Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[C:3](=[O:13])[NH:2]1.[H-].[Na+].Cl[CH2:17][C:18]1[N:19]=[CH:20][N:21]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]=1[CH3:23].O>CN(C)C=O>[CH3:23][C:22]1[N:21]([C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:20]=[N:19][C:18]=1[CH2:17][N:2]1[CH2:1][C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[C:3]1=[O:13]
Reactant: O=C1NCc2cc3ccccc3n21
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CN2Cc3cc4ccccc4n3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,2-dihydro-imidazo[1,5-a]indol-3-one (3 g; 0.0174 moles) in 50 ml of anhydrous dimethylformamide kept under nitrogen atmosphere, 50% NaH (0.84 g; 0.0174 moles) is added. The solution is stirred for 1 hour at 60° C.; then, at room temperature, 4-chloromethyl-5-methyl-1-triphenylmethyl-1H-imidazole (6.5 g; 0.0174 moles) is added. The reaction mixture is stirred for 6 hours at 70° C., then cooled, poured into water and extracted with methylene chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[N:9]1([C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:8][C:4]1[CH:3]=[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:14][CH2:13]2)[CH:7]=[CH:6][N:5]=1
Reactant: CC(C)COC(=O)N1CCNCC1
Reactant: Clc1cc(Br)ccn1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)COC(=O)N1CCN(c2ccnc(Cl)c2)CC1
Temperature: 150 °C
Yield: 63.1 %

Procedure:
4-Bromo-2-chloropyridine (125 mg, 0.65 mmol), isobutyl piperazine-1-carboxylate (93 mg, 0.5 mmol), Pd2(dba)3 (10 mg, 10 μmol), t-BuONa (72 mg, 0.75 mmol), and Xantphos (17 mg, 30 μmol) in dry toluene (5 mL) were sealed in a microwave vessel and heated by microwave irradiation at 150° C. for 15 minutes. The reaction was diluted with EtOAc, washed with water, dried over Na2SO4, and evaporated under reduced pressure. Purification by flash chromatography (SiO2, MeOH/CH2Cl2) afforded 3a as a tan oil (94 mg, 63% yield). LCMS: m/z 298.5 (M+H)+ at 1.93 minutes (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA).
Reaction SMILES: C(OC(=O)[CH2:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)C.N12CCN(CC1)CC2>>[O:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:25])[CH3:5]
Reactant: CCOC(=O)CC(=O)CCCCCCCCCCCOC1CCCCO1
Agent: C1CN2CCN1CC2
Product: CC(=O)CCCCCCCCCCCOC1CCCCO1

Procedure:
The title compound was prepared from 3-oxo-14-[(tetrahydro-2H-pyran-2-yl)oxy]-tetradecanoic acid ethyl ester (7.97 g, 0.021 mol), 1,4-diazabicyclo-[2.2.2]octane (24.13 g, 0.215 mol), and xylenes (39.3 mL, 15 eq) using the procedure described in Example 3, Step B.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8]C(=O)OCC2C=CC=CC=2)=[CH:6][N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:3]=1.[H][H]>CO.[Pd]>[NH2:8][C:7]1[C:2]([OH:1])=[N:3][C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:5][CH:6]=1
Reactant: O=C(Nc1cnc(-c2ccccn2)nc1O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(-c2ccccn2)nc1O

Procedure:
Benzyl 4-hydroxy-2-(pyridin-2-yl)pyrimidin-5-ylcarbamate, 7-a, (1 g, 3.1 mmol) in methanol (20 ml) was hydrogenated under 1 atm of hydrogen in the presence of Pd/C (500 mg) overnight. The mixture was filtered and the filtrate was concentrated to provide the crude product, 7-b, (240 mg).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][N:5]([CH:28]([CH3:30])[CH3:29])[C:6]([C:8]1[N:17]=[C:16]2[N:10]([CH2:11][CH2:12][O:13][C:14]3[CH:21]=[C:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:19]=[CH:18][C:15]=32)[CH:9]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38]([CH3:43])[C:39](=[O:42])[CH2:40]Cl>CN(C=O)C>[CH3:37][N:38]([CH3:43])[C:39](=[O:42])[CH2:40][N:25]1[CH2:26][CH2:27][CH:22]([C:20]2[CH:19]=[CH:18][C:15]3[C:16]4[N:10]([CH:9]=[C:8]([C:6]([N:5]([CH2:4][CH2:3][OH:2])[CH:28]([CH3:30])[CH3:29])=[O:7])[N:17]=4)[CH2:11][CH2:12][O:13][C:14]=3[CH:21]=2)[CH2:23][CH2:24]1
Reactant: CC(C)N(CCO)C(=O)c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(CCO)C(=O)c1cn2c(n1)-c1ccc(C3CCN(CC(=O)N(C)C)CC3)cc1OCC2
Reaction time: 72 h
Yield: 19.8 %

