Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:10]([CH3:14])([CH3:13])[C:11]#[N:12].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[CH3:13][C:10]([CH3:14])([CH:9]([C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)[O:8][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[C:11]#[N:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C#N)C(O)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC(c2ccncc2)C(C)(C)C#N)cc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 37.3 %

Procedure:
Triethylamine (1.57 ml, 11.3 mmol) was added to a solution of 3-hydroxy-2,2-dimethyl-3-(4-pyridyl)propionitrile (1.00 g, 5.67 mmol) in dichloromethane (20 ml) at room temperature. Further, p-toluenesulfonyl chloride (1.30 g, 6.80 mmol) was added to the mixture, and the whole was warmed at 50° C. with stirring for three days. The reaction mixture was allowed to stand and then concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give 699 mg (37.4%) of 2,2-dimethyl-3-(4-pyridyl)-3-(p-tolylsulfonyloxy)propionitrile as a pale yellow solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][CH:14]=[CH:15][N:16]=2)=[CH:8][CH:7]=1)=[N+]=[N-].[H][H]>CCO.[Pd]>[NH:13]1[CH:14]=[CH:15][N:16]=[C:12]1[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][NH2:1])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCCc1ccc(-c2ncc[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: NCCc1ccc(-c2ncc[nH]2)cc1
Reaction time: 5 h

Procedure:
To a solution of 2-[4-(2-azidoethyl)phenyl]-1H-imidazole (120 mg, 0.56 mmol) in EtOH, Pd/C (6 mg, 0.06 mmol) was added. A hydrogen balloon was placed over the reaction and the reaction was complete after approximately five hours. Reaction mixture was filtered through a pad of celite and concentrated to give 2-[4-(1H-imidazol-2-yl)phenyl]ethanamine which was used without further purification. LCMS (ES) m/z 188.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O: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)=[CH:10][C:11]=1[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:29]
Reactant: Oc1ccc(OCc2ccccc2)cc1CC1CCCCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1CC1CCCCC1
Temperature: 55 °C

Procedure:
4-Benzyloxy-2-cyclohexylmethylphenol (1,77 mmol) was dissolved in anhydrous DMF (4 mL), followed by the addition of ethyl bromoacetate (0.29 mL, 2.65 mmol), and cesium carbonate (0.75 g, 2.30 mmol). The mixture was then heated for 18 h (55° C.). The reaction mixture was then cooled and concentrated in vacuo. The crude residue was partitioned between ethyl acetate (70 mL) and water (40 mL). The organic layer was washed with brine, dried (Na2SO4), and removed in vacuo to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](C=O)=[CH:5][C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[C:27]([C:32]1C=CC=C[C:33]=1P(=C)(C1C=CC=CC=1)C1C=CC=CC=1)([O:29][CH2:30][CH3:31])=[O:28].C(OCC)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:27](=[O:28])[CH:32]=[CH:33][C:4]1[C:3]([O:2][CH3:1])=[CH:16][C:15]2[CH:14]3[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)[CH:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:7][C:6]=2[CH:5]=1)[CH3:31]
Reactant: COc1ccc(C2Cc3cc(C=O)c(OC)cc3C3CCCCC23)cc1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1C(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C=Cc1cc2c(cc1OC)C1CCCCC1C(c1ccc(OC)cc1)C2
Yield: 74.6 %

Procedure:
Combine 3-Methoxy-9-(4-methoxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-2-carbaldehyde (1.77 g, 5.13 mmol), carboethoxy-methylene triphenylphosphorane (03.19 g, 9.03 mmol) in toluene (53 ml) and reflux 15 hours. Remove solvent in vacuo, slurry with diethyl ether and chromatograph the residue from the concentrated filtrate on silica gel with 20% ethyl acetate/hexanes, then 25% ethyl acetate/hexanes to yield the titled compound (1.61 g, 76%). MS m/z 421(M+1).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH2:5]([O:12][C:13](=[O:21])[N:14]([CH2:18][C:19]#[CH:20])[CH2:15][C:16]#[CH:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)Cl>C1(C)C=CC=CC=1>[CH2:5]([O:12][C:13]([N:14]1[CH2:18][C:19]2[C:16](=[CH:17][CH:3]=[C:2]([CH2:1][OH:4])[CH:20]=2)[CH2:15]1)=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCO
Reactant: C#CCN(CC#C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1Cc2ccc(CO)cc2C1
Temperature: 55 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
A solution of propargyl alcohol (2.11 Kg, 37.7 mol) in toluene (32.48 L) was degassed and heated to 55° C. The solution of di-prop-2-ynyl-carbamic acid benzyl ester (4.06 Kg, 17.86 mol, step 6) in toluene and Wilkinsons catalyst (0.162 Kg) were added in 10 equal portions such that temperature <65° C. (the exotherm was allowed to subside before the next addition was made). The solution was then stirred at 55° C. for 1 h and then cooled to 20° C. DCM (8.12 L) was added and the mixture was concentrated to a small volume. Toluene (8 L) was added and the solution evaporated to constant weight giving the title compound 5.72 Kg (113%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15]Br>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]([CH2:15][C:14]2[CH:13]=[C:12]([F:11])[CH:19]=[C:18]([F:20])[CH:17]=2)[C:2]1=[NH:1]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: Fc1cc(F)cc(CBr)c1
Product: N=c1n(Cc2cc(F)cc(F)c2)c2ccccc2n1Cc1cc(F)cc(F)c1

