Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][CH:21]=[CH:20]5)[N:14]=[N:15][C:10]3=[C:9](O)[CH:8]=2)[CH:4]=[N:3]1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:35]>>[Cl:35][C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[N:12]=[C:11]2[N:13]([CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[N:14]=[N:15][C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1cc(-c2cc(O)c3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(-c2cc(Cl)c3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
5-(1-Methyl-1H-pyrazol-4-yl)-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-ol (120 mg, 0.336 mmol) was dissolved in POCl3 (2 ml). The reaction mixture was stirred at 110° C. for 1 h. After cooled to 0° C., the mixture was basified with aqueous NaHCO3 to pH=7, and extracted with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, concentrated, and purified by chromatography to afford the title compound (25 mg). MS: 376 (M+1)+.
Reaction SMILES: [N:1]1C=CC=CC=1.[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>C(Cl)Cl>[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:1])=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1ccc(I)cc1
Reaction time: 8 h

Procedure:
The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-iodobenzoyl chloride (5.3 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.O1[CH2:15][CH2:14][NH:13]C1=O.C(=O)=O>COCCOCCO>[CH3:2][O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:15][CH2:14][NH2:13])=[CH:6][CH:5]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1NCCO1
Agent: Cl
Agent: O=C=O
Solvent: COCCOCCO
Product: COc1ccc(NCCN)cc1
Temperature: 175 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
A mixture of 4-methoxyaniline hydrochloride (17.1 g, 0.107 mole), 2-oxazolidinone (8.7 g, 0.10 mole) and 50 ml of 2-(2-methoxyethoxy)ethanol was heated to 175° C. After five hours, carbon dioxide gas evolution had ceased and the dark mixture was allowed to cool to room temperature. Neutralization in a manner similar to that described in Example 1, and distillation at 130° C. to 140° C. (0.5 mm Hg) afforded a 45 percent yield of the amine as a colorless liquid which slowly solidified on standing at ambient temperature to a low-melting solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:20]=[C:21](/[CH3:27])\[C:22]([O:24]CC)=[O:23])[C:6]2[C:11]([C:12]=1[O:13]COC)=[C:10]([CH2:17][CH2:18][CH3:19])[CH:9]=[CH:8][CH:7]=2.[OH-].[K+].Cl>C(O)C>[OH:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:17][CH2:18][CH3:19])[C:5](/[CH:20]=[C:21](/[CH3:27])\[C:22]([OH:24])=[O:23])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCc1cccc2c(/C=C(/C)C(=O)OCC)cc(OC)c(OCOC)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(O)c12
Temperature: 10 °C
Yield: 110.1 %

Procedure:
170 g of ethyl (Z)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoate was dissolved in 850 ml of ethanol and a potassium hydroxide aqueous solution (potassium hydroxide 60 g/water 120 ml) was added, followed by refluxing for 1 hour. After cooling to 10° C., 2.5N hydrochloric acid was added to make it pH~5, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant crystals were filtered to obtain 151 g of the titled compound as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C@@H:4]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)=[CH:18][CH:17]=2)[CH2:14][OH:15])=[C:8](Br)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>[CH3:1][O:2][C:3](=[O:41])[C@@H:4]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=4)=[CH:18][CH:17]=3)[CH2:14][O:15][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC(CO)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c(Br)c1)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Product: COC(=O)[C@H](Cc1ccc2c(c1)OCC(c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Temperature: 52 °C
Yield: 142.2 %

