Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[F:4][C:5]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:6]=1[CH2:7][S:8][C:9]1[N:14]=[C:13]([NH:15][S:16]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:12]=[C:11]([O:26][CH3:27])[N:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].Cl>C(Cl)Cl.C(O)(=O)C>[F:4][C:5]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:6]=1[CH2:7][S:8][C:9]1[N:14]=[C:13]([NH:15][S:16]([N:19]2[CH2:20][CH2:21][CH:22]([NH:3][CH2:1][CH3:2])[CH2:23][CH2:24]2)(=[O:17])=[O:18])[CH:12]=[C:11]([O:26][CH3:27])[N:10]=1
Reactant: CCN
Reactant: COc1cc(NS(=O)(=O)N2CCC(=O)CC2)nc(SCc2cccc(F)c2F)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNC1CCN(S(=O)(=O)Nc2cc(OC)nc(SCc3cccc(F)c3F)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethylamine (0.56 mL of 2M solution in methanol) was added to a solution of acetic acid (0.025 mL) and N-{2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-4-oxopiperidine-1-sulfonamide (the product of example 148, step iii) (0.10 g) in DCM (4 mL). The solution was stirred at room temperature for 1 h then sodium triacetoxyborohydride (0.24 g) was added in portions. The mixture was stirred at room temperature overnight then 3M aqueous sodium hydroxide (6 mL) added to the residue. The mixture was shaken vigorously then acidified to pH 8 with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were concentrated then methanol (1 mL) was added and the resulting suspension filtered. The solid was washed with water, methanol and ethyl acetate to afford the title compound as a very pale yellow powder. Yield: 52 mg
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:20])[NH:13][C:12]([CH2:21][O:22][CH2:23][CH2:24][OH:25])=[C:11]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:20])[NH:13][C:12]([CH2:21][O:22][CH2:23][CH2:24][O:25][C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[C:11]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1=C(COCCO)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCCOc2ncccn2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 12.6 %

Procedure:
Sodium hydride (90 mg of an 80% by weight dispersion in oil) was added to a solution of 4-(2-chlorophenyl)-3-ethoxycarbonyl-2-(2-hydroxyethoxymethyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.60 g) in tetrahydrofuran (20 ml) and the mixture stirred at room temperature for 45 minutes and then treated with 2-chloropyrimidine (0.17 g). The mixture was stirred at room temperature for 3 days and evaporated. The residue was dissolved in ethyl acetate and the solution washed successively with 2M hydrochloric acid, 5% aqueous sodium carbonate solution and brine, dried over MgSO4 and evaporated. The residue was crystallised from ether to give the title compound (90 mg), m.p. 101°.
Reaction SMILES: [Cl-].[Li+].C(N(C(C)C)CC)(C)C.[CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=O.[N+:27]([C:30]1[CH:46]=[CH:45][C:33]([C:34]([CH2:36]P(=O)(OCC)OCC)=[O:35])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(#N)C.O>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH:12]=[CH:36][C:34]([C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:46][CH:45]=2)=[O:35])[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOP(=O)(CC(=O)c1ccc([N+](=O)[O-])cc1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C=CC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.6 %

Procedure:
0.28 g of lithium chloride, 0.85 g of diisopropylethylamine and 2.13 g of 4-formyl-l-t-butoxycarbonylpiperidine were added to 2.0 g of diethyl (4-nitrobenzoylmethyl)phosphonate dissolved in 20 ml of acetonitrile, and the mixture was stirred at room temperature for about 3 days. Then, water was added to the reaction mixture, and the mixture was extracted with toluene. The extract was dried over anhydrous sodium sulfate and condensed. The obtained residue was applied to silica gel column chromatography to obtain 1.76 g of the title compound as pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:27])=[C:5]([C:18]([O:25][CH3:26])=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:27])=[C:5]([C:18]([O:25][CH3:26])=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1Oc1cccc(OC)c1
Yield: 19.3 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-hydroxybenzoate (0.805 g, 2.14 mmol) was dissolved in methylene chloride (50 ml) and after adding thereto in sequence copper acetate (0.429 g, 2.36 mmol), 3-methoxyphenylboronic acid (0.651 g, 4.28 mmol), Molecular Sieves 4A (0.500 g), triethylamine (0.541 g, 5.35 mmol) and pyridine (0.423 g, 5.35 mmol), the solution was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was poured into water and then extracted with methylene chloride. The extract was washed with saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (0.200 g, 0.414 mmol, 19%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:6](C(OC)=O)[C:5](=[O:11])[C:4](=[O:12])[N:3]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(O)=O.O>[CH3:1][C:2]1([CH3:20])[N:3]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:4](=[O:12])[C:5](=[O:11])[CH2:6]1
Reactant: COC(=O)C1C(=O)C(=O)N(Cc2ccccc2)C1(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CC(=O)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.8 %

Procedure:
A solution of methyl 2,2-dimethyl-4,5-dioxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate (5.6429 g, 20.50 mmol) in 10:1 HOAc-water (100 mL) was heated at 100° C. and stirred for 2 days. The solution was cooled to room temperature and concentrated in vacuo. The residue was partitioned between DCM (200 mL) and sat. aq. NaHCO3 (100 mL). The aqueous phase was extracted with a fresh portion of DCM (50 mL), and the combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give crude 5,5-dimethyl-1-(phenylmethyl)-2,3-pyrrolidinedione (3.9096 g, 88% crude yield) as a light orange solid. LCMS: (M+H)+: 218.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]([O:27]CC)=[O:26])[C:22]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)=[N:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[C:22]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)=[N:21]2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C(=O)O)c(-c3cccs3)n2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
A mixture of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate (900 mg), 1N sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at 80° C. for 5 hours. After cooling, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole -4-carboxylic acid (750 mg, yield: 88%). This was recrystallized from acetone-hexane. Melting point: 204˜205° C.
Reaction SMILES: Cl.[N:2]1([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(O)C>ClCCl>[C:24]([N:13]1[CH2:14][CH2:15][CH2:16][N:10]([C:8]([N:2]2[CH2:3][CH2:4][O:5][CH2:6][CH2:7]2)=[O:9])[CH2:11][CH2:12]1)(=[O:26])[CH3:25]
Reactant: O=C(N1CCCNCC1)N1CCOCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of 1-(4-morpholinecarbonyl)-1,4-diazepane hydrochloride (50 g, 0.2 mol) and triethylamine (42 ml, 30.5 g, 0.3 mol) in dichloromethane (400 ml) at 5° C. was added acetic anhydride (23 ml, 24.9 g, 0.24 mol) dropwise over 15 minutes and the reaction was then stirred for a further 2 hours at room temperature under nitrogen. Dilution with dichloromethane (600 ml) was followed by washing with saturated aqueous sodium bicarbonate (2×200 ml) and the combined aqueous layers extracted with dichloromethane (1×100 ml). The dichloromethane layers were combined and washed with saturated brine, dried over MgSO4 and evaporated to give a light brown oil. This was dissolved in dichloromethane (300 ml) and treated with triethylamine (8 ml, 5.8 g, 0.06 mol) and ethanol (5 ml), stirred for 1 hour at room temperature then washed with saturated sodium bicarbonate and the aqueous layer extracted with dichloromethane (5×). The combined dichloromethane layers were dried over MgSO4 and evaporated under reduced pressure to give a yellow oil which was then azeotroped with dichloromethane (4×) to give the title compound as a yellow oil (47.1 g, 92%). Rf 0.45 (0.880 aqueous ammonia: methanol:dichloromethane 1:10:90, v/v). MS m/z 256 (MH)+. Found: C,52.62; H,8.18; N,15.02; C12H21N3O3 0.3CH2Cl2 requires C, 52.61; H, 7.75; N,14.96%.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(Cl)Cl.[Cl:21][C:22]1[N:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24](OCC)=[O:25]>[Cl-].[Na+].O>[Cl:21][C:22]1[C:23]([CH2:24][OH:25])=[CH:29][CH:30]=[CH:31][N:32]=1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1cccnc1Cl
Reaction time: 0.25 h

Procedure:
At −78° C., diisobutylaluminum hydride (a 1.0M toluene solution; 4.68 ml) was added dropwise to a methylene chloride (10 ml) solution of ethyl 2-chloronicotinate (347 mg, 1.87 mmol). Thirty minutes later, the reaction mixture was ice cooled, followed by stirring for 15 minutes. After the completion of the reaction was confirmed, brine was added to the reaction mixture and the temperature of the resulting mixture was allowed to rise back to room temperature. The reaction mixture was filtered through Celite. The filtrate was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column and the fraction obtained from the hexane:ethyl acetate (=1:1) eluate was concentrated under reduced pressure, whereby the title compound (211 mg, 79%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[O-:12][C:13]#[N:14].[K+].C(O)(=O)C.[OH-].[Na+]>O.O1CCOCC1>[CH3:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:13](=[O:12])[NH:14][C:4]2=[O:5]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1ccc2[nH]c(=O)[nH]c(=O)c2c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
2.00 g of 2-amino-5-methylbenzoic acid was suspended in 20 mL of water, to which 1.18 g of potassium cyanate was added and a mixture of 0.23 mL of acetic acid and 1 mL of water were added dropwise, and this suspension was stirred for 1.5 hours at 50° C. Then, after a solution of 1.42 g of sodium hydroxide in 2 mL of water was added drowise, to which 40 mL of water and 20 mL of 1,4-dioxane were added, and this solution was stirred for 3.5 hours while heating it under reflux. The reaction mixture was ice-cooled, from which precipitated solid was filtered, and then 30 mL of water and 3 mL of 6M of hydrochloric acid were added to the resultant solid, which was then stirred for 1.5 hours while heating it under reflux. The reaction mixture was cooled to room temperature, from which resultant precipitate was filtered and washed with water to yield 1.17 g of 6-methyl-2,4-(1H,3H)-quinazolinedione as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18](=[O:23])[CH2:19][CH2:20][CH:21]=C)[C:5]2=[O:24].[O:25]=[O+][O-].CSC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[O:25])[C:5]2=[O:24]
Reactant: O=[O+][O-]
Reactant: C=CCCC(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Solvent: ClCCl
Solvent: CSC
Product: O=CCCC(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Temperature: -78 °C

Procedure:
A mixture of 6-chloro-2-hydroxy-3-(4-pentenoyl)-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-4-one (0.65 g, 1.9 mmol) in 50 mL DCM was stirred at −78° C. and treated with O3 until the solution remained blue. The mixture was stirred at −78° C. for 30 minutes and then treated with 1 mL dimethyl sulfide and stirred from −78° C. to 0° C. for 2 hours. The mixture was concentrated in vacuo and purified by column eluting with 40:100=EtOAc/hexane to give the desired product. MS m/e: 349 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=1Cl)#[N:2].[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].CC([O-])(C)C.[K+].C1COCC1>CN(C=O)C>[NH2:2][C:1]1[C:3]2[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=2[S:13][C:12]=1[C:11]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CS
Reactant: N#Cc1c(Cl)ccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccnc(Cl)c2c1N
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To 3-cyano-2,4dichloropyridine (653 mg) and methyl thioglycolate (340 μL) in DMF (12 mL) at 5° C. was added a solution of 1.0M KOtBu/THF (4.5 mL). The reaction was stirred 20 min at 5° then 1 h at RT, then quenched in sat'd NH4Cl, the solid precipitate collected, washed with water and sucked dry to give 800 mg (88%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21]([O:23][C:24](=[O:46])[CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=2)=[CH:32][CH:31]=1)[C:27]#[C:28][CH3:29])[CH3:22]>C(#N)C>[N:1]1([CH2:44][C:41]2[CH:40]=[CH:39][C:38]([CH2:37][O:36][C:33]3[CH:34]=[CH:35][C:30]([C@@H:26]([C:27]#[C:28][CH3:29])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:46])=[CH:31][CH:32]=3)=[CH:43][CH:42]=2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Reactant: CC#CC(CC(=O)OCC)c1ccc(OCc2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(CN3CCC4(CCc5ccccc54)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 2,3-dihydrospiro[indene-1,4′-piperidine] (0.37 g, 1.68 mmol) in acetonitrile (20.0 mL), is added Cs2CO3 (1.37 g, 4.21 mmol at room temperature, followed by the addition of 3-[4-(4-bromomethyl-benzyloxy)-phenyl]-hex-4-ynoic acid ethyl ester (0.70 g, 1.68 mmol). The reaction mixture is stirred overnight at room temperature. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated. The crude product is purified by silica gel column chromatography (gradient 3% methanol in DCM) to give the title compound as colorless gel, (0.82 g, 93.7%). ESI/MS 522.2 (M+H)+.
Reaction SMILES: Cl.[N:2]1[C:7]2[NH:8][CH:9]=[C:10]([C:11]3[N:16]=[C:15]([C:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=4)[CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:23]([CH2:25][C:26](ON1CCCC1)=[O:27])#[N:24].C(N(C(C)C)CC)(C)C.O>C(O)C>[O:27]=[C:26]([N:20]1[CH2:19][CH:18]=[C:17]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]3[C:6]4[CH:5]=[N:4][CH:3]=[N:2][C:7]=4[NH:8][CH:9]=3)[N:16]=2)[CH2:22][CH2:21]1)[CH2:25][C:23]#[N:24]
Reactant: C1=C(c2cccc(-c3c[nH]c4ncncc34)n2)CCNC1
Reactant: N#CCC(=O)ON1CCCC1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CC=C(c2cccc(-c3c[nH]c4ncncc34)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 16.1 %

