Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1([C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:7]([CH3:8])[C:5]1=[O:6])[CH3:4].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].O>CS(C)=O>[CH2:27]([N:12]1[C:13]2[C:14](=[O:15])[N:3]([CH3:4])[C:5](=[O:6])[N:7]([CH3:8])[C:9]=2[N:10]=[CH:11]1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: C=CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
This example illustrates a synthesis of 7-(11,10-Oxidondecyl)-1,3-dimethylxanthine (inventive compound no. 1423). Sodium hydride (95%) (0.575 g, 24 mmol) was added to a solution of theophylline (3.6 g, 20 mmol) in dimethylsulfoxide (100 mL). After 20 minutes of stirring, 1-bromoundec-10-ene (4.66 g, 20 mmol) was added and stirred for 12 hours at room temperature. The reaction mixture was then poured into a separatory funnel containing water (300 mL) and extracted with dichloromethane (5×100 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 50% hexane/ethyl acetate eluant, yielding 6.26 g (94% yield) of 7-(10-undecenyl)-1,3-dimethylxanthine (inventive compound no. 1420).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1cccc(Br)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of ester from step 1 in THF-MeOH (4:1, 0.5M) was added LiOH (3 eq, 2M) and the mixture was stirred at 50° C. for 1 h. The organic solvent evaporated, aqueous was acidified with HCl 1N and the acid extracted with EtOAc (3×). The organic was washed with brine, dried and solvent evaporated to afford the acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]2[C:72]3([CH2:76][CH2:75][CH2:74][CH2:73]3)[O:71][B:70]([OH:77])[C:69]=2[CH:78]=1>CN(C=O)C>[OH:77][B:70]1[C:69]2[CH:78]=[C:65]([CH2:64][NH:63][C:19](=[O:21])[C:18]3[CH:22]=[CH:23][C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:25]([F:26])([F:28])[F:27])[O:14][N:13]=4)=[CH:16][C:17]=3[CH3:24])[CH:66]=[CH:67][C:68]=2[C:72]2([CH2:73][CH2:74][CH2:75][CH2:76]2)[O:71]1
Reactant: NCc1ccc2c(c1)B(O)OC21CCCC1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC21CCCC1
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
A solution of 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (0.3 g, 0.67 mmol) and DIPEA (346 mg, 2.68 mmol) in DMF (10 mL) was stirred at rt for 5 min and then HATU (510 mg, 1.34 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-1H-spiro[benzo[c][1,2]oxaborole-3,1′-cyclo-pentan]-1-ol hydrochloride (202 mg, 0.80 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified on column chromatography and prep-HPLC to provide the product (150 mg, yield 34%). 1H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.89 (t, 1H), 7.82 (s, 2H), 7.59 (t, 3H), 7.44 (m, 2H), 7.36 (d, 1H), 4.45 (d, 2H), 4.36 (d, 1H), 4.28 (d, 1H), 2.41 (s, 3H), 1.99 (m, 8H) ppm; HPLC purity: 98.37% at 220 nm and 98.66% at 254 nm; MS: m/z=652.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: CC(=O)c1ccc(C(=O)Nc2ccc3[nH]c4c(c3c2)CC(N(C)C)CC4)cc1
Yield: 51.9 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 16.6 mg (0.101 mMol) 4-acetylbenzoic acid, 7.8 mg (52%) of the title compound were recovered as a beige solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18].[Br:19][CH2:20][CH2:21]Br>C(#N)C>[Br:19][CH2:20][CH2:21][O:18][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[O:8][CH3:7]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])ccc1OCCBr
Yield: 57.2 %

