Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:35])([F:34])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=4)[NH2:30])[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1.[C:36](O)(=[O:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[F:35][C:11]([F:10])([F:34])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[C:29]([NH:30][C:36](=[O:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1
Reactant: CC(=O)O
Reactant: Nc1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
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: CC(=O)N(C)C
Product: CC(=O)Nc1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
DIPEA (123 μl, 0.70 mmol) was added to 3-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]aniline (obtained as described in Example 616) (85 mg, 0.23 mmol), acetic acid (16 μl, 0.28 mmol) and HATU (107 mg, 0.28 mmol) in DMA (2 mL). The resulting solution was stirred at ambient temperature for 2 hours then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness to give N-[3-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenyl]acetamide (89 mg, 94%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][C:13]#[N:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Li][CH2:16]CCC.CI>C1COCC1>[CH3:1][C:2]1[C:3]([CH:12]([CH3:16])[C:13]#[N:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: [Li]CCCC
Reactant: Cc1cc2ccccc2cc1CC#N
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2ccccc2cc1C(C)C#N
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
To a stirred solution of (3-methyl-2-naphthalenyl)acetonitrile (2.17 g, 12 mmol) in dry THF (125 mL) cooled to -78° C. was added n-BuLi (8.44 mL, 13.5 mmol; 1.6M solution in hexanes)dropwise over 10 minutes. The resulting orange solution was stirred for 20 minutes at -78° C. and MeI (1.92 g, 13.5 mmol) was added in one portion. The reaction mixture was stirred at -78° C. for 1.25 hours and quenched with saturated NH4Cl (20 mL). After warming to room temperature, the volatiles were removed in vacuo and the residue was diluted with H2O (150 mL). The aqueous phase was extracted with Et2O (2×150 mL). The combined organic layers were washed with saturated NaCl (1×150 mL) and dried (MgSO4). Removal of the solvent in vacuo afforded the product as a light yellow solid (2.34 g, 100%). This material was of sufficient purity to be used as such.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][C:26]=1[CH3:33]>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])=[CH:27][C:26]=1[CH3:33]
Reactant: Cc1cc([Mg]Br)ccc1Cl
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Product: Cc1cc(C(=O)c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)ccc1Cl

