Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]1[CH:11]=[CH:10][C:9](=[O:12])[CH2:8]C1)=O.C(N(CC)CC)C.[CH:25]([OH:27])=O>CN(C=O)C.C(O[Pd]OC(=O)C)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:3]2[C:2]=1[C:25](=[O:27])[N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:4]12
Reactant: O=CO
Reactant: O=C1C=CN(C(=O)c2cccc(Cl)c2Br)CC1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCN2C(=O)c3c(Cl)cccc3C2C1
Temperature: 80 °C
Yield: 31.1 %

Procedure:
A mixture of 1-(2-bromo-chlorobenzoyl)-2,3-dihydro-4-pyridinone (Preparation 3) (300 mg, 0.954 mmol), triethylamine (0.39 mmol, 0.54 ml), formic acid (0.05 ml, 1.3 mmol) and di(triphenylphosphine) diacetoxypalladium (47 mg, 0.063 mmol) in DMF (3 ml) was heated to 80° C. for 2 h. The cooled solution was filtered through celite, diluted with water, extracted twice with ethyl acetate, the extracts dried over sodium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 50% ethyl acetate in hexane to yield the title compound as a colourless oil (70 mg). MS (+CI) m/z 235/237 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Cl.[C-:11]#[N:12].[Na+].O>CN(C=O)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][C:11]#[N:12])=[C:2]([F:1])[CH:7]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
2-Fluoro-4-bromo-chloromethylbenzene (25.0 g, 112 mmol) and NaCN (6.32 g, 129 mmol) were dissolved in DMF (70 mL) and the solution was stirred under a N2 atmosphere for 18 hrs at ambient temperature. The solution was poured into water (300 mL), and was extracted with EtOAc (1×1 L, 4×300 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure, yielding the title compound (22.5 g, 105 mmol, 93%) as a yellow oil that contained some traces of DMF. 1H-NMR (CDCl3, 300 MHz): 3.75 (s, 2H); 7.20-7.4 (m, 3H)
Reaction SMILES: Cl.[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH:20]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21]1>CN(C=O)C.O>[C:2]1([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH:19][S:23]([CH:20]3[CH2:22][CH2:21]3)(=[O:25])=[O:24])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1)C1CC1
Reaction time: 1.5 h
Yield: 63.8 %

Procedure:
To a mixture of (1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.300 g, 0.952 mmol, Example #6, Step C) in DMF (9 mL) was added TEA (0.462 mL, 3.33 mmol) and cyclopropanesulfonyl chloride (0.097 mL, 0.95 mmol). After about 1.5 h at ambient temperature, the reaction was diluted with water (10 mL) and extracted with DCM (3×15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. To the crude material was added MeOH (˜50 mL) and a small amount of insoluble material (<0.01 g) was removed by filtration. Silica gel (2 g) was added to the filtrate and the mixture was concentrated under reduced pressure. The mixture was purified by silica gel chromatography eluting with a step-wise gradient of DCM/MeOH/NH4OH 990:9:1 to 980:18:2 to give an off-white solid that was dried in a vacuum oven at about 70° C. The solid was dissolved in hot MeOH, filtered while hot to remove particulates and then the filtrate was sonicated while cooling to provide a fine suspension which was concentrated under reduced pressure and dried in a vacuum oven at about 100° C. to give N-((1S, 3R)-3-(6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.21 g, 64%): LC/MS (Table 2, Method a) Rt=1.51 min; MS m/z: 347 (M+H)+.
Reaction SMILES: C[C:2]1[O:3][C:4]([CH:7]=O)=[CH:5][CH:6]=1.Cl.[NH2:10][N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16].[OH-].[Na+]>O>[CH3:7][C:4]1[O:3][C:2](=[N:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:6][CH:5]=1
Reactant: Cc1ccc(C=O)o1
Reactant: NN1CCNC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1=CCC(=NN2CCNC2=O)O1
Reaction time: 8 h

