Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH2:10]([N:13]1[C:22](=[O:23])[C:21]2[NH:20][C:19]([C:24]3[N:28]([CH3:29])[N:27]=[C:26]([O:30][CH2:31][C:32](O)=[O:33])[CH:25]=3)=[N:18][C:17]=2[N:16]([CH2:35][CH2:36][CH3:37])[C:14]1=[O:15])[CH2:11][CH3:12]>>[CH3:37][CH2:36][CH2:35][N:16]1[C:14](=[O:15])[N:13]([CH2:10][CH2:11][CH3:12])[C:22](=[O:23])[C:21]2[C:17]1=[N:18][C:19]([N:20]=2)=[C:24]1[N:28]([CH3:29])[NH:27][C:26]([O:30][CH2:31][C:32]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=2)=[O:33])=[CH:25]1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Reactant: Cc1ccc(N)cc1C
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=NC(=C1C=C(OCC(=O)Nc3ccc(C)c(C)c3)NN1C)N=2

Procedure:
Using 3,4-dimethylaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[N:11]([CH3:19])[C:10](=[O:20])[C:9]([C:21]([OH:23])=O)=[CH:8]2)(=[O:3])[CH3:2].S(Cl)([Cl:26])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[N:11]([CH3:19])[C:10](=[O:20])[C:9]([C:21]([Cl:26])=[O:23])=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2cc(C(=O)O)c(=O)n(C)c2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2cc(C(=O)Cl)c(=O)n(C)c2cc1OC(C)=O

Procedure:
A mixture of 6,7-diacetoxy-1-methyl-1,2-dihydro-2-oxoquinoline-3-carboxylic acid (60 mg), thionyl chloride (40 μL), and dimethylformamide (one drop) was heated under reflux for 2 hours in 40 mL of benzene, and the solvent was distilled off. Benzene (30 mL) was added to the residue and the benzene was distilled off again, followed by vacuum drying, to yield 6,7-diacetoxy-1-methyl-1,2-dihydro-2-oxoquinoline-3-carbonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:24]([O-])=O)[C:21]([F:23])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([NH2:24])[C:21]([F:23])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3cc(F)c([N+](=O)[O-])cc3O2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC2COc3cc(F)c(N)cc3O2)cc1

Procedure:
To a mixture of 3.52 g (9.17 mmole) of [(2S)-7-nitro-6-fluoro-2,3-dihydro-1,4-benzodioxin-2y]methyl 4-methylbenzenesulfonate and 2.5 mL of 4 N isopropanolic HCl in 200 mL of ethyl acetate was added 0.50 g of 10% palladium on carbon and the mixture treated with 50 psi of hydrogen on a Parr apparatus for 15 hours. The catalyst was then removed by filtration through celite and the filtrate concentrated in vacuum to give 3.04 g of the (R)-enantiomer of the title compound as beige solid hydrochloride salt. 1H-NMR (DSMO-d6): doublet 7.8 δ(2 H); doublet 7.5 δ(2 H); doublet 6.8 δ(1 H); doublet 6.55 δ(1 H); multiplet 4.4 δ(1 H); doublet of doublets 4.3 δ(1 H); multiplet 4.2 δ(2 H); multiplet 3.85 δ(1 H); singlet 2.4 δ(3 H).
Reaction SMILES: [OH-:1].[K+].[C:3]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]2[CH:12]=[CH:13][CH:14]=[C:6]12)#N.[OH2:15]>C(O)CO>[CH:14]1[CH:13]=[CH:12][N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH:5]([C:3]([OH:15])=[O:1])[C:6]=12
Reactant: N#CC1CCCCn2cccc21
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: OCCO
Product: O=C(O)C1CCCCn2cccc21
Reaction time: 3 h
Yield: 92 %

Procedure:
A solution of potassium hydroxide (2.02 g) in water (1.2 ml.) is added to a solution of 9-cyano-5,6,7,8-tetrahydro-9H-pyrrolo[1,2-a]azepine (1.0 g., 0.006 moles) in ethylene glycol (11 ml.) at 5°. The solution thus obtained is placed in an oil bath at 118° and after 3 hours the cooled solution is poured into water (50 ml.). The aqueous alkaline phase is extracted with ether (20 ml.) the aqueous phase is made acidic to pH-2 with concentrated hydrochloric acid at 5°. The product is extracted into ethyl acetate (4×40 ml.), the extract is washed with water to neutrality, dried and evaporated. Crystallization of the residue from ethyl acetate-ether gave 5,6,7,8-tetrahydro-9H-pyrrolo[1,2,a]azepine-9-carboxylic acid, (92% yield), m.p. 129°-130° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[N:11]=[C:10]2[O:23][CH2:24][CH3:25])=[C:4]([F:26])[CH:3]=1.S(OC)(O[CH3:31])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:24]([O:23][C:10]1[N:9]([C:5]2[CH:6]=[C:7]([O:8][CH3:31])[C:2]([Cl:1])=[CH:3][C:4]=2[F:26])[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:21])([F:22])[C:17]([F:20])([F:18])[F:19])[N:11]=1)[CH3:25]
Reactant: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(OC)c(Cl)cc1F