Procedure:
The product from Example 71E and 4-chloro-3-methylphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.47 (d, 3H), 1.75 (m, 1H), 1.80 (m, 2H), 2.10 (m, 2H), 2.38 (m, 1H), 2.44 (s, 3H), 3.50 (m, 2H), 3.55 (m, 1H), 3.80 (m, 2H), 6.85 (s, 1H), 7.5 (m, 3H), 7.7 (bs, 1H), 7.79 (dd, 1H), 8.01 (d, 1H); MS (ESI) m/z 382 (M+H)+.
Reaction SMILES: C([O:5][CH:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]#[N:13])[CH2:7]1)(=O)CC.[OH-].[Na+].Cl>C1COCC1.CCO>[OH:5][CH:6]1[CH2:7][C:8]([C:12]#[N:13])=[CH:9][CH2:10][CH2:11]1
Reactant: CCC(=O)OC1CCC=C(C#N)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: N#CC1=CCCC(O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R or S)-3-cyanocyclohex-3-en-1-yl propanoate (210 g, 1.17 mol) in 1:1 THF/EtOH (2 L) at 0° C. was added 3M aqueous NaOH (586 mL, 1.76 mol) dropwise via addition funnel over 30 minutes. After addition, The mixture was stirred at ambient temperature for 2 hours. The mixture was carefully neutralized with 3N aqueous HCl (195 mL), concentrated to remove most of the THF/EtOH. The resulting mixture was diluted with brine (1.5 L) and extracted with EtOAc (1.2 L, then 600 mL×4). The combined organics were washed with brine (200 mL×2). The aqueous layer was back-extracted with EtOAc (200 mL×2), and the combined organic extracts were dried over anhydrous Na2SO4, and concentrated in vacuo to give the enantioenriched title compound (chiral HPLC: 98.4% ee). 1H NMR data was consistent with that reported in the literature for racemic 5-Hydroxycyclohex-1-enecarbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:33]([CH:32]=[CH2:31])(=[O:35])=[O:34])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1cc2ncnc(Nc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)Nc1ccc(Nc2ncnc3cc(OC)c(OC)cc23)cc1
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of dichloromethane (10 mL), compound 41 (100 mg, 0.337 mmol) and triethylamine (141 μL, 1.02 mmol) was cooled to 0° C. 2-chloro-1-ethane sulfonyl chloride (32 μL, 0.304 mmol) was added and the reaction was allowed to proceed for 1 hour prior to removal of a precipitate and addition of saturated sodium bicarbonate (10 mL) and extraction with dichloromethane (2×10 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The product was purified by preparative RP-HPLC and lyophilized (24 mg, 20% yield): 1H NMR (400 MHz, DMSO) δ 10.81 (br, 1H), 10.13 (s, 1H), 8.75 (s, 1H), 8.02 (s, 1H), 7.58 (d, J=8.9, 2H), 7.25 (m, 3H), 6.83 (dd, J=16.4, 10.0, 1H), 6.15 (d, J=16.5, 1H), 6.07 (d, J=10.0, 1H), 3.99 (s, 3H), 3.98 (s, 3H); 13C NMR (100 MHz, DMSO) δ 157.93, 156.16, 150.10, 149.26, 136.23, 135.75, 132.76, 127.82, 125.54, 120.00, 107.16, 103.16, 100.51, 56.55, 56.45; [M+H]+ calculated for C18H18N4O4S 387.1, found 387.4.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[C:5]3[CH2:21][N:20]([CH2:22][CH2:23][CH2:24][CH:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[OH:26])[CH2:19][C:6]=3[N:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.[OH2:34]>>[C:25]([OH:34])(=[O:26])[CH3:27].[Cl:2][C:3]1[C:4]2[C:5]3[CH2:21][N:20]([CH2:22][CH2:23][CH2:24][CH:25]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[OH:26])[CH2:19][C:6]=3[N:7]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O
Agent: Cl
Agent: OC(CCCN1Cc2c(n(-c3ccc(F)cc3)c3cccc(Cl)c23)C1)c1ccc(F)cc1
Product: CC(=O)O

Procedure:
Five grams of 8-chloro-4-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-1,2,3,4-tetrahydropyrrolo[3,4-b]indole hydrochloride in 75 ml. of water is treated with 3 ml. of water containing 1.0 g. of sodium hydroxide, and the liberated free base extracted into 150 ml. of diethyl ether. The ether layer is separated, dried over magnesium sulfate and treated with 1 ml. of glacial acetic acid. The organic solvent and excess acetic acid are removed under reduced pressure and the residue triturated with hexane and filtered.
Reaction SMILES: NCCCN[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11]N.C1C2[C:19]3[C:30](=O)[C:29]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:20]=3OC(=O)C=2C=CC=1>C(Cl)(Cl)Cl>[CH:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:20]=[C:19]1[C:24]3=[C:20]4[C:27](=[CH:26][C:25]3=[C:6]3[C:11]([CH:10]=[CH:9][N:8]=[CH:7]3)=[C:30]12)[CH:28]=[CH:29][CH:30]=[CH:19]4
Reactant: NCCCNCCNCCCN
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Solvent: ClC(Cl)Cl
Product: C1=c2ccccc2=c2c1c1cnccc1c1c2=Cc2ccccc2-1