Procedure:
98.3 pts. by wt. of 2-methylfuran-5-aldehyde ar added to a solution of 1-amino-2-oxo-imidazolidine hydrochloride in 1,000 pts. by vol. of water which has been brought to pH 4.5 with sodium hydroxide solution and the mixture is stirred overnight. The precipitae is filtered off, washed with water and recrystallised from ethanol. 126 pts. by wt. of 1-(5-methylfurylideneamino)-2-oxo-imidazolidine of melting point 194°-6° C. are obtained.
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:41][CH2:42][C:43]1[N:48]([CH2:49][C:50](O)=[O:51])[C:47]2[N:53]=[CH:54][CH:55]=[CH:56][C:46]=2[C:45](=[O:57])[N:44]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:41][CH2:42][C:43]1[N:48]([CH2:49][C:50]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[CH:11]2[CH2:12][CH2:13][N:8]([C:2]([CH3:1])([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[CH2:9][CH2:10]2)=[O:51])[C:47]2[N:53]=[CH:54][CH:55]=[CH:56][C:46]=2[C:45](=[O:57])[N:44]=1
Reactant: COC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.3 %

Procedure:
A mixture of methyl 2-methyl-2-{4-[({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-l piperidinyl}propanoate (Int. B6) (145 mg, 1 equiv), [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (122 mg, 1 equiv), DIPEA (0.084 ml, 1.5 equiv) and DMF (2.0 ml) was stirred at room temperature for 5 min. The HATU (160 mg, 1.3 equiv) was added in 1 portion and stirred an additional 1 hour under nitrogen. The crude reaction mixture was applied directly to reverse-phase HPLC (Preparative Method A) to obtain methyl 2-{4-[{[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}({4′-[(trifluoromethyl)oxy]-4-biphenylyl} methyl)amino]-1-piperidinyl}-2-methylpropanoate (116 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[OH-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O1CCOCC1.O>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:12](=[O:13])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Reaction time: 64 h

Procedure:
Trans-4-hydroxycyclohexylamine (23 g) was dissolved in 1,4-dioxane (360 ml) and water (360 ml), and cooled at 0° C. Aqueous 5 N sodium hydroxide solution (160 ml) and benzyl chloroformate (72 ml) were added to the reaction liquid successively, then restored to room temperature and stirred for 64 hours. The white solid formed in the reaction system was collected by filtration, then successively washed with water and ethyl acetate, and dried at 50° C. under reduced pressure to obtain the entitled compound (32.3 g) as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[S:5][CH:6]=1.[C:24]([NH:28][S:29]([C:32]1[S:33][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:36]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[S:33][C:34]([C:2]2[N:3]=[C:4]([C:7]3[CH:12]=[C:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[CH:10]=[C:9]([CH3:23])[N:8]=3)[S:5][CH:6]=2)=[CH:35][CH:36]=1)(=[O:30])=[O:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(Br)cs2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)cs2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-thiazol-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.80) (0.150 g, 0.375 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.143 g, 0.413 mmol) according to the general procedure VI. Obtained as a white solid (0.130 g, 64%). MS (ISP) 538.3 [(M+H)+]; mp 171° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[CH:8][O:7][NH:6]1)=O.[CH3:15][NH:16][C:17]([NH2:19])=[S:18]>C(O)(=O)C>[CH2:13]([O:12][C:10]([C:5]1([C:3]2[N:19]=[C:17]([NH:16][CH3:15])[S:18][CH:2]=2)[CH:9]=[CH:8][O:7][NH:6]1)=[O:11])[CH3:14]
Reactant: CCOC(=O)C1(C(=O)CBr)C=CON1
Reactant: CNC(N)=S
Solvent: CC(=O)O
Product: CCOC(=O)C1(c2csc(NC)n2)C=CON1

Procedure:
A solution of ethyl 3-(bromoacetyl)isoxazole-3-carboxylate (100 mg, 0.40 mmol) and methylthiourea (69 mg, 0.76 mmol) in acetic acid (3.0 mL) was heated at 150° C. in the microwave for 15 minutes. Solvent was removed in vacuo to give the crude which was used without purification. MF=C10H11N3O3S; LCMS calculated for C10H11N3O3S; (M+H)+: m/z=254.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:21][NH2:22])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:32](=S)=[S:33].[Cl-].[NH4+]>C(O)C>[F:24][C:2]([F:23])([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:32]([SH:33])=[N:22][N:21]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(S)o4)cc23)c1

Procedure:
A mixture of the obtained 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carbohydrazide, triethylamine (5.6 mL, 40.4 mmol), carbon disulfide (18.2 mL, 303 mmol) and ethanol (70 mL) was heated under reflux for 5 hr. After cooling, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/2) and recrystallized from hexane/ethyl acetate to give 5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CN(C)C1C=CC=CC=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].Cl>CC(C)=O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([N:2]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:1])=[O:26]
Reactant: O=C(Cl)CCCCCBr
Reactant: CNc1ccc(O)cc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CC(C)=O
Product: CN(C(=O)CCCCCBr)c1ccc(O)cc1
Temperature: 0 °C