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-ethoxy-4-pentafluoroethyl-6(1H)-pyrimidinone and dimethyl sulphate with sodium carbonate in acetone there is obtained 2-ethoxy-1-(4-chloro-2-fluoro-5 -methoxyphenyl)-4-pentafluoroethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.33 ppm (d,1H), 6.79 ppm (d,1H), 6.65 ppm (s,1H), 4.48 ppm (m,2H), 3.89 ppm (s,3H), 1.29 ppm (t,3H);
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].B([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.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:7]([C:6]1[CH:9]=[C:2]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[CH:3]=[N:4][CH:5]=1)#[N:8]
Reactant: N#Cc1cncc(Br)c1
Reactant: CC(C)(C(=O)O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
5-bromonicotinonitrile (8.8 g, 48.08 mmol), 2-(4-boronophenyl)-2-methylpropanoic acid (example 21b) (11.50 g, 52.89 mmol) and K2CO3 (13.3 g, 96.16 mmol were dissolved in a mixture of DME (120 mL) and water (30 mL). The mixture was degassed for 30 minutes and Pd(PPh3)4 (2.7 g, 2.40 mmol) was added. The reaction mixture was heated to reflux for 16 hr then cooled to room temperature, and evaporated under reduced pressure. The residue was diluted with aq. 0.5 N NaOH (100 mL) and stirred for about 30 min., and then the mixture was extracted with ether (30 mL×3) The aqueous layer was cooled to 0° C., acidified with 2 N HCl, and then extracted with EtOAc. The combined organic layers were washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane, filtered and dried to give 9.4 g of 2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methylpropanoic acid as a white solid in 73% yield.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[Li].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]1[NH:20][C:19](=[O:21])[CH2:18][CH2:17]1.C(Br)CC.C(O)(=O)C>C1COCC1>[CH2:2]([CH:18]1[CH2:17][CH:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)[NH:20][C:19]1=[O:21])[CH2:1][CH3:3]
Reactant: O=C1CCC(Cc2ccccn2)N1
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCBr
Solvent: CC(=O)O
Product: CCCC1CC(Cc2ccccn2)NC1=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a 2 M lithium diisopropylamine solution in THF of −78° C. is added 5-(pyridin-2-ylmethyl)pyrrolidin-2-one, and the mixture is stirred for 1.5 hours at −78° C. Then 1-propyl bromide is added and the reaction is stirred for another 1.5 hours at −78° C. The reaction mixture is allowed to warm up to 0° C. before ice-cold water with acetic acid is added and subsequently extracted 3 times with dichloromethane. The dichloromethane is concentrated in vacuo and the residue is dissolved in dichloromethane, washed with saturated NaHCO3 and brine. Crude 3-propyl-5-(pyridin-2-ylmethyl)pyrrolidin-2-one is obtained after removal of the solvents in vacuo. The product is purified by column chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([Sn](CCCC)(CCCC)CCCC)=[N:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([CH:30]1[CH2:33][N:32]([C:34](=[O:58])[C@H:35]([NH:37][C:38]([C:40]2[C:48]3[C:43](=[N:44][CH:45]=[C:46](Br)[N:47]=3)[N:42]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:41]=2)=[O:39])[CH3:36])[CH2:31]1)#[N:29]>CN(C=O)C.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.[Cu]I>[C:28]([CH:30]1[CH2:31][N:32]([C:34](=[O:58])[C@H:35]([NH:37][C:38]([C:40]2[C:48]3[C:43](=[N:44][CH:45]=[C:46]([C:9]4[C:8]5[C:12](=[CH:13][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=5)[N:11]([CH3:14])[N:10]=4)[N:47]=3)[N:42]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:41]=2)=[O:39])[CH3:36])[CH2:33]1)#[N:29]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C(C)(C)C)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(C(C)(C)C)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 80 °C
Yield: 83.9 %