Procedure:
The title compound was prepared from 2-aminobenzimidazole and 3,5-difluorobenzyl bromide by Procedure A. The title product was isolated by filtration and washed with acetonitrile and water to give the title compound as the free base (white solid, mp 144-145° C.). MS(ES+) m/z 386 ([M+1]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH:34]1([NH2:37])[CH2:36][CH2:35]1>>[CH:34]1([NH:37][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NC1CC1

Procedure:
5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with cyclopropylamine to give the titled compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10](O)=[O:11])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>C1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10]([N:24]=[N+:25]=[N-:26])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C=CC(=O)O)ccc1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: C=CCOc1cc(C=CC(=O)N=[N+]=[N-])ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
26.2 g (0.1 mol) of 3-allyloxy-4-acetoxy-cinnamic acid are suspended in 90 ml of benzene and 14.6 ml (0.2 mol) of thionyl chloride are added. The reaction mixture is heated to the boil under reflux for 30 minutes. Thereafter the solvent and the excess thionyl chloride are removed by distillation under reduced pressure. The crude 3-allyloxy-4-acetoxy-cinnamic acid chloride which is left is dissolved in 100 ml of absolute dimethoxyethane, 19.5 g (0.3 mol) of sodium azide are added and the reaction mixture is subsequently stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated under reduced pressure at 30° C. Hereupon, colourless crystals separate out. The crystallisation is completed by addition of ether. 3-Allyloxy-4-acetoxy-cinnamic acid azide of melting point 83°-84° C is obtained.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([NH:12][C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:15][CH:14]=1)=[O:11])([OH:6])=[O:5]
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(NC(=O)c2ccccc2C(=O)O)nc1
Reaction time: 48 h
Yield: 15.6 %

Procedure:
Phthalic anhydride (0.81 g, 5.48 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.44 g, 1.37 mmole) and sodium bicarbonate (0.58 g, 6.85 mmole) in THF (70 mL) at RT, and the reaction was heated at reflux under nitrogen. After 48 hr, the reaction was concentrated in vacuo and the residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (10% MeOH/CHCl3) gave the title compound (0.10 g, 16%) as a light yellow solid: MS (ES) m/e 469 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:5]2=[N:6][CH:7]=1.C1(C)C=CC(S(O[CH2:39][C@H:40]2[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[C:25]([O:24][C:22]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]2[C:18]([O:19][CH2:39][C@H:40]3[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]3)=[CH:17][CH:16]=[C:15]([F:20])[C:14]=2[Cl:21])[CH3:12])=[CH:9]1)=[O:23])([CH3:27])([CH3:26])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: C[C@H](c1c(O)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](c1c(OC[C@H]2COC(C)(C)O2)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Temperature: 110 °C

