH:11]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2OCc2ccccc2)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2OCc2ccccc2)c2cc[nH]c2c1=O

Procedure:
Example 63b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 63a for the product of Example 2b, to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:16])([CH3:15])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:5].CCN(C(C)C)C(C)C.[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)[CH3:27]>C(Cl)Cl>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][NH:6][C:4](=[O:5])[C:3]([CH3:16])([CH3:15])[CH2:2][NH:1][C:35]([NH:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:26][CH3:27])=[CH:29][CH:30]=1)=[O:36]
Reactant: CC(C)(CN)C(=O)NCc1ccccc1Cl
Reactant: CCc1ccc(N=C=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1ccc(NC(=O)NCC(C)(C)C(=O)NCc2ccccc2Cl)cc1
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of 3-amino-N-(2-chlorobenzyl)-2,2-dimethylpropanamide (0.45 mmol) in DCM (5 mL) was added DIEA (157 μL, 0.90 mmol, 2 equiv.) and 4-ethylphenyl isocyanate (97.0 μL, 0.675 mmol, 1.5 equiv.). The reaction mixture was stirred for 30 min. The mixture was concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give N-(2-chlorobenzyl)-3-(3-(4-ethylphenyl)ureido)-2,2-dimethylpropanamide (29.6 mg, 17% for two steps). LRMS (M+H+) m/z 388.1.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[OH:2][CH2:3][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6]1
Reactant: COC(=O)C1CCc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OCC1CCc2ccccc2O1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
At room temperature and while stirring, a solution of 36.4 g (0.19 mol) of 2-methoxycarbonylchroman in 400 ml of absolute tetrahydrofuran is added dropwise within a period of 1 hour to a suspension of 7.2 g (0.19 mol) of lithium aluminium hydride in 400 ml of absolute diethyl ether. After continuing to stir for a further 16 hours at room temperature, the reaction mixture is carefully decomposed with 7.2 ml of water, 7.2 ml of sodium hydroxide solution (15% strength) and 21.6 ml of water. The precipitate formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether. The ethereal solution is washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 31 g (99.3%) of 2-hydroxymethylchroman are thus obtained in the form of a colourless oil.
Reaction SMILES: [OH:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[CH3:9][C:2]1([OH:1])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1
Reactant: CC1(O)CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(O)CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a cooled (0° C.) solution of 4-hydroxy-4-methylcyclohexanone (1 equiv) in methanol (0.5 M) was added sodium borohydride (2 equiv).The resulting mixture was stirred at room temperature overnight. After the reaction was complete, the resulting mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography (0-10% DCM in methanol) to afford the title compound as a white solid (87% yield, cis/trans mixture). 1H NMR (300 MHz, DMSO-d6) δ ppm 4.34-4.32 (d, J=4.5 Hz, 1H), 4.29-4.27 (d, J=3.6 Hz, 0.45H), 4.12-4.06 (m, 0.47H), 4.00 (s, 0.39H), 3.97 (s, 1H), 3.82 (s, 0.48H), 3.55-3.50 (m, 0.47H), 3.20-3.17 (d, J=7.5 Hz, 1H), 1.76-1.62 (m, 1H), 1.60-1.40 (m, 8H), 1.35-1.20 (m, 4H), 1.07 (s, 1.5H), 1.05 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:18]=[C:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=2)[NH:20]1>>[OH:18][C:19]1[NH:20][C:21]2[C:26]([C:27]=1[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:6][N:7]=1)=[CH:25][C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=2
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Product: COC(=O)c1ccc2[nH]c(O)c(-c3ccc(S(=O)(=O)N4CCN(C)CC4)cn3)c2c1

Procedure:
The title compound was prepared as described for Example 103 using 1-[(6-chloropyridine-3-yl)sulfonyl]-4-methylpiperazine (described in: Thunus. L. Annales Pharmaceutiques Francaises 1977, 35, 197-204) and methyl 2-oxoindoline-5-carboxylate to give the title compound in 59% yield, but without the treatment of the base with hydrochloric acid to from the salt: 1H NMR (D2O, 400 MHz) δ 8.03 (d, J=2 Hz, 1H), 7.44 (m, 1H), 7.30 (d, J=8 Hz, 1H), 7.23 (s, 1H), 6.82 (d, J=9 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 3.93 (m, 2H), 3.82 (s, 3H), 3.65 (m, 2H), 3.28 (m, 2H), 3.03 (m, 2H), 2.94 (s, 3H); MS (TSP) m/z 431 (M++1).
Reaction SMILES: [C:1](OC)([O:5][CH3:6])([O:3]C)[CH3:2].C(O)(=O)CC.[CH2:14]=[CH:15][CH:16](O)[CH2:17][CH:18]=[CH2:19]>COC(C)(C)C>[C:1]([O:5][CH3:6])(=[O:3])[CH2:2][CH2:14]/[CH:15]=[CH:16]/[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCC(O)C=C
Reactant: COC(C)(OC)OC
Solvent: CCC(=O)O
Solvent: COC(C)(C)C
Product: C=CC/C=C/CCC(=O)OC
Temperature: 120 °C
Reaction time: 2 h

Procedure:
78.0 g (about 0.71 mol) of 1,5-hexadien-3-ol, obtained by a Grignard reaction from allylmagnesium bromide and acrolein, were dissolved in 198.0 g (1.65 mol) of trimethyl orthoacetate and 3.0 g (0.04 mol) of propionic acid were then added. The reaction mixture was heated to 120° C. and the methanol formed during the reaction was distilled off over a 15 cm Widmer column. After 2 hours, the reaction mixture was held at 130° C. for a further 1 hour to complete the reaction and was then cooled to room temperature, diluted with 500 ml of tert-butyl methyl ether and the solution was washed twice with 100 ml of saturated sodium bicarbonate solution, dried with sodium sulphate and concentrated. Distillation of the resulting 128 g of crude product over a 20 cm Widmer column gave 51.6 g of olfactorily good methyl (E)-4,7-octadienoate of boiling point 76° C./17 mbar and with a purity of about 98%.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][N:6]1[CH:10]=[C:9]([CH2:11]O)[N:8]=[N:7]1)([CH3:4])[CH3:3].[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25]([NH:28][CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1)(=[O:27])=[O:26])([O-:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CCOC(C)=O.C1C=CC=CC=1>[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25]([N:28]([CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1)[CH2:11][C:9]1[N:8]=[N:7][N:6]([CH2:5][Si:2]([CH3:1])([CH3:3])[CH3:4])[CH:10]=1)(=[O:26])=[O:27])([O-:15])=[O:14]
Reactant: C[Si](C)(C)Cn1cc(CO)nn1
Reactant: COC(=O)c1ccc(CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN(Cc2cn(C[Si](C)(C)C)nn2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1

Procedure:
A solution of {1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methanol (241 mg, 1.30 mmol), methyl 4-({[(2,4-dinitrophenyl)sulfonyl]amino}methyl)benzoate (514 mg, 1.30 mmol), triphenylphosphine (409 mg, 1.56 mmol) and benzene (4.34 mL) was treated with diethylazodicarboxylate (247 uL, 1.56 mmol). After one hour additional portions of triphenylphosphine (204 mg, 0.780 mmol) and diethylazodicarboxylate (124 uL, 0.780 mmol) The reaction was diluted with EtOAc and washed with 2M aq. HCl 2×, water, brine, dried (MgSO4) and concentrated to afford a brown oil used crude in the next reaction. MS: cal'd 563 (MH+), exp 563 (MH+).
Reaction SMILES: B(F)(F)F.CCOCC.CN(C(F)(F)C(F)F)C.FC(F)(F)C(=O)CC(OCC)=O.N1C=CC=CC=1.Cl.[C:38]([NH:42][NH2:43])([CH3:41])([CH3:40])[CH3:39].[OH-].[K+].[F:46][C:47]([F:64])([F:63])[C:48]([C:50](=[C:56](N(C)C)[CH:57]([F:59])[F:58])[C:51]([O:53][CH2:54][CH3:55])=[O:52])=O>ClCCl.C(#N)C.CO>[CH2:54]([O:53][C:51]([C:50]1[C:56]([CH:57]([F:58])[F:59])=[N:43][N:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:48]=1[C:47]([F:64])([F:63])[F:46])=[O:52])[CH3:55]
Reactant: CC(C)(C)NN
Reactant: CCOC(=O)C(C(=O)C(F)(F)F)=C(C(F)F)N(C)C
Agent: CCOC(=O)CC(=O)C(F)(F)F
Agent: CN(C)C(F)(F)C(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)c1c(C(F)F)nn(C(C)(C)C)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
BF3.OEt2 (2.7 ml, 22.0 mmol) was added to a solution of TFEDMA (2.5 ml, 22.0 mmol) in dry dichloromethane (20 ml) under argon in a Teflon flask. The solution was stirred at room temperature for 15 min, before the dichloromethane was removed under reduced pressure. The residue was then taken up in dry acetonitrile (20 ml). In a second Teflon flask, ethyl 4,4,4-trifluoroacetoacetate (2.8 ml, 20.0 mmol) was added to a solution of pyridine (7.1 g, 90.0 mmol) in dry acetonitrile (40 ml) and the mixture was stirred at room temperature for 15 min. To this were added dropwise, at −30° C., the contents of the first flask. The reaction mixture was brought to room temperature in the cold bath and stirred overnight. tert-Butyl hydrazine hydrochloride (3.74 g, 30.0 mmol) was added to a solution of potassium hydroxide (1.68 g, 30 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 30 minutes. This mixture was then added to the previously prepared intermediate (ethyl 2-(2,2,2-trifluoroacetyl)-3-(dimethylamino)-4,4-difluorobut-2-enoate) and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel with a pentanes/diethyl ether mixture (9:1). N-tert-Butyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (3.29 g, 10.5 mmol, 53%) was isolated as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][C:9]3[N:10]([C:12]([C:15]4([C:18]5[CH:19]=[C:20]6[C:25](=[CH:26][CH:27]=5)[N:24]=[CH:23][CH:22]=[CH:21]6)[CH2:17][CH2:16]4)=[CH:13][N:14]=3)[CH:11]=2)[CH:3]=[N:2]1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:28][N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][C:9]3[N:10]([C:12]([C:15]4([C:18]5[CH:19]=[C:20]6[C:25](=[CH:26][CH:27]=5)[N:24]=[CH:23][CH:22]=[CH:21]6)[CH2:17][CH2:16]4)=[CH:13][N:14]=3)[CH:11]=2)[CH:3]=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: c1cnc2ccc(C3(c4cnc5ncc(-c6cn[nH]c6)cn45)CC3)cc2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-{1-[6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline (6 mg, 0.017 mmol) in N,N-dimethylformamide (200 μL) was added potassium carbonate (4.0 mg, 0.029 mmol) and methyl iodide (3 μL, 0.048 mmol). After stirring at RT for 16 h, the reaction mixture was purified by RP-HPLC to afford the desired product. LCMS: (M+H)=367.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[CH2:10][N:9]([C:11](=[O:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1.Cl.Cl[C:22]1N=C(N2CCOC[C@@H]2C)C2CNCC=2N=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][C@@H:19]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11](=[O:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1

Procedure:
Method as described for 1-(2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)ethanone (intermediate 23) using (S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 6) as a TFA salt to yield a dark brown oil, which was used without further purification.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:15][CH2:16][Cl:17])=[CH:9][CH:8]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:17][CH2:16][CH2:15]/[C:14](/[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[C:13](/[C:10]1[CH:9]=[CH:8][C:7]([NH:6][CH2:5][CH2:4][OH:3])=[CH:12][CH:11]=1)\[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)CNc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCNc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Z)-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenylamino]acetic acid ethyl ester (2.9 g, 6.9 mmol) is dissolved in tetrahydrofuran and lithium aluminum hydride (0.34 g, 8.97 mmol) is added in small portions during fifteen minutes. The mixture is stirred at room temperature for two hours. Then the solvent is evaporated to dryness and the residue is dissolved in ethyl acetate and washed with water. Ethyl acetate phase is evaporated to dryness and the product is purified by flash chromatography with toluene:methanol:triethylamine solution (10:0.3:0.3) as an eluent. Yield 0.47 g.