Procedure:
A mixture of potassium carbonate (27.6 g, 0.2 mol), 2-methoxy-4-nitrophenol (16.9 g, 0.1 mol), 1,2-dibromoethane (94 g, 0.50 mol) and acetonitrile was refluxed for 2 days, concentrated, extracted in ethyl acetate with water three times, dried, filtered, concentrated to a white powder, triturated with ether, filtered, then concentrated to give a pale yellow powder (15.8 g, 58%). 1H NMR (300 MHz, DMSO-d6) δ 7.90 (d, 1H), 7.80 (s, 1H), 7.20 (d, 1H), 4.55 (t, 2H), 3.80 (s, 3H), 3.75 (t, 2H) ppm.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1.[CH:20]([P:23](=[O:29])([CH:26]([CH3:28])[CH3:27])[CH:24]=[CH2:25])([CH3:22])[CH3:21]>C1COCC1>[CH:20]([P:23]([CH2:24][CH2:25][N:10]([CH2:9][C:8]1[CH:18]=[CH:19][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])([CH:26]([CH3:28])[CH3:27])=[O:29])([CH3:22])[CH3:21]
Reactant: COc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: C=CP(=O)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(CCP(=O)(C(C)C)C(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60%, 157 mg, 3.93 mmol) in THF (5 mL) at 0° C. was added tert-butyl (4-methoxybenzyl)carbamate (889 mg, 3.75 mmol) in THF (5 mL). After stirring for 30 minutes at 0° C., diisopropyl(vinyl)phosphine oxide (300 mg, 1.873 mmol) in THF (3 mL) was added. The reaction was allowed to slowly warn to room temperature and subsequently heated to 60° C. for 3 h. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/EtOAc) afforded the title compound as a pale yellow oil. MS: cal'd 398 (MH+), exp 398 (MH+).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[C:27]([C:31]1[N:36]=[C:35]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH2:39][CH2:38]2)[CH:34]=[C:33]([CH:48]2[CH2:51][CH2:50][CH2:49]2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:27]([C:31]1[N:36]=[C:35]([N:37]2[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[CH2:41][CH2:42]2)[CH:34]=[C:33]([CH:48]2[CH2:51][CH2:50][CH2:49]2)[N:32]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3cccnc3)CC2)n1
Reaction time: 16 h
Yield: 58.6 %

Procedure:
0.35 g of nicotinic acid (2.84 mmol) and 0.87 g of triethylamine (8.62 mmol) were dissolved in 30 ml of dimethylformamide. 0.45 g of hydroxybenzotriazole (HOBt, 3.33 mmol), 1.1 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (3.18 mmol), and 0.6 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 3.13 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2-10%). The residue was treated with acetonitrile, filtered and dried to yield 0.75 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:7]1[C:12](=O)[CH:11]2[CH:9]([C:10]2([CH:23]([CH3:25])[CH3:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O1CCCC1.B.CO>O1CCCC1>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH:23]([CH3:24])[CH3:25])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C2C(C1=O)C2(c1cccc([N+](=O)[O-])c1)C(C)C
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1)C2(c1cccc([N+](=O)[O-])c1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-hexyl-6-isopropyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (Preparation 59, 0.57 g, 1.6 mmol) in tetrahydrofuran (6 ml), under nitrogen, was added borane tetrahydrofuran complex (1M in tetrahydrofuran, 3.0 ml, 3.0 mmol) and the reaction mixture was heated under reflux for 2 h. The reaction mixture was cooled to room temperature before the addition of further borane tetrahydrofuran complex (1M in tetrahydrofuran, 3.0 ml, 3.0 mmol). After 20 min, the reaction mixture was cooled to room temperature and methanol (8 ml) was added and then the reaction mixture was once more heated under reflux for 6 h. The reaction mixture was concentrated in vacuo and the residue was dried under vacuum at room temperature. The residue was treated with dichloromethane (4 ml), filtered and purified by chromatography on a Biotage Flash40S™ cartridge packed with silica gel (40 g) eluting with hexane:ethyl acetate (6:1). The title compound was obtained initially as a yellow oil which crystallised upon standing (0.2 g, 40%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:16][C:15](=[O:17])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])=[O:16])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc3ccccc3c(=O)o2)cc1
Reactant: Nc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccccc2)cc1
Yield: 8.9 %

Procedure:
To a stirred solution of 2-(4-tert-butylphenyl)-4H-3,1-benzoxazin-4-one (1.0 g, 3.6 mmol) in toluene (15 mL) was added aniline (0.33 g, 3.6 mmol). After refluxing for 8 h, the solution was allowed to cool, diethyl ether was added, and the precipitate was filtered and dried In vacuo to give 120 mg (9%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Br[CH2:17][C:18]1[C:19]([C:42]([F:45])([F:44])[F:43])=[N:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:12])([CH3:13])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[N:3]1[CH2:17][C:18]1[C:19]([C:42]([F:45])([F:43])[F:44])=[N:20][N:21]([C:23]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1CBr
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 72.9 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole (0.23 g, 0.49 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. over the weekend. The reaction mixture was evaporated and the residue was purified by flash chromatography, eluting with 3% methanol/dichloromethane, followed by drying under high vacuum to give (4S,7R)-1,7,8,8-tetramethyl-2-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (213 mg, 73%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:32]=[CH:31][C:22]([C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].CN1CCOCC1.[CH:40]1(Br)[CH2:44][CH2:43][CH2:42][CH2:41]1>C(#N)C>[CH:40]1([N:28]2[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([C:17]([N:14]4[CH2:15][CH2:16][N:11]([C:6]5[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=5)[CH2:12][CH2:13]4)=[O:18])=[CH:32][CH:31]=3)[CH2:30][CH2:29]2)[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: BrC1CCCC1
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCN(C4CCCC4)CC3)cc2)CC1
Reaction time: 20 h
Yield: 71 %