Procedure:
(S)-3-(3-Bromo-4-{1-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (8.0 g), palladium acetate (224 mg), racemic 2-(di-tert-butylphosphino)1,1′-binaphthalene (480 mg), and cesium carbonate (5.86 g) were placed into a 100 mL round-bottom flask. The flask was evacuated and flushed with nitrogen twice. Anhydrous toluene (40 mL) was added and the resulting suspension was heated for 48 h at 52° C. After concentration of the reaction mixture to a brown oil, the residue was purified by silica gel chromatography (ethyl acetate/hexanes to give the desired product 10 g as a fluffy white solid. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.44 (d, 1H), 7.33 (m, 3H), 7.26 (m, 1H), 6.98 (m, 2H), 6.87 (d, 1H), 6.69 (d, 1H), 6.62 (dd, 1H), 5.04 (s, 2H), 4.98 (m, 1H), 4.56 (m, 1H), 4.28 (dd, 1H), 3.98 (m, 1H), 3.74 (s, 3H), 3.0 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Pd].C1(C)C=CC=CC=1.C(O)C>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCC[C@H]1CC[C@H](C=Cc2ccc(-c3ccc([C@H]4CC[C@H](CCCCC)CC4)cc3)cc2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(-c3ccc([C@H]4CC[C@H](CCCCC)CC4)cc3)cc2)CC1

Procedure:
2.20 g of 4-(trans-4-pentylcyclohexyl)-4'-[2-(trans-4-pentylcyclohexyl)vinyl]biphenyl were suspended in a toluene/ethanol mixture (3:2) in a sulphonation flask, treated with 200 mg of palladium/carbon (10%) and hydrogenated at normal pressure and 50° C. until the hydrogen uptake came to a standstill. Filtration of the mixture and concentration of the filtrate gave a white, semi-crystalline residue which, after recrystallization from 100 ml of hexane, yielded 1.55 g of 4-(trans-4-pentylcyclohexyl)-4'-[2-(trans-4-pentylcyclohexyl)ethyl]biphenyl as colourless needles; transition (presumably S-S) 219.5° C., transition S-N 243.2° C., cl.p. (N-I) 256.1° C. This substance showed itself to be very considerably super-coolable; it did not crystallize upon cooling to room temperature. Rf value (hexane): 0.32.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5]2.[CH:19]([C:21]1[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][CH:22]=1)=[O:20].C1CCN2C(=NCCC2)CC1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[C:5]2[CH:19]([OH:20])[C:21]1[N:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc2[nH]c(-c3ccccc3)cc2cc1F
Reactant: COC(=O)c1cccc(C=O)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1cccc(C(O)c2c(-c3ccccc3)[nH]c3cc(OC)c(F)cc23)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.8 %