Procedure:
Bis-1,2-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-(6-propyl-tert-BOCamino)}ethane (13b), N,N′-Bis(3-aminopropyl)-1,2-ethanediamine (11h) (0.16 g, 0.85 mmol) was added to a stirred solution of indenobenzopyran 4d (0.46 g, 1.87 mmol) in CHCl3 (150 mL) and the reaction mixture was stirred under reflux for 72 h, providing bisindenoisoquinoline 12 h as a crude intermediate. Upon allowing the reaction mixture to cool to room temperature, Et3N (0.6 mL, 4.24 mmol) and Boc2O (0.56 g, 2.60 mmol) were added to the reaction mixture and the mixture was allowed to stir at room temperature for 8 h. The crude reaction mixture was purified by flash column chromatography (SiO2/20% EtOAc in hexane, then 1-5% MeOH in CHCl3) to provide Boc-protected bisindenoisoquinoline 13b (550 mg, 76%) as an orange solid: mp 106-108° C. 1HNMR (CDCl3) δ 8.60 (bs, 2H), 8.23 (bs, 2H), 7.65 (bs, 2H), 7.55 (d, J=6.7 Hz, 2H), 7.40-7.32 (m, 8H), 4.48 (bs, 4H), 3.45 (bs, 8H), 2.12 (bs, 4H), 1.44 (s, 9H), 1.39 (s, 9H); ESIMS m/z (rel intensity) 835 (MH+, 22), 735 (MH+-Boc, 100). Anal. Calcd for C50H50N4O8.0.3H2O: C, 71.46; H, 6.07; N, 6.67. Found: C, 71.15; H, 6.19; N, 6.61.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:28]([Cl:29])=[CH:27][C:10]3[N:11](CC=C)[C:12]([O:14][CH2:15][CH:16]4[CH2:18][CH:17]4[C:19]([O:21]CC)=[O:20])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.CN1C(=O)CC(=O)N(C)C1=O>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.CCO>[C:1]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:28]([Cl:29])=[CH:27][C:10]3[NH:11][C:12]([O:14][CH2:15][CH:16]4[CH2:18][CH:17]4[C:19]([OH:21])=[O:20])=[N:13][C:9]=3[CH:8]=2)=[CH:5][CH:6]=1
Reactant: C=CCn1c(OCC2CC2C(=O)OCC)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: CCO
Product: O=C(O)C1CC1COc1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1

Procedure:
The title compound was prepared from ethyl 2-({[5-(biphenyl-4-yl)-6-chloro-1-(prop-2-en-1-yl)-1H-benzimidazol-2-yl]oxy}methyl)cyclopropanecarboxylate (115 mg, 0.236 mmol), 1,3-dimethylbarbituric acid (111 mg, 0.708 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol) and EtOH (2.5 ml) according to the procedure described for Example 13, Step B. Purification of the resulting crude product by reverse phase HPLC eluting with 35-100% MeCN:water afforded the title compound as a white solid. LC-MS: calculated for C24H19ClN2O3 418.11, observed m/e: 418.97 (M+H)+ (Rt 2.12/4 min). 1H NMR (500 MHz, CD3OD): 7.75-7.35 (m, 11H), 4.50 (dd, 2H), 4.30 (dd, 2H) 1.85 (m, 1H), 1.70 (m, 1H), 1.10 (m, 11H), 1.05 (m, 1H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([NH2:13])[C:10](=[CH2:12])[CH3:11]>>[CH:1](=[N:13][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C=C(C)CN
Reactant: CCCCCCC=O
Product: CCCCCCC=NC=C(C)C