Procedure:
1-[4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoyl]piperazine (0.5 g) was dissolved in acetonitrile (25 ml) and then, N-methylmorpholine (0.17 ml) and cyclopentyl bromide (0.3 ml) were added. The solution was heated to 65~75° C. and stirred for 20 hours. The solvent was concentrated under reduced pressure and then, the residue was dissolved in chloroform (40 ml). The solution was washed with water twice and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether and hexane, and further recrystallized using ethanol and isopropyl ether. The recrystallized product was filtered and dried to give 0.41 g (yield: 71%) of the desired compound.
Reaction SMILES: FC(F)(F)C(O)=O.CC([NH:16][C:17]1[C:22]2[CH:23]=[CH:24][N:25]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[C:21]=2[CH:20]=[CH:19][N:18]=1)(CC(C)(C)C)C>ClCCl>[NH2:16][C:17]1[C:22]2[CH:23]=[CH:24][N:25]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[C:21]=2[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)CC(C)(C)Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
Trifluoroacetic acid (10 ml) was added drop wise to an ice-cooled suspension of benzyl 4-[(2,4,4-trimethylpentan-2-yl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (5 g, 9.7 mmol, Step c) in dichloromethane (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Upon completion, the reaction mixture was concentrated under vacuum and the residue was stirred in excess aqueous ammonia solution. The precipitated solid was filtered under suction, washed with water and dried to yield benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.5 g, 95%) as off-white solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:4]([O:3][C:1]([NH:8][CH2:9][C:10]([O:12][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])=[O:11])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reaction time: 1 h

Procedure:
N-Boc-glycine (7.31 g, 41.7 mmol) was dissolved in 100 mL of DCM and to the cooled (15° C.) solution N-hydroxysuccinimide (5.28 g, 45.9 mmol) was added. N,N′-dicyclohexylcarbodiimide (9.47 g, 45.9 mmol) was added to the formed suspension under vigorous stirring. After a few seconds, a cloudy white suspension formed, the mixture was allowed to reach room temperature and stirred for 1 h. It was subsequently filtrated over celite, washed with 50 mL saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo to yield a crystalline powder. Yield: 7.02 g, 61.8%
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[N:6]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[CH3:12][C:7]1[CH:8]=[C:9]([CH3:11])[N:10]=[C:5]([O:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[C:22]2[CH:21]=[CH:20][C:19]([C:33]3[CH:38]=[N:37][C:36]([NH2:39])=[N:35][CH:34]=3)=[C:18]([F:17])[CH:23]=2)[N:6]=1
Reactant: Cc1cc(C)nc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Cc1cc(C)nc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)-4,6-dimethylpyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H18FN5O, 387.15; m/z found, 388.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 2H), 7.52-7.46 (m, 2H), 7.44-7.39 (m, 1H), 7.35-7.25 (m, 3H), 7.18 (d, J=8.0, 1H), 6.90 (s, 1H), 6.85 (s, 2H), 2.24 (s, 6H).
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8].[CH3:14][NH:15][C@H:16](C(O)=O)[CH3:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]12[CH2:3][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:10][CH:11]1[N:15]([CH3:14])[CH:16]([CH3:17])[CH2:13]2
Reactant: C=C(Cl)CN(CC=O)C(=O)OCC
Reactant: CN[C@@H](C)C(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2N(C)C(C)CC2(Cl)C1