Procedure:
To a suspension of 5-fluoro-6-methoxy-2-phenyl-1H-indole (176 mg) and methyl 6-formylpyridine-2-carboxylate (133 mg) in dichloromethane (3.6 mL) was added 1,8-diazabicyclo[5,4,0]-7-undecene (0.011 mL), and this mixture was stirred at room temperature for 20 hours. The reaction mixture was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (210 mg). 1H-NMR (CDCl3) δ ppm: 3.88 (3H, s), 4.05 (3H, s), 5.31 (1H, d, J=2.8 Hz), 6.10-6.16 (1H, m), 6.81 (1H, d, J=11.8 Hz), 6.91 (1H, d, J=7.0 Hz), 7.23-7.29 (1H, m), 7.38-7.54 (3H, m), 7.66-7.75 (3H, m), 8.00-8.06 (1H, m), 8.12 (1H, br s).
Reaction SMILES: [C:1]([C:3]1[C:4]2[CH:5]=[C:6](C#CC3C=CC(C(O)=O)=CC=3)[CH:7]=[CH:8][C:9]=2[C:10]([CH3:14])([CH3:13])[CH2:11][CH:12]=1)#[N:2].CC1(C)C2C=C([C:37]#[C:38][C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)C=CC=2C(=O)CC1>>[C:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([C:37]#[C:38][C:39]3[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[CH:8][C:9]=2[C:10]([CH3:14])([CH3:13])[CH2:11][CH:12]=1)#[N:2]
Reactant: CC1(C)CC=C(C#N)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Reactant: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CC=C(C#N)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(8-cyano-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoic acid (Compound 129), 63 mg (0.26 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7) was converted into the title compound (yellow powder) using 0.06 ml (0.54 mmol) of cyanotrimethylsilane and 6 drops of boron trifluoride etherate.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][O:35]1)[C:4]1[C:5]2[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[N:9]=1)[CH3:2].Cl>CO>[CH2:1]([N:3]([CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][O:35]1)[C:4]1[C:5]2[CH2:25][NH:24][CH2:23][CH2:22][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[N:9]=1)[CH3:2]
Reactant: CCN(CC1CCCO1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Product: CCN(CC1CCCO1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(ethyl((tetrahydrofuran-2-yl)methyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (320 mg, 0.61 mmol) was dissolved in methanol (5 mL). Hydrochloric acid (0.019 mL, 0.61 mmol) was added and the reaction mixture was stirred at 80° C. for 1 h. The solvent was evaporated under reduced pressure and the crude was used as such in the subsequent step. MS (ES+) m/z 421.0 (M+H)+
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]1([C:11]2[C:19]3[C:18]([N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][C:23](=O)[CH2:24]5)=[N:17][CH:16]=[N:15][C:14]=3[S:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C(Cl)Cl>[CH:1]([NH:4][CH:23]1[CH2:22][CH:21]2[N:20]([C:18]3[C:19]4[C:11]([C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=5)=[CH:12][S:13][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:25]([CH2:26][CH2:27]2)[CH2:24]1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=C1CC2CCC(C1)N2c1ncnc2scc(-c3ccccc3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)NC1CC2CCC(C1)N2c1ncnc2scc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropylamine (0.0385 mL, 0.4472 mmol) was added to a solution of 8-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-one (0.05 g, 0.1491 mmol) in DCM (2 mL). Sodium triacetoxyborohydride (0.1663 g, 0.7454 mmol) was added and the mixture was stirred at room temperature overnight. A second batch of isopropylamine (0.0385 mL, 0.4472 mmol) and sodium triacetoxyborohydride (0.1663 g, 0.7454 mmol) was added and the mixture was stirred overnight. A third batch of isopropylamine (0.0385 mL, 0.4472 mmol) and sodium triacetoxyborohydride (0.1663 g, 0.7454 mmol) was added and the mixture was stirred over three nights. Methanol (2 mL) was added to quench the reaction. The solvent was evaporated and the residue was dissolved in dichloromethane (2 mL) and water (2 mL). The layers were separated and the aqueous was extracted with dichloromethane (2×2 mL). The combined organic layers were evaporated to give a colourless oil. Mass: 77 mg. This was purified by silica chromatography (10 g cartridge; eluent dichloromethane/0.5 M ammonia in methanol 0 to 10%; all output collected). Fractions containing the target compound (by TLC and LCMS; broad peak) were combined and evaporated to give N-isopropyl-8-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-amine a white solid. (19 mg). LCMS RT=3.04 min. M+1=379.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:8]1[C:4]([C:5]([OH:7])=[O:6])=[C:3]([CH3:12])[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=2)=[CH:10][CH:9]=1
Reactant: Cc1c(Br)ccc(F)c1C(=O)O
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccc(F)c2)ccc(F)c1C(=O)O
Temperature: 95 °C
Yield: 47.2 %

Procedure:
To a solution of 3-bromo-6-fluoro-2-methylbenzoic acid (1.35 g, 5.8 mmol, 1.0 eq) and 3-fluorophenyl boronic acid (970 mg, 6.9 mmol, 1.2 eq) in DMF (25 mL) under N2 were added Na2CO3 (2.45 g, 23.1 mmol, 4 eq) and Pd(PPh3)4 (0.33 g, 0.29 mmol, 0.05 eq). The reaction was heated at 95° C. overnight, then the reaction acidified by addition of 4M HCl to a final pH of 4. The reaction mixture was filtered through celite and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound (680 mg, 48%). This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]2[OH:17])[C:3]=1[CH2:18][CH:19](OCC)OCC.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]2[CH:18]=[CH:19][N:8]([C@@H:9]3[CH2:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]3[OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(Cc1c(Cl)ncnc1N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: OC[C@H]1C[C@@H](n2ccc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 69.5 h