Procedure:
As shown in FIG. 7—step v, compound 29 (30 mg) and 2-cyano acetic acid, pyrrolidin-1-yl ester (47 mg) were mixed in ethanol (2 mL) and diisopropylethylamine (0.084 mL) was added. After stirring at rt for 12 hours, water (30 mL) was added. Extraction with dichloromethane (3×) and chromatographic purification (SiO2, ethyl acetate) afforded 5.3 mg of 3-oxo-3-[6-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-yl]-propionitrile (compound 30).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f6) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>CCOCC.O>[N:21]1([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: FC(F)(F)c1ccc2c(c1)ncn2-c1cccc(I)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)ncn2-c1cccc(-n2ccnc2)c1
Temperature: 200 °C

Procedure:
A mixture of 1-(3-iodophenyl)-5-trifluoromethyl-benzimidazole (2a)(1.0 g, 2.58 mmol), imidazole (0.19 g, 2.73 mmol), potassium carbonate (0.38 g, 2.78 mmol), CuBr (20 mg, 0.15 mmol), and 1-methyl-2-pyrrolidone was heated to 200° C. for 18 hours. Dilution with water and extractive workup with ether was followed by chromatography on silica gel. Yield: 0.43 g, 1.51 mmol, 51%. mp 177°-180° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].C1N2CCN(CC2)C1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][C:15](=[S:16])[N:14]([CH3:18])[CH3:13]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of 5-Bromo-2-hydroxy-benzoic acid methyl ester (29.8 g, 129 mmol) and dimethylthiocarbamoyl chloride (17.54 g, 142 mmol) in DMF at room temperature was added DABCO (21.7 g, 193.5 mmol). The resulting mixture, after being stirred at room temperature overnight, was diluted with water (1.25 L) and acidified to a pH˜4 using 1 N HCl. The precipitate was collected, rinsed with water and dried in vacuo to provide crude 5-bromo-2-dimethylthiocarbamoyloxy-benzoic acid methyl ester as an off-white solid in 91% yield. The product was used directly in the subsequent reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13](=[O:20])[CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[NH2:30]O.Cl>CO.CO.O.O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C@H:7]2[CH2:12][C@H:11]([C:13]3[O:20][NH:30][C:15](=[O:16])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(Cc2ccc(Cl)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
A solution of methyl 2-(4-chlorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (780 mg, 2.04 mmol) (from example 115, step 2) in MeOH (5 mL) was added to a solution of sodium hydroxide (1.705 mL, 2.05 mmol) in MeOH/H2O (1.608 mL/0.097 mL) at −30° C. After 10 min a solution of hydroxylamine hydrochloride (284 mg, 4.09 mmol) and sodium hydroxide (163 mg, 4.09 mmol) in MeOH (5 mL) and H2O (5 mL) was added. Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (3.40 mL, 20.43 mmol) at 80° C. and heated at 80° C. for 30 min. Concentration of the organic solvent and extraction with diethyl ether (×3), drying over Na2SO4 and evaporation gave a yellow foam. Purification using prepLC (pH=3, large column 20-80% MeCN over 30 min) yielded trans-methyl 2-(4-chlorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (272.5 mg, 38%). 1H NMR (400 MHz, cdcl3) δ 1.44-2.18 (m, 4H), 2.70-3.01 (m, 2H), 3.02-3.14 (m, 2H), 3.42-3.76 (m, 3H), 4.04-4.37 (m, 1H), 4.39-4.79 (m, 1H), 5.64 (s, 1H), 7.05-7.31 (m, 4H). MS m/z 351, 353 (M+H)+
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13]([S:15][CH3:16])[N:12]=[C:11]([NH:17][C:18](=[O:20])[CH3:19])[CH:10]=2)[CH2:5][CH2:4]1.[Cl:21][C:22]1[C:26]([Cl:27])=[C:25]([CH3:28])[NH:24][C:23]=1[C:29](NC1CCN(C2C=C(C3N=CON=3)C=C(Cl)N=2)CC1)=[O:30]>>[C:18]([NH:17][C:11]1[N:12]=[C:13]([S:15][CH3:16])[N:14]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:29]([C:23]3[NH:24][C:25]([CH3:28])=[C:26]([Cl:27])[C:22]=3[Cl:21])=[O:30])[CH2:8][CH2:7]2)[CH:10]=1)(=[O:20])[CH3:19]
Reactant: CSc1nc(NC(C)=O)cc(N2CCC(N)CC2)n1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(-c4ncon4)cc(Cl)n3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CSc1nc(NC(C)=O)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was synthesised by an analogous method to Example 118 starting from N-[6-(4-aminopiperidin-1-yl)-2-(methylthio)pyrimidin-4-yl]acetamide hydrochloride (Intermediate 69) and 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3).