Procedure:
10.3 g (50 mmol) of ethyl N-(2-chloroallyl)-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 5.2 g (50.5 mmol) of N-methylalanine in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[CH:7][CH:6]=1.[CH2:25]([C:28]1[C:32]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][NH:30][N:29]=1)[CH2:26][CH3:27].CN(C)C=O>O>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][O:9][C:8]1[CH:23]=[CH:24][C:5]([CH2:4][N:30]2[CH:31]=[C:32]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:28]([CH2:25][CH2:26][CH3:27])=[N:29]2)=[CH:6][CH:7]=1
Reactant: CCCc1n[nH]cc1CCC(=O)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)OCC
Reaction time: 12 h
Yield: 53.5 %

Procedure:
Sodium hydride (60%, oily, 110 mg) was added to a mixture of 4-[(4-chloromethylphenoxy)methyl]-5-methyl-2-phenyloxazole (910 mg), ethyl 3-(3-propyl-1H-pyrazol-4-yl)propionate (500 mg) and N,N-dimethylformamide (10 ml), which was stirred for 12 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-propyl-1H-pyrazol-4-yl]propionate (620 mg, yield: 53%) was obtained as a colorless oily substance.
Reaction SMILES: O1CCC[CH2:2]1.Br[C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[C:10]#[N:11].CB1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[CH3:18][O:17][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([CH3:2])[C:14]=1[O:15][CH3:16])[C:10]#[N:11]
Reactant: C1CCOC1
Reactant: COc1cc(C#N)cc(Br)c1OC
Agent: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C#N)cc(C)c1OC
Temperature: 100 °C
Reaction time: 4 h

Procedure:
50 mg [1,1″-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) and 5 mL tetrahydrofuran was stirred for 10 min at ambient temperature before 500 mg 3-bromo-4,5 dimethoxybenzonitrile, 0.1 mL trimethylboroxine and 0.85 g cesium carbonate as a solution in 1 mL water were added. The suspension was stirred at 100° C. for 4 h and then diluted with water and ethyl acetate. The phases were separated and the water phase was extracted with additional ethyl acetate (×2). The organic phases were combined, dried over magnesium sulfate and concentrated. The residue was purified with silica gel chromatography (SiO2:cyclohexane/ethyl acetate 9:1 to 7:3) to provide 4.17.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:15])[NH:9][C@H:10]1[CH2:13][C@H:12]([OH:14])[CH2:11]1)([CH3:6])([CH3:5])[CH3:4].Cl[C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=1>CN(C=O)C.O>[C:3]([O:7][C:8](=[O:15])[NH:9][C@H:10]1[CH2:13][C@H:12]([O:14][C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]=2)[CH2:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(O[C@H]2C[C@H](NC(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydride, 60% in oil (0.141 mL, 6.70 mmol) was added portionwise to a solution of tert-butyl(trans-3-hydroxycyclobutyl)carbamate (0.57 g, 3.04 mmol) and 2-chloro-1-methyl-1H-benzoimidazole (0.558 g, 3.35 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 3 h, diluted with water and extracted with EtOAc. EtOAc extract was concentrated and residue purified with ISCO eluting with 0-40% EtOAc/hexanes to give the desired product tert-butyl(trans-3-((1-methyl-1H-benzo[d]imidazol-2-yl)oxy)cyclobutyl)carbamate (0.388 g, 1.222 mmol, 40.2% yield). m/z: 318.2 (M+1)
Reaction SMILES: Cl.[F:2][C@@H:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH:19]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([F:32])[CH:26]=2)[C:20]1=[O:33].CCN(C(C)C)C(C)C>CN(C=O)C>[F:2][C@@H:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=2)[CH2:7][CH2:6][N:5]([CH:19]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([F:32])[CH:26]=3)[C:20]2=[O:33])[CH2:4]1
Reactant: COc1ccc([C@H]2CCNC[C@@H]2F)cc1F
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@H]2CCN(C3CCN(Cc4ccc(C)c(F)c4)C3=O)C[C@@H]2F)cc1F
Temperature: 120 °C
Yield: 121.7 %

Procedure:
A mixture of (3R,4R)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine hydrochloride (30 mg, 0.114 mmol, from step K), 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (54 mg, 0.189 mmol, intermediate 6) and DIPEA (0.020 mL, 0.114 mmol) in DMF (3 mL) was heated to 120° C. for 90 min in the a microwave reactor. The solvent was then removed under reduced pressure to obtain 60 mg of 3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair) which was used in the next step without further purification. LCMS (Method P) RT=1.12 min, m/z 433 (M+H+).