Procedure:
To a stirred mixture of 8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide hydrochloride (127 mg, 0.23 mmol) in DMF (2 mL) was added potassium carbonate (127 mg, 0.92 mmol), N,N-dimethyl-2-chloroacetamide (36 mg, 0.3 mmol) and KI (catalytic) and stirring continued at RT for 72 h before concentrating in vacuo. The resultant residue was diluted with ethyl acetate and washed with water followed by brine, then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was passed down an Isolute SCX-2 cartridge eluting with DCM/methanol then 2M NH3 in methanol. Basic fractions were combined and concentrated in vacuo, the residue subjected to RPHPLC (C18 column, gradient 5 to 95% CH3CN in water+0.1% HCO2H) to give 356 as a colourless glass (22 mg, 20%). LCMS: RT=1.90 min, [M+H]+=484 1H NMR 400 MHz (CDCl3) δ: 8.42 (2H, s), 8.20 (1H, br, s), 8.34 (1H, d, J=8.32 Hz), 7.81 (1H, s), 7.04 (1H, dd, J=8.40, 1.77 Hz), 6.90 (1H, d, J=1.69 Hz), 4.63 (2H, m), 4.45-4.44 (4H, m), 3.38 (3H, m), 3.32 (2H, m), 3.16 (2H, d, J=11.21 Hz), 3.11 (3H, s), 2.99 (3H, s), 2.56 (1H, m), 2.48 (2H, m), 1.87 (4H, m), 1.42 (6H, d, J=6.46 Hz)
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[N:2]1C(OCC1C=CC=CC=1)=O.N#N>CO.[Pd]>[NH:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:2]1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCNN1

Procedure:
A solution of 3-(1,1-dimethylethyl) 1,2-bis(phenylmethyl) 1,2,3-pyrazolidinetricarboxylate (2.00 kg, 4.54 mol) in 10 L methanol was charged into a 20 L four-necked round-bottomed flask under N2 (gas). Then 200 g Pd/C (10%, 65% water) was added carefully to the mixture solution. H2 (gas) was introduced to exchange N2 (gas) three times. The mixture solution was allowed to react at 25° C. under 1 atm of H2 for 8 h until the starting material was consumed completely. N2 (gas) was introduced to remove excess H2 (gas). A filtration was performed to remove the catalyst. The filtrate can be used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:36])[CH2:32][CH2:33][C:34]#[CH:35].CCN(CC)CC>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:35]=[C:34]([CH2:33][CH2:32][CH2:31][OH:36])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CCCO)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A suspension of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (800 mg), PdCl2(PPh3)2 (104.6 mg), CuI (34.1 mg), 4-pentyn-1-ol (0.17 mL), and Et3N (0.42 mL) in CHCl3 (14.9 mL) is stirred at room temperature overnight. Reaction condensed to remove CHCl3. The solvent is replaced with EtOH (15 mL) and additional Et3N (0.38 mL) is added to the reaction mixture. N2 is passed over the surface and the reaction is heated at 76° C. for 6 h, then allowed to cool to room temperature. Reaction mixture is condensed, adsorbed onto silica, and chromatographed eluting with 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2. Product-containing fractions are combined, condensed, and recrystallized from hot acetonitrile to afford 408.9 mg (56%) of N-(4-chlorobenzyl)-2-(3-hydroxypropyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7]2)([O-])=O>C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7]2
Reactant: CC(C)(C)OC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2cc(N)ccc2[nH]1
Yield: 90.6 %

Procedure:
A flask was charged with 9 (3.5 g, 13.3 mmol) and 100 mL dry THF, and purged with argon. To this solution was then added palladium hydrogenation catalyst (10% on carbon, 0.6 g) and hydrogen was bubbled into the reaction mixture for 2.5 days. The catalyst was removed by filtration and the solvent was evaporated to give 10 (2.8 g, 91% yield) as a brown solid: NMR (acetone-d6) δ1.6 (s, 9H), δ6.6-7.6 (m, 4H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:31]1([CH2:30][O:29][C:21]2[CH:22]=[CH:23][C:24]([CH:26]([F:28])[F:27])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:34])=[C:11]([C:9]([NH:8][C@@H:5]4[CH2:6][CH2:7][C@@H:2]([NH:1][C:36](=[O:39])[CH2:37][CH3:38])[CH2:3][C@H:4]4[F:35])=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:32][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CC[C@@H](N)C[C@H]1F
Product: CCC(=O)N[C@@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@H](F)C1

Procedure:
Starting from N-[(1R*,2R*,4R*)-4-amino-2-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f67) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][CH:19]1[CH2:24][CH2:23][N:22]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:21][CH2:20]1
Reactant: CC1CCNCC1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: CC1CCN(c2nc(Cc3ccsc3)[nH]c(=O)c2C#N)CC1

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 377 mg (3.80 mmol) of 4-methylpiperidine to give 65 mg (54% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([CH3:18])[NH:6][CH2:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:17])[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([CH3:18])[NH:6][CH2:7][C:8]1[C:9]([Cl:17])=[CH:10][CH:11]=[CH:12][C:13]=1[NH2:14])[CH3:2]
Reactant: CCOC(=O)[C@@H](C)NCc1c(Cl)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)[C@@H](C)NCc1c(N)cccc1Cl
Yield: 98.4 %

Procedure:
A solution of 14.3 g of N-(2-chloro-6-nitrobenzyl)-D-alanine ethyl ester in 50 ml of ethanol was hydrogenated in the presence of 1 g of Raney nickel. 3.35 liters of hydrogen were taken up in 2 hours. The catalyst was then filtered off and the filtrate was evaporated to dryness. There were obtained 12.6 g (99% of theory) of N-(2-amino-6-chlorobenzyl)-D-alanine ethyl ester; nD23 =1.5405; [α]D =+55.8° (c=1% in ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:12]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]2[NH:10][N:9]=[N:8][C:7]=2[CH:11]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc2[nH]nnc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2nn[nH]c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
5-Nitro-1H-benzotriazole was dissolved in conc. sulphuric acid (60 ml) and cooled to 0° C. in an ice bath. Nitric acid (60 ml, excess) was added drop wise to the cooled solution over a period of 20 minutes. Stirring was continued for another 15 minutes at 0° C. and then at 115° C. overnight, by which time TLC (A) indicated the conversion of starting material. The solution was cooled to room temperature and poured over ice to precipitate a pale yellow solid and a clear yellow solution. The solid was collected by filtration and washed with copious amounts of water until neutral to afford [19] in 67% yield. Rf (A) 0.34; δH(400 MHZ; DMSO-d6) 9.02 (2H, s, BT); m/z (FAB) 210.02695 [(M+H)+ calc. for C6H4N5O4 210.02633].
Reaction SMILES: [C:1]1([CH:7]2[CH2:15][C:14]3[N:13]([CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:10]=3[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][C:14]2[N:13]([CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:10]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: CCCn1ccc2c1CC(c1ccccc1)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCn1ccc2c1CC(c1ccccc1)CC2=NNC(=N)N
Yield: 91.6 %

