Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:11](=[O:21])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cu][C:23]#[N:24]>CN(C)C=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:11](=[O:21])[N:10]=2)=[CH:3][C:2]=1[C:23]#[N:24]
Reactant: O=c1nc(-c2ccc(F)c(Br)c2)cc(-c2ccccc2)[nH]1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2cc(-c3ccccc3)[nH]c(=O)n2)ccc1F
Yield: 114.4 %

Procedure:
A solution of 4-(3-bromo-4-fluorophenyl)-6-phenylpyrimidin-2(1H)-one (0.3 g, 0.9 mmol) and copper(I) cyanide (0.16 g, 1.7 mmol) in N,N-dimethylformamide (3 mL) was heated to 155° C. for 24 hours. The crude reaction mixture was concentrated in vacuo then partitioned between saturated sodium bicarbonate (aqueous) and ethyl acetate/methanol (10:1). The layers were separated and the aqueous layer was extracted once with 10:1 ethyl acetate/methanol. The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo to give 0.30 g (quantitative yield) of crude 2-fluoro-5-(2-oxo-6-phenyl-1,2-dihydropyrimidin-4-yl)benzonitrile that was used without further purification for the next step. A solution of 2-fluoro-5-(2-oxo-6-phenyl-1,2-dihydropyrimidin-4-yl)benzonitrile (0.30 g, 1.0 mmol) and hydrazine monohydrate (1.7 mL, 36 mmol) in t-butanol (34 mL) was heated at 120° C. for 12 hours. The solution was concentrated in vacuo to give a solid, which was taken into hot methyl alcohol and treated with an excess of 4.0M hydrogen chloride in dioxane. After concentration in vacuo, the resultant solid was triturated in hot ethyl acetate, collected by vacuum filtration then lyophilized from aqueous solution to give 4-(3-amino-1H-indazol-5-yl)-6-phenylpyrimidin-2(1H)-one dihydrochloride (0.034 g, 11% yield). 1H NMR (400 MHz, DMSO): 8.93 (broad s, 1H), 8.20 (d, 1H), 8.11 (d, 1H), 7.70 (t, 1H), 7.65 (t, 2H), 7.57 (broad s, 1H), 7.47 (d, 1H). MS (EI) for C17H13N5O: 304 (MH+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[CH3:52][N:53]1[C:57]([CH3:58])=[C:56]([CH2:59][N:60]2[CH2:65][CH2:64][N:63]([C:66]3[C:71]([C:72]4[CH:79]=[CH:78][C:75]([CH2:76][NH2:77])=[CH:74][CH:73]=4)=[N:70][CH:69]=[CH:68][N:67]=3)[CH2:62][CH2:61]2)[CH:55]=[N:54]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:52][N:53]1[C:57]([CH3:58])=[C:56]([CH2:59][N:60]2[CH2:61][CH2:62][N:63]([C:66]3[C:71]([C:72]4[CH:73]=[CH:74][C:75]([CH2:76][NH:77][C:6]([CH:3]5[CH2:4][CH2:5][O:1][CH2:2]5)=[O:8])=[CH:78][CH:79]=4)=[N:70][CH:69]=[CH:68][N:67]=3)[CH2:64][CH2:65]2)[CH:55]=[N:54]1
Reactant: O=C(O)C1CCOC1
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CN)cc3)CC2)cnn1C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CNC(=O)C4CCOC4)cc3)CC2)cnn1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.8 %