Procedure:
A suspension of tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (82.9 mg, 0.176 mmol), (R)-(−)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl p-toluenesulfonate (77.8 mg, 0.272 mmol), and potassium carbonate (102.5 mg, 0.7416 mmol) in DMF (3 mL) was subjected to microwave heating [Biotage, 110° C.] for 90 min. EtOAc was added to dilute the reaction mixture and a standard aqueous workup was performed. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled silica gel loading cartridge [RediSepRf 5 g] and purified using the Teledyne/ISCO system [RediSepRf silica 12 gram GOLD column], eluting with a solvent system of 5-20% EtOAc:heptane. Fractions containing product were combined and concentrated in vacuo. The recovered material was dissolved in minimal MeOH, passed through a syringe filter, and purified a second time by MDP, under acidic conditions (formic acid). Fractions were combined and concentrated in vacuo, giving the title material as an off-white solid. 1H NMR (400 MHz, CDCl3): δ=8.42 (d, J=2.3 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.01 (dd, J=9.1, 8.3 Hz, 1H), 6.70 (dd, J=9.1, 4.0 Hz, 1H), 4.91 (q, J=6.8 Hz, 1H), 4.01-4.18 (m, 2H), 3.81-3.89 (m, 1H), 3.78 (dd, J=7.7, 4.9 Hz, 1H), 3.73 (br s, 1H), 1.73 (d, J=7.1 Hz, 3H), 1.68 (s, 9H), 1.34 (d, J=14.9 Hz, 6H). MS (ES+): m/z 604.96/606.80/608.57 (21/100/24) [MH++Na]. HPLC: tR=4.13 min (ZQ3, nonpolar—5 min).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[C:13]([Cl:19])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.Cl[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28]>C1COCC1.C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[C:13]([Cl:19])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(CO)c(Cl)c2)n1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2N)cc1Cl)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
To a solution of 3-(tert-butyl)-1-(3-chloro-4-(hydroxymethyl)phenyl)-1H-pyrazol-5-amine (1.15 g, 70% purity, 2.9 mmol) in dry THF (10 mL) under N2 was added imidazole (320 mg, 4.7 mmol) and chlorotriisopropylsilane (970 μL, 870 mg 4.5 mmol) and the reaction mixture maintained at RT for 18 hr. The resulting mixture was diluted with DCM (5.0 mL) and was treated with an additional aliquot of chlorotriisopropylsilane (970 μL, 870 mg, 4.5 mmol) and after a further 5 hr with imidazole (320 mg, 4.7 mmol). After 20 hr the reaction mixture was treated for a third time with chlorotriisopropylsilane (200 μL, 180 mg, 0.90 mmol) and imidazole (100 mg, 1.6 mmol) and after 3 days was evaporated in vacuo. The residue was taken up into EtOAc (20 mL) and was washed with water (20 mL) and brine (10 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-100%, gradient elution) and then by SCX capture and release to afford a blue oily liquid which comprised of a mixture of starting material and the desired product. This mixture was taken up into THF (1.0 mL) and was treated with imidazole (50 mg, 0.74 mmol) chlorotriisopropylsilane (140 μL, 130 mg, 0.65 mmol) and maintained at RT for 24 hr and then evaporated in vacuo. The residue was taken up EtOAc (10 mL) and was washed with water (10 mL) and brine (10 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 0-100%, gradient elution) to afford the title compound, Intermediate A22 as a white solid (300 mg, 24%); Rt 3.42 min (Method 2); m/z 436 (M+H)+, (ES+).
Reaction SMILES: C(O[C:6]([N:8]1[C:20]2[C:11](=[C:12]3[C:17](=[C:18]([OH:21])[CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:10]([CH2:22][Cl:23])[CH2:9]1)=[O:7])(C)(C)C.Cl.[CH3:25][O:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32]C(O)=O)=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>O1CCOCC1.CC(N(C)C)=O>[Cl:23][CH2:22][CH:10]1[C:11]2=[C:12]3[C:17](=[C:18]([OH:21])[CH:19]=[C:20]2[N:8]([C:6](=[O:7])/[CH:32]=[CH:31]/[C:30]2[CH:36]=[CH:37][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH2:9]1)[N:16]=[CH:15][CH:14]=[CH:13]3
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(O)c1ncccc21
Reactant: COc1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COc1ccc(/C=C/C(=O)N2CC(CCl)c3c2cc(O)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17 %