Procedure:
A mixture of 6-phenyl-1-propyl-4,5,6,7-tetrahydroindol-4-one (0.80 g), aminoguanidine hydrochloride (0.46 g), concentrated hydrochloric acid (0.19 ml), water (0.19 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water and washed with diethylether. To the mixture was added 1N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added a solution of 4N hydrochloric acid in ethyl acetate (2 ml). The solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-6-phenyl-1-propyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 9) (1.0 g) as colorless crystals of E/Z compounds.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH:22]([OH:24])=[O:23].[OH-].[K+]>O>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:22]([OH:24])=[O:23])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Reactant: O=CO
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Temperature: 15 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a 250 mL RB-flask was added 4,4′-dimethylbenzhydrol (1.06 g, 5.00 mmol) and 97% sulfuric acid (44.0 mL). The mixture was cooled to 15° C. by an ice/water bath and formic acid (12.0 mL) was added dropwise via an addition funnel over 0.5 h. The resulting foaming solution was stirred at 15° C. for 2 h. Water (300 mL) was added and the pH was adjusted to 3 with potassium hydroxide pellets and 10% KOH solution. The aqueous solution was extracted with ethyl acetate (3×100 mL) and the combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (0.281 g, 26%) as a pale yellow solid, which was used in the subsequent step without further purification: 1H NMR (400 MHz, CD3OD) δ 7.28–6.99 (m, 8H), 6.96 (br s, 1H), 4.94 (s, 1H), 2.29 (s, 6H).
Reaction SMILES: I[Si](C)(C)C.[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:21]([CH3:29])=[N:22][C:23]([O:27]C)=[N:24][C:25]=4[CH3:26])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:30]([O:35][CH:36]([F:38])[F:37])[C:31]([F:34])([F:33])[F:32])=[CH:9][CH:8]=1.[I-].[Na+]>C(#N)C.C(=O)([O-])O.[Na+]>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:21]([CH3:29])=[N:22][C:23]([OH:27])=[N:24][C:25]=4[CH3:26])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:30]([O:35][CH:36]([F:37])[F:38])[C:31]([F:34])([F:33])[F:32])=[CH:9][CH:8]=1
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: Cc1nc(O)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
Iodo(trimethyl)silane (0.52 mL, 3.63 mmol) was added to a stirred mixture of 9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (595 mg, 1.21 mmol) and sodium iodide (544 mg, 363 mmol) in acetonitrile (8.0 mL) at room temperature, and the mixture was stirred at room temperature for 8 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethanol/ethyl acetate to give the title compound as a colorless crystal (366 mg, 0.766 mmol, 63%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][CH:5]=2.Cl[CH2:16][C:17]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[O:19][N:18]=1>>[CH3:1][C:2]1[N:3]([CH2:16][C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)[O:19][N:18]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:7]=[CH:6][CH:5]=2
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)cccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.24 (d, J=8.1 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.64 (m, 2H), 7.38 (d, J=7.9 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 6.52 (s, 1H), 5.45 (s, 2H), 2.66 (s, 3H); MS (ES) m/z 426 (M+1).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[CH2:10](Br)[CH:11]=[CH2:12].[Cl-].[NH4+]>CCOCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:12][CH:11]=[CH2:10])=[CH:5][CH:4]=1
Reactant: C=CCBr
Reactant: Clc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium turnings (9.6 g) in anhydrous ether (50 ml) was added dropwise to a solution of p-chlorobromobenzene (76.6 g) in anhydrous ether (500 ml) at such a rate as to maintain reflux. After refluxing for a further 20 minutes, the solution was cooled to 5o and a solution of allyl bromide (48.4 g) in anhydrous ether (100 ml) was added over 15 minutes. After 30 minutes the solution was allowed to warm to room temperature, and then saturated ammonium chloride was added dropwise, cautiously to avoid excessive frothing. The organic layer was separated and the aqueous phase was extracted with ether. After washing the ether extracts with water and drying, evaporation of the solvent gave a pale yellow oil which was purified by fractional distillation to give 3-(4-chlorophenyl)prop-1-ene as a colourless oil, b.p. 72°-74°/4 mm Hg. (532 Pa).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[NH2:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].Cl.O1CCOCC1>CO>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][C:22]3[CH:29]=[C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:27]=[CH:26][C:23]=3[C:24]#[N:25])=[C:3]([CH3:20])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:5]2)=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(N2CCOCC2)cc1N
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)ccc1C#N

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (70 mg, 0.24 mmol), 2-amino-4-morpholinobenzonitrile (49 mg, 0.24 mmol) and a 4.0M solution of HCl in dioxane (0.030 mL, 0.121 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 2-((7-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)amino)-4-(4-morpholinyl)benzonitrile was obtained as a yellow film. 1H NMR (500 MHz, chloroform-d) δ ppm 7.94-8.03 (1H, m), 7.82 (1H, dd, J=9.8, 2.7 Hz), 7.60-7.66 (1H, m), 7.43-7.52 (2H, m), 7.32-7.40 (2H, m), 7.13-7.22 (1H, m), 6.56 (1H, br. s.), 6.41 (1H, dd, J=8.8, 2.2 Hz), 5.81 (1H, d, J=2.7 Hz), 3.68-3.77 (4H, m), 2.98-3.15 (4H, m), 2.12-2.26 (3H, s). Mass Spectrum (ESI) m/e=457.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[C:6]([Br:9])[N:5]=[C:4]([Cl:10])[C:3]=1[NH2:11].[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1>[CH2:16]([NH:11][C:3]1[C:4]([Cl:10])=[N:5][C:6]([Br:9])=[C:7]([CH3:8])[C:2]=1[Br:1])[CH:15]=[CH2:14]
Reactant: Cc1c(Br)nc(Cl)c(N)c1Br
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: CN1CCCC1=O
Product: C=CCNc1c(Cl)nc(Br)c(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4,6-dibromo-2-chloro-5-methyl-pyridin-3-ylamine (9.3 g, 31 mmol) and tetrabutylammonium bromide (1.0 g, 3.1 mmol) in anhydrous NMP (30 mL) is added NaH (60%, 1.5 g, 37.5 mmol) in one portion at 0° C. The mixture is gradually warmed to room temperature and stirred for two hours, then treated with allyl bromide (3.3 mL, 37.5 mmol) at 0° C., and stirred at 60° C. for three hours. The reaction mixture is cooled and partitioned between EtOAc and water. The organic layer is separated washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. Chromatography of the residue on silica gel (Hexane/EtOAc, 10:1) gives allyl-(4,6-dibromo-2-chloro-5-methyl-pyridin-3-yl)-amine.