Procedure:
A solution of 69 g (0.56 mol) of 4-methylaminophenol and 73.9 g (0.61 mol) of N,N-dimethylaniline in about 1.5 L of acetone was stirred mechanically under nitrogen in a 3 L flask. A solution of 119.6 g (0.56 mol) of 6-bromohexanoyl chloride in 100 mL of acetone was added as rapidly as the exotherm would allow at about 40° C. The reaction was refluxed for 2 hours on a steam bath, allowed to cool and poured into a solution of about 560 mL of 2N HCl in 2 L of ice. The aqueous solution was extracted twice with ethyl acetate and the ethyl acetate extracts were combined and dried over magnesium sulfate. The ethyl acetate solution was stripped to dryness under high vacuum to yield 143.4 g (85%) of greenish-white, low melting, solid 6-bromo-N-(4-hydroxyphenyl)-N-methylhexanamide.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1>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.C(O)C>[CH3:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: COCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(COC)cc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
Ethyl 4-iodobenzoate (5.5 g), tetrakis(triphenylphosphine)palladium (1.2 g), and cesium carbonate (9.8 g) were added to an ethanol (0.10 L) solution of 2-[4-(methoxymethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.1 g), as obtained in Example 3-(1). The mixture was stirred for 30 minutes at 80° C., and then the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (hexane/ethyl acetate=85/15) to obtain ethyl 4′-(methoxymethyl)biphenyl-4-carboxylate (light yellow solid) (3.5 g, 80%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][N:23]([C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=4[CH3:15])[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)c1C

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(2,3-dimethylphenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 83% overall yield. FDMS m/e=379 (M+ of free base). α[D]589 =-9.84 (c=0.75, methanol).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][Cl:28]>CO>[Cl:28][CH2:27][CH2:26][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClCCBr
Reactant: O=c1[nH]c(-c2ccccc2)c(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1[nH]c(-c2ccccc2)c(OCCCl)c2ccccc12
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a suspension of 180 mg (0.76 mmol) of 4-hydroxy-3-phenyl-2H-isoquinolin-1-one in methanol (6 mL), 315 mg (2.28 mmol) of potassium carbonate and 190 L (2.28 mmol) of 1-bromo-2-chloroethane were added and the mixture was submitted to microwaves at 120° C. for 10 min. The solvent was concentrated under reduced pressure and the resulting crude was purified by flash chromatography (eluant: ethyl acetate/hexane 1/2) affording 100 mg of the title compound (44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])[CH:16]=[CH:17][CH:18]=1>C1(C)C=CC=CC=1.CC(C)([O-])C.[K+]>[C:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:11]
Reactant: N#CCc1ccc(F)c(F)c1
Reactant: COC(=O)C=Cc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)CC(c1cccc(F)c1)C(C#N)c1ccc(F)c(F)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
Under protective gas (Ar), 3.828 g (25.0 mmol) of (3,4-difluorophenyl)acetonitrile and 0.281 mg of potassium tert-butoxide were added to 4.099 g (22.7 mmol) of methyl 3-(3-fluorophenyl)acrylate in 25.0 ml of toluene, and the mixture was stirred in a closed vessel at 65° C. for 5 h. The solvent was removed under reduced pressure, the residue was taken up in ethyl acetate and the mixture was washed twice with in each case 25 ml of water. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel (ethyl acetate/heptane=20:80) gave 7.3 g (87% of theory) of the diastereomeric methyl 4-cyano-4-(3,4-difluorophenyl)-3-(3-fluorophenyl)butanoate (erythro:threo=65:35 according to integration of the methyl singlets in the 1H-NMR in CDCl3 at 3.68 and 3.59 ppm).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[CH3:32][O:33][C:34](=[O:37])[CH2:35]Br.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Reactant: COC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CNCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1