Procedure:
A suspension of 16 (0.10 g, 0.30 mmol) in dioxane (5 mL) was saturated with HCl, stirred at r.t. over 5 h and evaporated. 4-Methoxycinnamic acid (predominantly trans) (0.064 g, 0.36 mmol), EDCI (0.29 g, 1.50 mmol) and DMA (3 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 3 h. The mixture was partitioned between CH2Cl2 and cold 5% KHCO3 solution. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4). Flash chromatography (CH2Cl2/MeOH; 93:7) followed by recrystallisation (CH2Cl2/Et2O) gave 18e (0.02 g, 17%) as a yellow solid: mp 208–211° C.; 1H NMR [(CD3)2SO]δ 9.96 (bs, 1 H), 8.73 (d, J=3.3, 1 H), 8.35 (d, J=7.7, 1 H), 8.18 (bs, 1 H), 7.78 (d, J=8.7, 2 H), 7.67 (d, J=15.3, 1 H), 7.54 (dd, J=8.5, 4.1, 1 H), 7.08 (d, J=15.4, 1 H), 7.01 (d, J=8.7, 2 H), 4.54 (dd, J=10.3, 9.5, 1 H), 4.45 (m, 1 H), 4.27 (m, 1 H), 3.99 (dd, J=11.1, 3.2, 1 H), 3.88 (dd, J=11.1, 7.3, 1 H), 3.82 (s, 3 H). C22H20ClN2O3 requires M+H 395.1163, 397.1133. Found (FAB) 395.1161, 397.1169.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:34]I>O1CCCC1>[I:34][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: II
Reactant: OCCC1CCCCC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ICCC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed 2-cyclohexylethan-1-ol (3 g, 23.40 mmol, 1.00 equiv), imidazole (2 g, 29.41 mmol, 1.26 equiv), PPh3 (8 g, 30.50 mmol, 1.30 equiv), tetrahydrofuran (60 mL) and I2 (7.7 g, 30.31 mmol, 1.30 equiv). The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of 100 mL of sodium bicarbonate (sat.). The resulting solution was extracted with 2×100 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. Purification afforded 4.4 g (79%) of (2-iodoethyl)cyclohexane as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(N(CC)CC)C.[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>ClCCl>[S:47]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])([C:44]1[CH:45]=[CH:46][C:41]([CH3:40])=[CH:42][CH:43]=1)(=[O:49])=[O:48]
Reactant: O=C(OCc1ccccc1)c1cccc(C#CCOCCOCCOCCOCCO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCC#Cc2cccc(C(=O)OCc3ccccc3)c2)cc1
Temperature: 0 °C

Procedure:
Into a 500-mL 3 neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of benzyl 3-(1-hydroxy-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate (25.2 g, 56.88 mmol, 1.00 equiv) in dichloromethane (300 mL), triethylamine (17.2 g, 170.30 mmol, 3.00 equiv). This was followed by the addition of a solution of 4-methylbenzene-1-sulfonyl chloride (16.3 g, 85.34 mmol, 1.50 equiv) in dichloromethane (100 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether/ethyl acetate (5:1-1:1). This resulted in 31 g (91%) of benzyl 3-(1-(tosyloxy)-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate as a brown oil.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:34][CH:33]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(=O)OC(C)(C)C)cc3)c(F)cn2c1=O
Yield: 108.9 %

Procedure:
Ethyl 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.31 mmol) and (4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-boronic acid (101 mg, 0.40 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (167 mg, 100%). ESI-MS m/z: 495 (M+Na)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=O)(C)(C)C.[C:39](O)([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[O:37]=[C:25]1[CH2:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=2)=[N:7][C:8]2[CH:13]=[C:12]([O:40][CH2:39][C:41]([F:44])([F:43])[F:42])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=2[NH:24]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3cc(OCC(F)(F)F)c(C(F)(F)F)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from [2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M75) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (100 mg).
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.Cl.[CH3:14][NH:15][CH:16]1[CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH:16]1([N:15]([CH3:14])[CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:18][CH2:17]1
Reactant: CNC1CC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C1CC1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
Combined a solution of tert-butyl 3-oxoazetidine-1-carboxylate (175 mg, 1.022 mmol) and N-methylcyclopropanamine hydrochloride (121 mg, 1.124 mmol) in methylene chloride (5 mL) and added sodium triacetoxyborohydride (325 mg, 1.533 mmol) and the solution stirred at 20° C. for 30 min. The solution was concentrated in vacuo to give white solid which was taken up in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate and concentrated in vacuo, and then purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes to give the title compound (128 mg, 0.566 mmol, 55.3%) as a clear, colorless oil. MS: 227 (M+H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.41-0.47 (m, 2H) 0.48-0.56 (m, 2H) 1.43 (s, 9H) 1.64 (tt, J=6.7, 3.9 Hz, 1H) 2.28 (s, 3H) 3.50 (tt, J=7.5, 5.7 Hz, 1H) 3.84-4.01 (m, 4H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[NH:14][NH2:15].C(O)C>C(OCC)(=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:15][NH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[O:4]
Reactant: CCOC(=O)NN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)NNC(=O)c1ccccc1N
Yield: 66.8 %

Procedure:
A mixture of 16.3 g of isatoic anhydride, 10.4 g of ethyl carbazate and 50 ml of ethanol was heated to reflux for 3 hours. After the reaction mixture was allowed to cool to around room temperature, ethyl acetate was added thereto and the mixture was washed with water two times. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was washed with methyl tert-butyl ether to obtain 14.9 g of N-(2-aminobenzoyl)-N′-ethoxycarbonylhydrazine of the formula: