Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.C[O:7][C:8](=O)[N:9]=[C:10](SC)[C:11]([C:25]1[CH:30]=[C:29]([OH:31])[CH:28]=[C:27]([O:32][CH2:33][CH3:34])[CH:26]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.[NH:38]([C:40]1[N:45]=[CH:44][CH:43]=[CH:42][N:41]=1)[NH2:39]>C(N(CC)CC)C>[CH2:33]([O:32][C:27]1[CH:26]=[C:25]([CH:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:17][CH:18]=2)[C:10]2[NH:9][C:8](=[O:7])[N:38]([C:40]3[N:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[N:39]=2)[CH:30]=[C:29]([OH:31])[CH:28]=1)[CH3:34]
Reactant: CCOc1cc(O)cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(O)cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
To 1 ml of a DMF solution containing 45 mg of {2-(3-ethoxy-5-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (78a)), 11 mg of 2-hydrazinopyrimidine and 0.014 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for one day under a nitrogen atmosphere and then concentrated. The residue was dissolved in 1 ml of methanol, 1 ml of THF, and 0.1 ml of acetic acid, and 100 mg of sodium cyanotrihydroborate was further added thereto. The mixture was stirred at room temperature for 3 hours. The reaction mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product of 5-{(3-ethoxy-5-hydroxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH2:14]([Mg]Br)[CH:15]([CH3:17])[CH3:16].C(OCC)C>O1CCCC1>[CH3:11][C:10]([O:9][C:7](=[O:8])[NH:3][CH2:4][CH2:5][CH2:6][C:2](=[O:1])[CH2:14][CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: CC(C)C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC(=O)CCCNC(=O)OC(C)(C)C

Procedure:
A solution of 1,1-dimethylethyl 2-oxo-1-pyrrolidinecarboxylate (7.5 g, 40.5 mmol) in dry tetrahydrofuran (150 ml) under a nitrogen atmosphere and at −78° C., was treated dropwise with a solution of isobutyl magnesium bromide in diethyl ether (2 molar, 22.5 ml, 45 mmol). The mixture was stirred at −78° C. for 2h then quenched into a saturated aqueous solution of ammonium chloride (100 ml). The products were extracted into ethyl acetate (2×250 ml) and the combined extracts dried over magnesium sulphate. Concentration of the extracts gave an oil which was purified on silica gel using isohexane/diethylether (1:1). The title compound was isolated as a colourless oil (2.3 g, 25%).
Reaction SMILES: Cl[C:2]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)([C:22]1[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1.CC(O)C.[NH3:37]>C1COCC1>[NH2:37][C:2]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)([C:22]1[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1
Reactant: Cn1cncc1C(Cl)(c1ccoc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reactant: N
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1cncc1C(N)(c1ccoc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 5 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
A mixture of 6-[chloro-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (obtained in stage b) (0.0045 mol) in THF (30 ml) was cooled to 5° C. 2-Propanol-NH3 saturated (30 ml) was added dropwise quickly. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated till dryness. The residue was taken up in DCM and water and the mixture was decanted. The organic layer was dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (2.2 g) was purified by column chromatography over silica gel (eluent: toluene/2-propanol/NH4OH 85/13/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN and DIPE. The precipitate was filtered off and dried, yielding 0.55 g (27.5%) of (±)-6-[amino-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, melting point 197° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[C:34]([N:36](C)C)=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.[C-]#N.[Zn+2].[C-]#N>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([F:20])[C:13]=1[N:12]1[C:3]2[C:2]([C:34]#[N:36])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[C:4]=2[C:10]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:23][CH:22]=2)=[N:11]1
Reactant: CC(=O)N(C)C
Reactant: COc1ncc(Br)c2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ncc(C#N)c2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cccc1F
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-(7-bromo-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)morpholine (93 mg) obtained in Step B of Example 218 in DMA (3 mL) were added tetrakis(triphenylphosphine)palladium(0) (43 mg) and zinc cyanide (33 mg) at room temperature, and the mixture was stirred under microwave irradiation at 120° C. for 30 min. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (77 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH:5]=O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[BH4-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNCC1
Reactant: COc1cc(Br)cc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Br)cc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a pre-stirred solution of 3-bromo-5-methoxybenzaldehyde (0.56 g, 2.61 mmol) and piperidine (0.29 mL, 3.93 mmol) in DCM (10 mL) at 0° C. was added sodium borohydride (197 mg, 5.22 mmol) in portions. The reaction mixture was allowed to warm to ambient temperature and stirred for an additional 2 h. The reaction was quenched by the addition of water (30 mL) and extracted into ethyl acetate (75 mL) then washed with water (50 mL) then the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (510 mg, 69%) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 7.08-7.06 (m, 1H), 6.94-6.91 (m, 1H), 6.83-6.80 (s, 1H), 3.79 (s, 3H), 3.39 (s, 2H), 2.40-2.30 (s, 4H), 1.61-1.51 (m, 4H), 1.47-1.38 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: COC(=O)c1cc2ncc(Cl)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2ncc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of methyl 3-chlorothieno[2,3-b]pyrazine-6-carboxylate 92 (2.62 mmol, 600 mg) in 5 mL THF was added sodium hydroxide 2N in water (13.12 mmol, 6560 μl) and stirred at rt for 2 h. The reaction was quenched in 2N HCl extracted with CH2Cl2/methanol (9/1) (3×). Organic layers was dried and concentrated under reduced pressure to give 3-chlorothieno[2,3-b]pyrazine-6-carboxylic acid 93 (563 mg, 100%).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)(OC(Cl)(Cl)Cl)[O:17][C:18]([Cl:21])(Cl)Cl.Cl>C(Cl)Cl>[CH2:9]([N:8]([CH3:7])[C:18]([Cl:21])=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
At −78° C. pyridine (1.25 mL, 15.5 mmol) followed by methyl benzylamine (2.0 mL, 15.5. mmol) are added to a solution of bis(trichloromethyl) carbonate (1.55 g, 5.2 mmol) in CH2Cl2 (20 mL). The reaction mixture is allowed to warm to RT and stirred for another 1.5 h. For workup 1N HCl is added to the yellow suspension and the mixture is extracted with ethyl acetate. Drying (Na2SO4) of the combined organic exctracts, filtration and evaporation of the solvent affords the title compound. MS (LC-MS): [M+H]+=184.1. tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 3.84 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][OH:9])([O-:3])=[O:2].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)([O:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCCc2cccc([N+](=O)[O-])c2)cc1
Yield: 96 %

Procedure:
3-Nitrophenethyl tosylate was prepared according to the general method as outlined in Preparation 1 starting from 3-nitrophenethyl alcohol (15 g, 89.7 mmol) and tosyl chloride (20.52 g, 110 mmol). The product was isolated as an off white powder (21.5 g). Yield 96%; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H), 7.87 (t, 1H), 7.63 (d, 2H), 7.46 (m, 2H), 7.25 (m, 2H), 4.26 (t, J=6 Hz, 2H), 3.04 (t, J=6 Hz, 2H), 2.40 (s, 3H).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.Cl.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:39])[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH2:21][CH2:20]1>ClCCl>[CH:16]1[C:3]2[CH:2]([N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:39])[CH2:31][CH2:32][C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[CH2:21][CH2:20]3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]=2[CH:13]=[CH:14][CH:15]=1
Reactant: ClC1c2ccccc2COc2ccccc21
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C2c3ccccc3COc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.46 g (15 mmol) 11-chloro-6,11-dihydrodibenzo[b,e]oxepine are dissolved in 90 ml absolute dichloromethane and 5.43 g (15 mmol) N-(4-piperidin-4-yl-butyl)-3-pyridin-3-yl-propionamide dihydrochloride is added. 5.0 g (49.5 mmol) TEA is dissolved in 20 ml absolute dichloromethane and added dropwise under ice cooling. The mixture is stirred for two days at RT without further cooling. Subsequently, the batch is washed twice, each with 50 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The resinous residue is chromatographically purified over silica gel with CHCl3/CH3OH (95/5) and after drawing off the solvent, is first crystallized twice, each from 10 ml 1-chlorobutane and subsequently once from 10 ml acetic acid ethyl ester. Colorless crystals with a MP of 110-112° C. in a yield of 0.2 g (3%) are recovered
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[N:8][CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>CN(C=O)C.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:4]1[C:5]2=[N:6][C:7]([CH3:11])=[N:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Cc1ncc2c(I)n[nH]c2n1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc2c(I)nn(Cc3ccccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
7.950 g (13.76 mmol) of 3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 4.930 g (15.13 mmol) of caesium carbonate were initially charged in 20 ml of DMF, and 2.860 g (15.13 mmol) of 2-fluorobenzyl bromide dissolved in 5 ml of DMF were added. The reaction mixture was stirred at RT overnight, diluted with 100 ml of water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). 1.030 g of the target compound were obtained (20% of theory).
Reaction SMILES: C(O)(=O)C.[CH3:5][CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:11]([C:50]([O:52][CH2:53][C:54]2[O:59][C:57](=[O:58])[O:56][C:55]=2[CH3:60])=[O:51])=[C:10]([C:61]([OH:64])([CH3:63])[CH3:62])[N:9]=1>CC(C)=O>[CH3:5][CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:11]([C:50]([O:52][CH2:53][C:54]2[O:59][C:57](=[O:58])[O:56][C:55]=2[CH3:60])=[O:51])=[C:10]([C:61]([OH:64])([CH3:63])[CH3:62])[N:9]=1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To 75% aqueous acetic acid (1000 ml) was slowly added trityl olmesartan medoxomil (110 gms) [prepared as described in example 5] at 25-30° C. The contents were stirred at 60° C. for 1 hour. The reaction mass was chilled to 0-5° C. and filtered to remove tritanol. The reaction mass was concentrated under reduced pressure. The residue was quenched with water (500 ml), neutralized with a base and extracted in dichloromethane (500 ml). The clear dichloromethane extract was then concentrated under reduced pressure and stripped off with acetone. The residue thus obtained was isolated from the acetone (250 ml) to give 55 gms of the title compound. Chromatographic purity->99%.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CS(C)=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]([C:6]2[CH:7]=[N:8][C:3]([CH2:2][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[CH:4][CH:5]=2)=[O:10])=[CH:13][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)nc1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)CC1

Procedure:
6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide was dissolved in 1 mL of DMSO and stirred for 1 h with N-methylpiperazine. The reaction was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((4-methylpiperazin-1-yl)methyl)pyridine-3-carboxamide as a pure product. MS (Q1) 422.3 (M)+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].Cl[C:23]1C(CC)=NC=C(C2CC2)N=1>>[CH:9]1([C:6]2[N:5]=[C:4]([NH:11][C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C@@H:13]3[OH:21])[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=2)[CH2:23][CH2:10]1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: CCc1ncc(C2CC2)nc1Cl
Product: CCc1ncc(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3-chloro-5-cyclopropyl-2-ethylpyrazine and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.92–0.95, 1.31–1.35, 1.93, 2.59–2.70, 3.03–3.10, 3.22–3.30, 4.74, 4.91, 5.49–5.52, 7.28–7.32, 7.82; MS (ESI+) for C18H21N3O m/z 296 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1.CO.[H][H]>[Pd].[O-]S([O-])(=O)=O.[Ba+2].C(Cl)Cl>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:2]=[N:3][C:4]([C:20]#[N:21])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2cnc(C#N)c(-c3ccccc3)c2c1
Reaction time: 8 h

Procedure:
A mixture of 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile (200 mg), 5% Pd/BaSO4 (50 mg), and 20 mL methanol was stirred under 1 atm hydrogen for 18 h. 5 mL of CH2Cl2 was then added, as was an additional 50 mg Pd/BaSO4. After stirring overnight, the reaction was filtered, concentrated, and purified by flash chromatography (30% EtOAc/hexanes) to give the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH:29]2[CH2:30][CH2:31][CH2:32][CH:25]1[CH2:26][C:27](=O)[CH2:28]2)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH:25]2[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:28][C:27](=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:26]2)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CC(=O)C2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CC2CCCC(C1)N2C(=O)OC(C)(C)C

Procedure:
0.54 ml of (diethoxy-phosphoryl)-acetic acid ethyl ester are added dropwise to a suspension of 108 mg of NaH (55% in mineral oil) in 5 ml of THF at 0°. The mixture obtained is stirred and 650 mg of 3-oxo-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester in 5 ml of THF are slowly added. The mixture obtained is stirred at 60° C. for 3 days, diluted with c-HEX and washed with 1M aqueous NaH2PO4 and saturated aqueous NaHCO3 solution. The organic layer obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography on silica gel. 3-Ethoxycarbonylmethylene-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester is obtained in the form of an oil. 13C-NMR: 171.79, 154.45, 154.27, 133.38, 132.77, 127.11, 126.30, 79.64, 79.54, 61.03, 61.00, 48.59, 47.20, 46.81, 45.22, 42.72, 33.61, 33.42, 32.59, 32.17, 30.73, 30.07, 28.87, 28.57, 28.13, 16.48, 14.59.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=[CH:9][C:10]=1[Cl:11])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[C:22]([NH2:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=1>N1C=CC=CC=1>[Br:16][C:17]1[C:22]([NH:23][S:12]([C:7]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)(=[O:14])=[O:13])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: Nc1cc(Cl)cnc1Br
Reactant: CC(C)(C)c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl

Procedure:
Prepared from 420 mg (1.57 mmol) of 3-tert-butyl-4-chloro-benzenesulfonyl chloride and 326 mg (1.57 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in 3 mL pyridine using procedure x. Yield: 0.48 g of a white solid. LC-MSD, m/z for C15H15BrCl2N2O2S [M+H]+=436.9, 438.8, 440.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([C:28]4[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=4)[N:20]=[CH:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(-n2cnc(I)c2)n1
Product: Nc1ccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 4-(3-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.72) (0.45 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.26 g, 1.2 mmol) according to the general procedure VI. Obtained as a yellow solid (0.27 g, 65%). MS (ISP) 417.2 [(M+H)+]; mp 248° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[CH3:13][SH:14].[Na]>CO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:14][CH3:13]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: CS
Agent: [Na]
Solvent: CO
Product: CSCC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 500 ml solution of 50 g (0.262 mol) of 2-chloro-2',4'-difluoroacetophenone [Compound (4)-1] in methanol, 147 g (0.314 mol) of a 15% aqueous solution of sodium methylmercaptan were added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. Water was then added to the reaction mixture and they were mixed. The resulting mixture was extracted with chloroform. The extract was washed successively with water and saturated saline and then, dried over anhydrous magnesium sulfate. The solvent was thereafter distilled off under reduced pressure. The oil so obtained was distilled under reduced pressure (93-95° C., 3 mmHg), whereby 47.3 g of the title Compound (2a-1) were obtained as a colorless oil (yield: 89.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:13]=[O:14].C(=O)=O.CC(C)=O.[NH4+].[Cl-]>C1COCC1>[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH:13]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:14]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Clc1ccc([Mg]Br)cc1
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)c(C(O)c2ccc(Cl)cc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of (4-chlorophenyl)magnesium bromide (1M in Et2O, 81 ml, 81 mmol) in THF (200 ml) was added drop wise a solution of 2-chloro-5-nitrobenzaldehyde (10 g, 53.9 mmol) in THF (100 ml) at −78° C. (dry ice/acetone bath). After the addition, the reaction mixture was further stirred at −78° C. for 1 h then 10 min at 0° C. (ice bath). A saturated aqueous NH4Cl solution (400 ml) was added and the resulting mixture was extracted with AcOEt (2×400 ml). The combined organic layers were washed with brine then dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/TBME 95:5→6:4) to yield the title compound (14.4 g, 48.4 mmol, 90%) as a beige solid. TLC: RF=0.80 (heptane/DCM/TBME 1:1:2); HPLC: AtRet=2.43 min; LC-MS: m/z not detected; 1H NMR (400 MHz, CDCl3): 6.20 (s, 1H), 7.36 (s, 4H), 7.53 (d, J=8.6, 1H), 8.13 (dd, J=8.8, 2.9, 1H), 8.66 (d, J=2.7, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=1)[C:16]#[N:17])#[CH:10]>>[OH:8][C:4]1[CH:3]=[C:2]([C:10]#[C:9][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:7]=[CH:6][CH:5]=1
Reactant: C#Cc1cncc(C#N)c1
Reactant: Oc1cccc(I)c1
Product: N#Cc1cncc(C#Cc2cccc(O)c2)c1
Yield: 16.6 %

Procedure:
Prepare essentially as described in EXAMPLE 10 using 3-iodophenol (0.69 g, 3.0 mmol) and 5-ethynylnicotinonitrile (0.4 g, 3.0 mmol) to give the title compound (110 mg, 17%).