Procedure:
The N-heptylidene-(2-methylpropenylamine) was prepared from heptanal and methallylamine, with subsequent isomerisation of the reaction product with potassium tert.-butylate; boiling point 54° C./5 Pa; nD20 =1.4662.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][CH:16]=[C:15]([CH2:18][OH:19])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][CH:16]=[C:15]([CH:18]=[O:19])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To a solution (35 mL) of [5-(4-cyclohexylphenyl)-1H-pyrrol-3-yl]methanol (1.00 g) in acetonitrile were added tetra-n-propylammonium perruthenate (115 mg), N-methylmorpholine N-oxide (0.60 g) and molecular sieves 4A powder (1.15 g) under ice-cooling. The mixture was stirred at room temperature for 1.5 hr, and the reaction mixture was suspended in ethyl acetate, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=2:1) to give the title compound as crystals (yield 0.53 g, 53%).
Reaction SMILES: II.Cl[CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.CN(C)[CH:12]=[CH:13][C:14](=[O:16])[CH3:15]>O1CCCC1>[O:7]1[CH2:8][CH2:9][CH:4]([CH:12]=[CH:13][C:14](=[O:16])[CH3:15])[CH2:5][CH2:6]1
Reactant: CC(=O)C=CN(C)C
Reactant: ClC1CCOCC1
Agent: II
Solvent: C1CCOC1
Product: CC(=O)C=CC1CCOCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
10.8 g (400 mmol) of Mg turnings are introduced into 30 ml of tetrahydrofuran containing a catalytic amount of iodine, and 5 ml of 4-chlorotetrahydropyran are added. The mixture is warmed to 50° C., and 45.2 g (375 mmol) of 4-chlorotetrahydropyran, dissolved in 120 ml of tetrahydrofuran, are added dropwise at such a rate that the internal temperature does not exceed 70° C. The mixture is stirred for a further 1 hour and subsequently cooled to room temperature. 42.4 g (375 mmol) of 1-(dimethylamino)but-1-en-3-one are added dropwise to the stirred mixture at such a rate that the reaction temperature does not exceed 30° C. The mixture is subsequently stirred for a further 2 hours and hydrolyzed, and the pH of the solution is adjusted to exactly 7. The phases are separated, and the aqueous phase is extracted several times with 200 ml of ethyl acetate or methyl tert.-butyl ether, dried and subjected to fractional distillation, to give 42.0 g (75%) of 1-(4-tetrahydropyranyl)but-1-en-3-one of boiling point 93° to 95° C./5 mmHg.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:3]C.C1([C@H](N)C)C=CC=CC=1>>[NH2:1][C@@H:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]([CH3:16])([CH3:18])[CH3:17])(=[O:13])=[O:12])=[CH:9][CH:10]=1)[CH3:3]
Reactant: CC[C@@H](N)c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Agent: C[C@@H](N)c1ccccc1
Product: C[C@@H](N)c1ccc(S(=O)(=O)NC(C)(C)C)cc1

Procedure:
(R)-4-(1-Amino-ethyl)-N-tert-butyl-benzenesulfonamide was synthesized in a manner analogous to (R)-4-(1-Amino-propyl)-N-tert-butyl-benzenesulfonamide in Example 12, using (R)-1-phenylethanamine in place of (R)-1-phenylpropan-1-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:38][N:39]1[CH2:44][CH2:43][N:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:48]3[CH2:47][CH2:46][CH:45]([N:42]4[CH2:41][CH2:40][N:39]([CH3:38])[CH2:44][CH2:43]4)[CH2:50][CH2:49]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN1CCN(C2CCNCC2)CC1
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCN(C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-methyl-4-piperidin-4-yl-piperazine (Oakwood Products) to give the title compound. HR-MS (ES, m/z) calculated for C37H43N5O2F3Cl2 [(M+H)+] 716.2741, observed 716.2746.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:3]=[N:2]1.Br[C:16]1[N:17]([CH3:41])[C:18]2[C:23]([N:24]=1)=[C:22]([N:25]1[CH2:30][CH2:29][CH:28]([N:31]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[NH:33][C:32]3=[O:40])[CH2:27][CH2:26]1)[N:21]=[CH:20][N:19]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:41][N:17]1[C:16]([C:4]2[CH:5]=[N:1][NH:2][CH:3]=2)=[N:24][C:23]2[C:18]1=[N:19][CH:20]=[N:21][C:22]=2[N:25]1[CH2:26][CH2:27][CH:28]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[NH:33][C:32]2=[O:40])[CH2:29][CH2:30]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cn1c(Br)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(-c2cn[nH]c2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 180 °C
Yield: 62.8 %