Procedure:
A suspension of crude (1R,2S,3R,5R)-3-((6-chloro-5-(2,2-diethoxyethyl)pyrimidin-4-yl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol in 1,4-dioxane (160 mL) was treated with a 1 M aqueous solution of HCl (30 mL, 30 mmol) and stirred at rt for 69.5 h; HPLC indicated clean conversion to one product, LC MS showed mass for desired product. The reaction mixture was neutralized with concentrated NH4OH (to pH 7) and the volatiles were removed in vacuo to afford a brown slurry, which was carried on without further purification: MS (ESI+) for C12H14ClN3O3 m/z 284.1 (M+H)+; MS (ESI−) for C12H14ClN3O3 m/z 282.2 (M−H)−, 328.2 (M+HCO2)−; HPLC purity>95% (ret. time, 1.947 min). Variation on route from J. Med. Chem. 10, 665 (1967).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:9][CH2:10][C:11]([N:13]2[CH2:18][C@H:17]([CH3:19])[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:15][C@H:14]2[CH3:28])=[O:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:29]([O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35]Br)[CH3:30].C(=O)(O)[O-].[Na+].[I-].[K+].C(OC(=O)C(Br)CC)C>C(O)C>[CH2:29]([O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35][NH:1][C:2]1[C:3]([O:9][CH2:10][C:11]([N:13]2[CH2:18][C@H:17]([CH3:19])[N:16]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:15][C@H:14]2[CH3:28])=[O:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1)[CH3:30]
Reactant: CCOC(=O)CCCBr
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1N
Agent: CCOC(=O)C(Br)CC
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCO
Product: CCOC(=O)CCCNc1cc(Cl)cnc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 70 °C
Reaction time: 18 h
Yield: 36.3 %

Procedure:
To a solution of 2-(3-amino-5-chloro-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.072 g, 0.18 mmol) in ethanol (1 mL) was added 4-bromo-butyric acid ethyl ester (0.030 mL, 0.21 mmol), sodium bicarbonate (0.031 g, 0.37 mmol) and potassium iodide (˜0.030 g). The resulting solution was stirred at 70° C. for 18 hours. Additional bromo-butyric acid ethyl ester (0.030 mL, 0.21 mmol) was added and the reaction was stirred at 70° C. for 18 hours. The reaction was cooled, concentrated in vacuo and purified via flash chromatography on silica gel to give the title compound (0.034 g).
Reaction SMILES: C(=[N:8][CH:9]1[C:30](=[O:31])[N:11]2[C:12]([C:18]([O:20]CC3C=CC(OC)=CC=3)=[O:19])=[C:13]([CH2:16][I:17])[CH2:14][S:15][C@H:10]12)C1C=CC=CC=1.[ClH:32].CC(C)=O.C(OC(C)C)(C)C>C(O)=O>[ClH:32].[NH2:8][CH:9]1[C:30](=[O:31])[N:11]2[C:12]([C:18]([OH:20])=[O:19])=[C:13]([CH2:16][I:17])[CH2:14][S:15][C@H:10]12
Reactant: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3C(N=Cc4ccccc4)C(=O)N23)cc1
Agent: Cl
Solvent: O=CO
Solvent: CC(C)OC(C)C
Solvent: CC(C)=O
Product: NC1C(=O)N2C(C(=O)O)=C(CI)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.7 %

Procedure:
3.25 g (59.3 mM) of p-methoxybenzyl 7-benzylideneamino-3-iodomethyl-3-cephem-4-carboxylate was dissolved in 55 ml of 99% formic acid. Under cooling with ice, 23 ml of concentrated hydrochloric acid was added to this solution, and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution, 200 ml of acetone and 400 ml of isopropyl ether were added. Precipitates were collected by filtration, washed with acetone and dried to obtain 12 g (yield: 53.7%) of 7-amino-3-iodomethyl-3-cephem-4-carboxylic acid hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[C:5]2=[O:20].CC(O)=O.[I:26][C:27]1[C:32]([CH:33]=O)=[C:31]([O:35][CH3:36])[N:30]=[CH:29][CH:28]=1>CO>[I:26][C:27]1[CH:28]=[CH:29][N:30]=[C:31]([O:35][CH3:36])[C:32]=1[C:33]1[NH:11][C:10]2[C:2]([N:1]=1)=[C:3]([CH3:21])[C:4]1[C:5](=[O:20])[N:6]([CH:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[C:7](=[O:12])[C:8]=1[CH:9]=2
Reactant: Cc1c(N)c(N)cc2c1C(=O)N(C1CCN(C)CC1)C2=O
Reactant: COc1nccc(I)c1C=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1nccc(I)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Temperature: 60 °C
Yield: 47.2 %