Procedure:
Dissolve racemic tetrahydro-furan-3-carboxylic acid (0.067 g, 0.58 mmol) in methylene chloride (5 mL). Add benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (0.453 g, 0.87 mmol). Add 1-hydroxybenzotriazole (0.118 g, 0.87 mmol). Add 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamine (0.24 g, 0.63 mmol) dissolved in methylene chloride (5 mL). Stir at rt for 5 min. Add diisopropylethylamine (0.113 g, 0.87 mmol). Stir at rt for 4 hr. Purify by normal phase chromatography (4% 7 N ammonia-methonal/ethyl acetate) to give racemic tetrahydro-furan-3-carboxylic acid 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamide (0.107 g, 39%). MS (ES): m/z=476.3[M+H]. Dissolve this racemate (0.107 g, 0.23 mmol) in acetonitrile (1 mL) and water (4 mL). Add aq. 1 N HCl (1 eq., 0.23 mmol, 0.23 mL). Freeze the solution to −78° C. in a dry-ice/acetone bath. Place the solution in the lyophilizer for 48 hr. to give the title compound (0.110 g, 94%). MS (ES): m/z=476.3 [M+H].
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[C:25]([F:28])([F:27])[F:26])[C:6]=1[CH3:29].C1COCC1.[OH-].[Na+]>O>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:30])=[O:2])=[C:6]2[CH3:29])=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:17]=1)(=[O:22])=[O:23]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a mixture comprising [1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: (11.8 g, 26.8 mmol) in water (100 ml) and THF (250 ml) is added dropwise NaOH (53.6 ml of a 1M aqueous solution) at room temperature and the two phase suspension is allowed to stir overnight. The solvent is removed in vacuo and the crude is triturated with diethyl ether, DCM and ethyl acetate. The resulting solid is dissolved in hot water (150 ml) and adjusted to pH 3-4 using 6M HCl. The suspension that forms is filtered and is further purified by dissolving in hot IPA (250 ml) and refluxing in the presence of charcoal for 5 minutes. The solution is filtered and the titled product is recrystallised from water/IPA as a white/pale green crystals. (MH+ 427)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[NH2:9].[CH2:11]([C:13]1[S:21][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[C:14]=1[S:22](Cl)(=[O:24])=[O:23])[CH3:12]>C1COCC1>[Cl:3][C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[NH:9][S:22]([C:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:21][C:13]=1[CH2:11][CH3:12])(=[O:24])=[O:23]
Reactant: Cc1noc(N)c1Cl
Reactant: CCc1sc2ncccc2c1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1sc2ncccc2c1S(=O)(=O)Nc1onc(C)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a mixture of NaH (38 mg, 1.6 mmoles) in THF (5 ml) at ambient temperature was added 4-chloro-3-methyl-5-amino isoxazole (84 mg, 0.63 mmoles). The mixture was stirred 1 hr. at ambient temperature then cooled to 0° C. followed by the addition of 2-ethylthieno[2,3-b]pyridine-3-sulfonyl chloride (0.19 g, 0.73 mmoles) via cannula in THF (2 ml). The cooling bath was removed and the brown mixture was stirred 1 hr. at ambient temperature and then diluted with 3% NaOH (50 ml) and washed with CHCl3 (2×75 ml). The aqueous layer was acidified to pH 4 using concentrated HCl, upon which a precipitate formed. The aqueous phase was extracted with EtOAc (50 ml), and the organic layer was dried (MgSO4), filtered and concentrated to collect 0.23 g of a yellow oil. Recrystallization from EtOAc/hexanes provided 0.18g (79%) of the title compound as a light yellow solid, m.p. 152°-154° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].I[C:16]1[C:24]2[C:19](=[N:20][CH:21]=[N:22][C:23]=2[NH2:25])[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]2[N:18]([CH:26]([CH3:28])[CH3:27])[N:17]=[C:16]([C:8]3[CH:7]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[CH:10][CH:9]=3)[C:24]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cccc(NS(C)(=O)=O)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 54 %

Procedure:
A solution of 3-Methanesulfonylaminophenylboronic acid (32 mg, 0.15 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA38 (24.3 mg, 54% yield). ESI-MS (M+H)+ m/z calcd 347.1, found 347.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:27][CH2:26][C:12]2=[C:13]([N:20]3[CH2:23][CH2:22][C@H:21]3[CH2:24][OH:25])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[CH3:32]COC(C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:27][CH2:26][C:12]2=[C:13]([N:20]3[CH2:23][CH2:22][C@H:21]3[CH2:24][O:25][CH3:32])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC[C@H]3CO)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@@H]1CCN1c1c2c(nc3ccnn13)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To 57.9 mg (0.155 mmol) (S)-10-(2-hydroxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 10 mL anhydrous THF was added 29.8 mg (1.24 mmol, 60% dispersion in mineral oil) NaH and the reaction was cooled to 0° C. 0.4 mL (1.24 mmol) methyl iodide was added and the reaction was stirred at room temperature for 6 hours. 25 mL EtOAc was added and the organic layer was washed with H2O (2×20 mL), 20 mL saturated brine, and dried over MgSO4. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 2:3).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:34])[N:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=1)([CH3:21])[CH3:22]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CSc1ccc(CNc2ccc(C(C)C)cc2)cc1
Product: CSc1ccc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)cc1
Yield: 82.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-isopropylphenyl)[(4-methylthiophenyl)methyl]amine (2.0 g) and 2,6-diisopropylphenyl isocyanate (2.1 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)-N-[(4-methylthiophenyl)methyl]urea (2.9 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[C:8](=[O:14])[CH2:7]2.[Cl-].[NH4+]>C(O)C.O.ClCCl.[Fe]>[NH2:15][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[N:9]([CH2:11][CH2:12][CH3:13])[C:8](=[O:14])[CH2:7]2
Reactant: CCCN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCCN1C(=O)Cc2cc(N)cc(F)c21
Temperature: 25 °C

Procedure:
Iron powder (0.855 g, 15.3 mmol) is added in small portions to 7-fluoro-5-nitro-1-propyl-1,3-dihydro-indol-2-one (0.910 g, 3.82 mmol) and ammonium chloride (2.02 g, 38.2 mmol) in ethanol (60 ml) and water (30 ml) at 90° C. The reaction mixture is stirred vigorously and heated for 60 min, cooled to room temperature, and diluted with dichloromethane (300 ml). The mixture is filtered through celite, the organic layer separated and washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a dark brown solid. HPLC r.t. 3.03 min; MS for C11H13FN2O m/z 209.0 (M+H)+.
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.[F:26][C:27]1([F:38])[O:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:35]([NH:36][NH2:37])[C:29]=2[O:28]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:38][C:27]1([F:26])[O:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:35]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:37]3)[C:29]=2[O:28]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc2c1OC(F)(F)O2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2c1OC(F)(F)O2

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 2,2-difluoro-benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=479.0 (M+H)+
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[NH:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH3:24][S:25]SC>C1COCC1.O>[CH3:12][C:9]1[NH:8][C:6]2=[N:7][C:2]([S:25][CH3:24])=[CH:3][CH:4]=[C:5]2[C:10]=1[CH3:11]
Reactant: CSSC
Reactant: Cc1[nH]c2nc(Br)ccc2c1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc2c(C)c(C)[nH]c2n1
Reaction time: 0.08 h
Yield: 83.2 %

Procedure:
A deaerated solution of 6-bromo-2,3-dimethyl-pyrrolo [2,3-b]pyridine (225 mg, 1.0 mmol) in 25 ml dry THF was cooled to -78° C. and treated with 1.6M n-BuLi in hexane (1,5 ml, 2.4 mmol). The reaction mixture was brought to 0° C. and the lithiate trapped with dimethyl disulfide (444 μl, 5 mmol). After reacting for 5 min 1.5 ml H2O was added and the THF evaporated. The residue was taken up in 100 ml CH2Cl2 and washed with 50 ml 5% NaHCO3, 50 ml 2M HCl (reextracted twice with 25 ml CH2Cl2), and 50 ml 5% NaHCO3. The organic layer was dried over MgSO4 and evaporated leaving 160 mg (83%) pure 2,3-dimethyl-6-methylthio-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH:8]=O.[NH2:16][C:17]1[C:18]([C:31]([NH:33][CH3:34])=[O:32])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH2:30])[CH:24]=2)=[CH:21][N:22]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[NH2:16][C:17]1[C:18]([C:31]([NH:33][CH3:34])=[O:32])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:30][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:3][C:2]=3[F:1])[CH:24]=2)=[CH:21][N:22]=1
Reactant: CNC(=O)c1nc(-c2cccc(CN)c2)cnc1N
Reactant: O=Cc1ccc(-c2ccccc2)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(=O)c1nc(-c2cccc(CNCc3ccc(-c4ccccc4)cc3F)c2)cnc1N
Yield: 20.2 %

Procedure:
A solution of 3-fluorobiphenyl-4-carbaldehyde (0.030 g, 0.15 mmol), 3-amino-6-[3-(aminomethyl)phenyl]-N-methylpyrazine-2-carboxamide (0.038 g, 0.15 mmol), glacial AcOH (0.010 mmol, 0.15 mmol) and NaBH(OAc)3 (0.047 g, 0.22 mmol) in THF (0.6 mL) was stirred at r.t. for 12 h. Saturated NaHCO3 (aq) was added (25 mL) and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified via HPLC (reverse-phase, CH3CN/H2O with 0.1% TFA). Upon removal of CH3CN/H2O, the product was taken up in MeOH and treated with Bio-Rad AG 1-X8 resin (hydroxide form) until pH 8. The product was filtered and concentrated in vacuo, to provide 13.4 mg (20% yield) of 3-amino-6-[3-({[(3-fluorobiphenyl4-yl)methyl]amino}methyl)phenyl]-N-methylpyrazine-2-carboxamide: 1H NMR (400 MHz, d6-DMSO): 8.84 (s, 1H), 8.79 (d, 1H), 8.09 (bs, 1H), 8.05 (m, 1H), 7.70 (m, 2H), 7.61 (t, 1H), 7.36-7.53 (m, 8H), 3.80 (d, 4H), 2.86 (d, 3H); MS (EI) for C26H24N5OF: 442 (MH+).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:11](#[N:14])[CH:12]=[CH2:13]>CO>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:13][CH2:12][C:11]#[N:14])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: C=CC#N
Solvent: CO
Product: CS(=O)(=O)N1CCN(CCC#N)CC1
Yield: 83.1 %

Procedure:
To 1-(methylsulfonyl)piperazine (1 g, 6.09 mmol) in MeOH (11 mL) at 0° C. is added acrylonitrile (0.402 mL, 6.09 mmol). The reaction mixture is concentrated in vacuo and the resulting residue diluted with 5 mL of water and extracted with EtOAc (3×25 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified over silica (2% MeOH in CH2Cl2) to afford 1.1 g (99% yield) of the desired compound. 1H NMR (CDCl3, 300 MHz) δ2.56 (t, J=6.9 Hz, 2H), 2.66 (t, J=4.8 Hz, 4H), 2.76 (t, J=6.9 Hz, 2H), 2.81 (s, 3H), 3.30 (t, J=4.8 Hz, 4H). MS (ESI, pos. ion) m/z: 218 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[CH2:25]([O:27][C:28](=[O:33])[CH2:29]C([O-])=O)[CH3:26].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7](=[O:9])[CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:33])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 178.7 %

Procedure:
To a solution of 4-methoxybenzoic acid (26.2 g, 172 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (30.7 g, 189 mmol) and the mixture was stirred at room temperature for 5 hrs. To the reaction solution was added monoethyl-malonate magnesium salt (27.1 g, 94.7 mmol) was added and the mixture was stirred at 60° C. for 2 hrs. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution, and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(4-methoxyphenyl)-3-oxopropionate (37.6 g, 94% w/w,. 92%) as a colorless oil.
Reaction SMILES: CC1(C)CC(C2C=CC=C([C:18]([F:21])([F:20])[F:19])C=2)C2C(=CC(O)=CC2)N1.[CH3:24][C:25]1([CH3:43])[CH2:34][CH:33]([C:35]2[CH:40]=[CH:39][C:38](Cl)=[CH:37][CH:36]=2)[CH:32]2[C:27](=[CH:28][C:29]([OH:42])=[CH:30][CH2:31]2)[NH:26]1>>[CH3:24][C:25]1([CH3:43])[CH2:34][CH:33]([C:35]2[CH:40]=[CH:39][C:38]([C:18]([F:21])([F:20])[F:19])=[CH:37][CH:36]=2)[CH:32]2[C:27](=[CH:28][C:29]([OH:42])=[CH:30][CH2:31]2)[NH:26]1
Reactant: CC1(C)CC(c2ccc(Cl)cc2)C2CC=C(O)C=C2N1
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)C2CC=C(O)C=C2N1
Product: CC1(C)CC(c2ccc(C(F)(F)F)cc2)C2CC=C(O)C=C2N1

Procedure:
2,2-dimethyl-7-hydroxy-4-(3-trifluoromethylphenyl)tetrahydroquinoline and 2,2-dimethyl-7-hydroxy-4-(4-chlorophenyl)tetrahydroquinoline.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Cl)[CH:10]=2)[N:5]=[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[O:22][CH3:23])[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH:3]=[C:2]2[NH:28][CH2:27][CH2:26][O:25][CH3:24])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COCCN
Reactant: COc1cc(F)ccc1CNc1cc(Br)c2cc(Cl)ccc2n1
Reactant: NCc1ccccc1
Product: COCCNc1cc(NCc2ccc(F)cc2OC)nc2ccc(NCc3ccccc3)cc12

Procedure:
The title compound, MS: m/e=461.1 (M+H+), was prepared in accordance with the general method of example 40 from (4-bromo-6-chloro-quinolin-2-yl)-(4-fluoro-2-methoxy-benzyl)-amine, methoxyethylamine and benzylamine.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O=[CH:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26][CH2:25]1.CC(O)=O.[Na]>ClCCCl.O>[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C@H:24]3[CH2:25][CH2:26][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:28][CH2:29]3)[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:12][CH2:13][CH2:14]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: [Na]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cc(C4CCC4)nc(C(C)(C)C)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-tert-butyl-4-cyclobutyl-6-(piperazin-1-yl)pyrimidine (7.16 g, 26.1 mmol) and tert-butyl trans-4-(2-oxoethyl)cyclohexylcarbamate (6 g, 24.86 mmol) in DCE (100 ml) was stirred at room temperature for 10 min. AcOH and sodium triacetoxyhydroborate (7.90 g, 37.3 mmol) were added. After 4 h, water was added. The aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil of (11.2 g, 21.29 mmol, 86% yield) which was used next step without purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([OH:27])[CH2:25][OH:26])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:28])[CH2:4][CH3:5])[CH3:2].CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C1COCC1.C(Cl)Cl>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([OH:27])[CH2:25][O:26][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:28])[CH2:4][CH3:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CO)cc3)no2)cc1C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)COS(C)(=O)=O)cc3)no2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 129.3 %

Procedure:
To a cooled (0° C.) solution of rac-3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-propane-1,2-diol (619 mg, 1.54 mmol) in THF (15 mL), DIPEA (399 mg, 3.08 mmol) followed by methansulfonyl chloride (247 mg, 2.16 mmol) is added. The mixture is stirred at 0° C. for 1 h, then at rt for 1 h. The mixture is diluted with DCM, washed with brine (3×50 mL), dried over MgSO4, filtered, concentrated and dried to give crude rac-methanesulfonic acid 3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-2-hydroxy-propyl ester (955 mg) as a light brown oil; LC-MS: tR=0.54 min; [M+1]+=480.10. b) A solution of the above rac-methanesulfonic acid 3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-2-hydroxy-propyl ester (600 mg, 1.33 mmol) in 7 M NH3 in methanol (10 mL) is stirred in a sealed vessel at 80° C. for 16 h. The mixture is diluted with EA and washed with water and brine. The organic extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (242 mg) as a pale yellow resin; LC-MS: tR=0.63 min; [M+1]+=400.93.