Procedure:
To a solution of Pyrazole-4-boronic acid pinacol ester (181 mg, 0.93 mmol) in dioxane (1.5 mL) and water (0.2 mL) were added 1-(1-(8-bromo-9-methyl-9H-purin-6-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (100 mg, 0.23 mmol), Pd(dppf)Cl2 (19 mg, 0.02 mmol), and tribasic potassium phosphate (297 mg, 1.4 mmol). The reaction mixture was heated in a microwave reactor to 180° C. for 60 min. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 60 mg (62.8% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 13.40 (s, 1H), 10.81 (d, 1H), 8.42 (s, 1H), 8.19-8.00 (m, 1H), 7.13 (dd, 1H), 6.99-6.88 (m, 3H), 4.60-4.47 (m, 1H), 3.84 (s, 3H), 3.18 (t, 2H), 2.40-2.25 (m, 2H), 1.80 (t, 2H); MS (EI) for C21H21N9O: 416.4 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[C:34]([F:36])[C:33]([O:37][CH3:38])=[CH:32][C:31]=2B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[C:34]([F:36])[C:33]([O:37][CH3:38])=[CH:32][C:31]=2[C:2]2[C:3]3[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(Cl)nc(C)nc12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Product: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(OC)c(F)cc3OCC3CC3)nc(C)nc12

Procedure:
Starting from methyl 4-chloro-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A.11) and 2-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane e (example B.c2) the title compound is obtained as off white solid.
Reaction SMILES: Cl.NC(N)=O.[OH-].[Na+:7].[C:8]([OH:15])(=[O:14])/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH3:13]>>[C:8]([O-:15])(=[O:14])/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH3:13].[Na+:7]
Reactant: C/C=C/C=C/C(=O)O
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Product: C/C=C/C=C/C(=O)[O-]

Procedure:
Japanese Unexamined Patent Application Publication No. 54-163516 discloses a process for producing a sorbic acid. In this process, a polyester obtained from ketene and crotonaldehyde is decomposed with hydrochloric acid in the presence of, for example, a urea compound, the resulting decomposition reaction mixture is filtrated and rinsed to yield a crude sorbic acid, followed by addition of an aqueous sodium hydroxide solution to the crude sorbic acid to thereby yield an aqueous sodium sorbate solution, the aqueous sodium sorbate solution is treated with activated carbon, is neutralized and is cooled to thereby crystallize sorbic acid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[CH2:10][CH:11]([CH:13]1[CH2:18][CH2:17][C:16]([N:21]([CH3:23])[CH3:22])([C:19]#N)[CH2:15][CH2:14]1)[OH:12].[C:24]1([Mg]Cl)[CH:29]=[CH:28]C=[CH:26][CH:25]=1.[Cl-].[NH4+].O>O1CCCC1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][N:2]1[CH2:10][CH:11]([CH:13]1[CH2:18][CH2:17][C:16]([N:21]([CH3:23])[CH3:22])([C:19]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:14]1)[OH:12]
Reactant: Cl[Mg]c1ccccc1
Reactant: CN(C)C1(C#N)CCC(C(O)CN2Cc3ccccc3C2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(C(O)CN2Cc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A solution of 4-[2-(1,3-dihydroisoindol-2-yl)-1-hydroxyethyl]-1-dimethylaminocyclohexanecarbonitrile (666 mg, 2.12 mmol) in anhydrous tetrahydrofuran (30 ml) was added dropwise to a 2 M solution of phenylmagnesium chloride in tetrahydrofuran (4.25 ml, 8.49 mmol), while cooling with ice, and the mixture was stirred at room temperature overnight. Saturated ammonium chloride solution and water (10 ml of each) were then added dropwise to the mixture, while cooling with ice. The tetrahydrofuran was distilled off in vacuo and the residue was extracted with diethyl ether (3×30 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The crude product (761 mg) was purified by flash chromatography with chloroform/methanol (9:1). Renewed flash chromatography with chloroform (saturated with 25% aqueous ammonia solution)/methanol (95:5) gave a yield of 83 mg (10%) of beige-coloured solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][C:22]([F:21])([F:32])[F:33])[CH:25]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1cccc(OC(F)(F)F)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 3-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 411.84 g/mol.