Procedure:
To a solution of 6-tert-butyl-1-methyl-3-tributylstannyl-1H-indazole (crude from Step 5, 217 mg, 0.45 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (125 mg, 0.25 mmol) in DMF (1.5 mL) were added Pd(PPh3)4 (14 mg, 0.012 mmol) and copper(I) iodide (9 mg, 0.05 mmol). The yellow reaction mixture was purged with argon then heated at 80° C. for 1.5 h then cooled to room temperature, quenched with sat NH4Cl and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to isolate 129 mg (85%) of 2-(6-tert-butyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:37]4[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(OC)cc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 4-methoxyphenyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4′-methoxybiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C-:11]#[N:12].[Na+].[C:14](Cl)(=O)[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:11]([C:14]([C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)=[CH2:15])#[N:12]
Reactant: [C-]#N
Reactant: CC(=O)Cl
Reactant: CC(C)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: C=C(C#N)c1ccc(CC(C)C)cc1

Procedure:
A process which comprises reacting isobutylbenzene with sodium cyanide and acetyl chloride in the presence of aluminum chloride at a temperature of about 60°-120° C. to form 1-cyano-1-(4-isobutylphenyl)ethene.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[O:13][CH3:14].[C:15](Cl)(=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>>[Cl:5][C:6]1[CH:11]=[C:10]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[C:8]([F:12])[C:7]=1[O:13][CH3:14]
Reactant: CCCCCC(=O)Cl
Reactant: COc1c(F)cccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCC(=O)c1cc(F)c(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 67 h

Procedure:
Aluminum chloride (1.16 g, 8.72 mmol) was added to a stirred mixture of 1-chloro-3-fluoro-2-methoxybenzene (1.00 mL, 8.72 mmol) and hexanoyl chloride (1.47 mL, 10.46 mmol) at room temperature. The mixture warmed and HCl evolution occurred. The resulting mixture was stirred at room temperature for 67 hours and then partitioned between EtOAc (40 mL) and ice cold water (40 mL). The EtOAc layer was washed with brine (30 mL), dried over MgSO4, filtered, and evaporated under vacuum to yield crude 1-(3-chloro-5-fluoro-4-methoxyphenyl)-1-hexanone as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([CH3:19])=[CH:12][N:11]=1.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:5][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([CH3:19])=[CH:12][N:11]=1
Reactant: COC(=O)CO
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1ncc(C)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
Hydroxy-acetic acid methyl ester (3.96 g, 47.0 mmol) was dissolved in 50 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and sodium hydride (2.01 g, 53.2 mmol) was added thereto at room temperature. After stirring for 30 minutes, 2-chloro-5-methyl-3-nitro-pyridine (5.39 g, 31.3 mmol) dissolved in 15 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction by adding water, the mixture was extracted with ethyl acetate, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The resulting solid was recrystallized from dichloromethane and ether to obtain (5-methyl-3-nitro-pyridin-2-yloxy)-acetic acid methyl ester as yellow solid (5.47 g, 77%).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH:19]=O)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].C(N(C(C)C)C(C)C)C.ClC1[N:39]=[C:38]([S:40][C:41]#[N:42])[C:37]([N+:43]([O-:45])=[O:44])=[CH:36][N:35]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]3[N:39]=[C:38]([S:40][C:41]#[N:42])[C:37]([N+:43]([O-:45])=[O:44])=[CH:36][N:35]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:21]=[CH:22][CH:23]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(NC=O)c2)c1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Nc3ncc([N+](=O)[O-])c(SC#N)n3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-[3-(formylamino)phenyl]benzamide (676 mg, 2.42 mmol) in tetrahydrofuran (10 mL) were added N-ethyl-N-isopropylpropane-2-amine (643 μL, 3.63 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (576 mg, 2.66 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (933 mg, 84%) as a yellow solid.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])(C)(C)C.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:13][C@H:10]2[CH2:11][CH2:12][N:8]([C:6]([OH:5])=[O:7])[CH2:9]2)=[N:16][CH:17]=1)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Reaction time: 48 h

Procedure:
To a solution of (S)-3-aminopyrrolidine-1-carboxylic acid-tert-butyl ester (5 g, 26.88 mmol) and 2-chloro-5-nitropyridine (4.26 g, 26.88 mmol) in THF (100 mL) was added potassium carbonate (7.42 g, 53.76 mmol). The mixture was refluxed for 72 hrs. The mixture was filtered and the filtrate was concentrated. The residue was extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate and solvents were evaporated. The oily residue was diluted with ether (50 mL) to give a clear solution which was kept at room temperature for 48 hrs. The crystalline material was filtered to give (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid test-butyl ester (6.66 g, 80.5% yield). LCMS for C14H20N4O4 calcd (m/e) 308, obsd 307 (M−H).
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[N:22]1[CH:27]=[C:26]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[CH:31][NH:32]3)[CH:25]=[N:24][CH:23]=1.[OH2:37]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[N:24]1[CH:25]=[C:26]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)[CH:27]=[N:22][CH:23]=1
Reactant: c1cc(-c2cncnc2)c2cc[nH]c2c1
Reactant: O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2cncnc2)N1
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Pyridinium tribromide (90% (Aldrich), 4 g, 11.22 mmol) was added portion-wise over 10 minutes to a suspension of 4-pyrimidin-5-yl-1H-indole (730 mg, 3.74 mmol) in 2-methyl-2-propanol (25 mL), ethanol (15 mL) and acetic acid (9 mL). The mixture was stirred at room temperature for 2 hours after which acetic acid (36 mL), water (1 mL) and zinc (3.2 g, 56.1 mmol) were added. Stirring was continued for 1.5 hours. Residual zinc dust was filtered and washed with methanol. The filtrate was concentrated and the syrupy residue was stirred in water (100 mL) overnight. The precipitate which formed was filtered, washed with water to remove zinc and pyridine salts and dried under high vacuum to give 595 mg (75%) of 4-pyrimidin-5-yl-1,3-dihydroindol-2-one as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:12]I>O1CCCC1>[Br:1][C:2]1[C:7]([CH2:8][O:9][CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: OCc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cccnc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of (2-bromopyridin-3-yl)methanol (20 g, 106.37 mmoles) in 140 mL of tetrahydrofuran is added 60% sodium hydride in mineral oil (6.38 g, 155.5 mmol) at 0° C. under nitrogen atmosphere. Solution is stirred at 0° C. for 30 minutes. Methyl iodide (7.95 mL, 127.6 mmol) is added over the solution and the mixture is stirred at room temperature overnight. The mixture is quenched by addition of water and the crude is extracted with ethyl acetate. The organic layer is separated, dried over magnesium sulfate and solvent evaporated in vacuo to afford 2-bromo-3-(methoxymethyl)pyridin in a 98% yield that is used with no further purification. MS (m/z): 202 (M+1), 204 (M+3).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([N:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)=[O:12])[CH2:6][CH2:5]1)[CH3:3].F[C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[N:23][CH:24]=1>>[CH3:3][CH:2]([N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([N:13]2[CH2:16][CH:15]([O:17][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[N:23][CH:24]=3)[CH2:14]2)=[O:12])[CH2:6][CH2:5]1)[CH3:1]
Reactant: CC(C)N1CCCN(C(=O)N2CC(O)C2)CC1
Reactant: CC(C)(O)c1ccc(F)cn1
Product: CC(C)N1CCCN(C(=O)N2CC(Oc3ccc(C(C)(C)O)nc3)C2)CC1

Procedure:
In a similar fashion (Route 20, GP I), 1-{[4-(1-methylethyl)-1,4-diazepan-1-yl]carbonyl}azetidin-3-ol (100 mg, 0.41 mmol) and 2-(5-fluoropyridin-2-yl)propan-2-ol (90 mg, 0.41 mmol) were used to give the title compound. Crude material (50 mg) after workup gave the title compound as colourless oil (17.7 mg) after purification by preparative HPLC.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]=[CH:18][C:13]=1[O:14][CH2:15][CH2:16][NH2:17].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]=[CH:18][C:13]=1[O:14][CH2:15][CH2:16][NH:17][C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCCCCc1ccc(OCCN)c(C)c1
Reactant: Clc1ncnc2sccc12
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(OCCNc2ncnc3sccc23)c(C)c1
Yield: 76 %

Procedure:
3.4 g (0.02 mole) of 4-chlorothieno[2,3-d]pyrimidine, 4.4 g (0.02 mole) of 2-(2-methyl-4-pentylphenoxy)ethylamine and 2 g (0.02 mole) of triethylamine were dissolved in 50 ml of toluene, and the solution was heated under reflux for 4 hours. At the end of this time, water was added to the reaction mixture, and the mixture was then extracted with toluene. The extract was dried over anhydrous sodium sulphate, and the solvent was distilled off, after which the residue was recrystallised from a mixture of toluene and hexane, to give 5.4 g (yield 76%) of the title compound in the form of colourless crystals melting at 93°-95° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:28]=1CBr>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:28]1[C:27]([F:26])=[CH:34][CH:33]=[CH:32][C:31]=1[F:35]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: Fc1cccc(F)c1CBr
Product: Cl
Product: Fc1cccc(F)c1CSc1c(Cl)ccc2c1CCNCC2

Procedure:
Use a method similar to the Example 330, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2,6-difluorobenzyl bromide to give, after deprotection by the General Procedure 1-4, the title compound.