Procedure:
Using General Procedure A: Reaction of (5-Aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol, methylbromoacetate and DIPEA in CH2Cl2 gave (4-{[(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzylamino)-acetic acid methyl ester as a white foamy solid. 1H NMR (CDCl3) δ 1.60 (m, 1H), 1.80 (br s, 1H), 1.98 (m, 1H), 2.19 (m, 2H), 2.22 (s 3H), 2.25 (s, 3H), 2.64 (m, 1H), 2.79 (m, 1H), 3.40 (s, 2H), 3.63-3.77 (m, 8H), 3.91 (t, 1H, J=7.5 Hz), 4.15 (m, 2H), 4.36 (d, 1H, J=12.0 Hz), 7.01 (dd, 1H, J=7.5, 3.0 Hz), 7.16 (d, 1H, J=7.5 Hz), 7.21-7.31 (m, 4H), 8.16 (s, 1H), 8.37 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.3, 18.6, 21.1, 22.1, 29.8, 50.4, 52.1, 53.3, 54.4, 54.6, 57.9, 63.0, 121.9, 127.4, 131.4, 131.8, 132.2, 133.8, 134.9, 136.3, 136.9, 139.3, 139.7, 142.6, 146.5, 146.9, 153.7, 157.3, 173.2. HPLC: 98%. ES-MS m/z 489 [M+H]+, 511 [M+Na]+. Anal. Calcd. for C29H36N4O3.0.1 CH2Cl2: C, 70.31; H, 7.34; N, 11.27. Found: C, 70.54; H, 7.48; N, 11.17.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)[CH2:14][CH2:13]1.[NH3:23].O>C1(C)C=CC=CC=1>[NH2:23][C:15]([CH:12]1[CH2:14][CH2:13]1)=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: N
Reactant: CCOC(=O)CC(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(N)C1CC1
Reaction time: 8 h

Procedure:
1.1 g of p-toluenesulphonic acid are added to 49.9 g (0.32 mol) of ethyl cyclopropylcarbonylacetate in 200 ml of dry toluene and the mixture is saturated with ammonia gas at room temperature with stirring. After allowing to stand overnight, the mixture is boiled under reflux for 8 hours in a water separator, ammonia gas being continuously introduced. The mixture is allowed to cool overnight and is filtered, and the toluene solution is concentrated in vacuo and removed by distillation in a high vacuum up to 65° C. from unreacted starting material. The substance is subsequently found in the residue.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(Br)C=C>CC#N.C1OCCOCCOCCOCCOCCOC1>[C:7]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:3][CH:2]=[CH2:1])=[CH:24][CH:23]=1)([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: CC(C)(C)[O-]
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: C=CCBr
Solvent: CC#N
Product: C=CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Potassium tert-butoxide (1.7 g, 15.2 mmol) and 18-crown-6 (0.1 g, 0.3 mmol) were added to a solution of 29 (4.3 g, 14.3 mmol) in dry MeCN (80 mL) and the mixture was stirred for 20 min at room temperature. After this time, allyl bromide (1.2 mL, 14.3 mmol) in MeCN (10 mL) was added. The reaction mixture was stirred overnight at room temperature, then the precipitate was filtered off and washed with ethyl acetate. The organic fractions were combined, the solvent was removed at reduced pressure and the residue was purified twice by flash chromatography (silica gel, 1:1 ethyl acetate/hexanes) to provide compound 30 (3.4 g, 71%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.55 (m, 4H), 2.54 (t, 2H), 3.20 (m, 2H), 4.50 (d, 2H), 5.08 (s, 2H), 5.28 (d, 1H), 5.40 (d, 1H), 6.06 (m, 1H), 6.82 (d, 2H), 7.05 (d, 2H), 7.33 (s, 5H)
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][S:17]([C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:12][CH2:11]1)#[N:9].[C:24]1([C:30]2[CH:35]=[CH:34][C:33](N)=[C:32]([NH2:37])[CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(OCC)(=O)C>[C:20]([S:17]([NH:16][CH:13]1[CH2:12][CH2:11][N:10]([C:8]2[NH:37][C:32]3[CH:31]=[C:30]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:35]=[CH:34][C:33]=3[N:9]=2)[CH2:15][CH2:14]1)(=[O:19])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: Nc1ccc(-c2ccccc2)cc1N
Reactant: CC(C)(C)S(=O)(=O)NC1CCN(C#N)CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)(=O)NC1CCN(c2nc3ccc(-c4ccccc4)cc3[nH]2)CC1
Temperature: 130 °C
Reaction time: 16 h
Yield: 32.4 %

Procedure:
To the toluene solution (1 mL) containing 1-cyano-4-(tert-butylsulfonylamino)piperidine (22 mg) were added 4-phenyl-1,2-phenylenediamine (20 mg) and ytterbium triflate (20 mg), and the mixture was stirred in a sealed tube at 130° C. for 16 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with aqueous saturated sodium hydrogencarbonate solution and aqueous saturated sodium chloride solutions successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified on a collective thin-layer chromatograph (chloroform:methanol=15:1) to give the title compound (12 mg).