Procedure:
To a solution of 5,6-Diamino-4-methyl-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione (1.7 g, 5.90 mmol) in MeOH (50 mL) were added AcOH (3 mL) and 4-iodo-2-methoxynicotinaldehyde (1.55 g, 5.90 mmol) and the resulting mixture was heated at 60° C. for overnight. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography (5-10% (6% NH3 in MeOH)/CHCl3) to afford 2-(4-Iodo-2-methoxy-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (1.48 g, 47%) as a yellow solid.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)[NH2:27]>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:35])=[O:36])=[CH:30][CH:29]=2)[N:27]=[CH:3][CH:4]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: NS(=O)(=O)c1ccc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-hydrazino-benzenesulfonamide according to the method described for example 43. MS: M=478.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.[CH2:13](Br)[C:14]#[CH:15]>C1(C)C=CC=CC=1>[F:9][C:7]1([F:10])[O:6][C:5]2[CH:11]=[CH:12][C:2]([NH:1][CH2:15][C:14]#[CH:13])=[CH:3][C:4]=2[O:8]1
Reactant: C#CCBr
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Solvent: Cc1ccccc1
Product: C#CCNc1ccc2c(c1)OC(F)(F)O2
Temperature: 80 °C

Procedure:
To a stirred solution of 5-amino-2,2-difluorobenzo-1,3-dioxole (2.8 g, 16.17 mmol) in 25 mL of anhydrous toluene was dropwise added propargyl bromide (0.99 mL, 11 mmol). The mixture was heated to 80° C. overnight after which it was allowed to cool to ambient temperature and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography using DCM as eluant to provide the titled compound. 1H NMR (CDCl3) δ ppm 2.22 (1H), 3.85 (2H), 6.30-6.85 (3H); MS (ESI) 212 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:30][CH:31]=1>>[C:18]1([CH3:22])[CH:19]=[CH:20][CH:21]=[C:16]([C:15]#[C:14][C@:9]2([O:23][C:33](=[O:34])[CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:36])([F:24])[F:37])[CH:27]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])[CH:17]=1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (3-trifluoromethyl-phenyl)-acetic acid to yield (3aR,4S,7aR)-methyl 4-(m-tolylethynyl)-4-(2-(3-(trifluoromethyl)phenyl)acetoxy)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=8.365 min; LCMS Method III
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=2)[CH2:8]1.[O:19]1[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl.CN(C=O)C>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:25]([CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[O:26])=[N:16][CH:17]=2)[CH2:8]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc(N)nc2)C1
Reactant: O=C(O)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc(NC(=O)C3CCOCC3)nc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.6 %

Procedure:
To a solution of 5-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-2-ylamine (0.091 g, 0.369 mmol) in DCM (3 mL) and DMF (1 mL), was added sequentially tetrahydro-2H-pyran-4-carboxlic acid (0.058 g, 0.443 mmol), N-methylmorpholine (0.122 mL, 1.11 mmol), 1-hydroxylbenzotriazole (HOBT) (0.065 g, 0.481 mmol), and EDCl.HCl (0.092 g, 0.481 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (3 mL) and 15 mL of dichloromethane. The aqueous layer was extracted with dichloromethane (15 mL, 2×). The combined organic layers were washed with sodium bicarbonate (15 mL), brine (15 mL), dried over Na2SO4, and concentrated under vacuum. Purification by column chromatography on silica gel (0-10%) methanol in dichloromethane afforded 4.7 mg (4.0%) of the title compound.