Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:11])[CH3:10].N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][Br:1])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(CBr)cc1
Reaction time: 1.33 h

Procedure:
N-Bromosuccinimide (60.0 g.) was added in portions during 40 minutes to a solution of 4-acetoxytoluene (50.0 g.) and 2,2'-azobis(2-methylpropionitrile) (10 mg.) in carbon tetrachloride (300 ml.) heated under reflux and illuminated by a high energy tungsten lamp (275 watt). Heating and illumination were continuted for 80 minutes after the addition was complete. The mixture was then cooled and filtered. The solid residue was washed with carbon tetrachloride (100 ml.) and the combined filtrate and washings were evaporated to give 4-acetoxybenzyl bromide as a syrupy solid, which was dissolved, without further purification, in ethanol (300 ml.). 1,2,3,6-Tetrahydropyridine (83.0 g.) was then added to the solution during 10 minutes. The subsequent mixture was left at 20°-25° C. for 16 hours, and then evaporated. Water (300 ml.) was added to the residue obtained and the subsequent mixture was acidified to pH2 with dilute hydrochloric acid, and then extracted with ether (2×100 ml.) and the extracts discarded. The aqueous phase was basified to pH9 (sodium hydroxide solution) and extracted with ether (3×100 ml.). The extracts were washed with water (2×50 ml.), dried (MgSO4) and evaporated. The residue was dissolved in acetone (200 ml.), the solution obtained was filtered, and the filtrate acidified to pH2 with ethereal hydrogen chloride. There was thus obtained 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine hydrochloride which was recrystallised from methanol/ethyl acetate to give pure material (34.6 g.), m.p. 234°-236° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([C:16]2[N:17]=[C:18]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:34])[O:19][C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.CCCCCC.C([Li])CCC>[C:10]1([C:16]2[N:17]=[C:18]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3([C:7]3[CH:2]=[CH:3][CH:4]=[C:5]([O:8][CH3:9])[CH:6]=3)[OH:34])[O:19][C:20]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCCCC1Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCCCC2Cc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 4-bromoanisole (1.00 g) in tetrahydrofuran (4 ml), n-butyllithium hexane solution (1.56M, 3.4 ml) was added at −78° C. under a flow of nitrogen. After stirring for 0.5 hour, a solution of 2-[(4,5-diphenyloxazol-2-yl)methyl]cyclohexan-1-one (1.36 g) in tetrahydrofuran (3 ml) was added below −50° C. to the reaction mixture and stirred for 0.5 hour. After usual workup, the crude product was purified by column chromatography (silica gel 50 g, eluent; hexane/ethyl acetate=9 then 4) to give 2-[(4,5-diphenyloxazol-2-yl)methyl]-1-(3-methoxyphenyl)-1-cyclohexanol (1.01 g) as a foam.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:11]2[N:10]=[C:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[NH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[C:13]([C:12]1[CH:26]=[CH:25][C:24](=[O:27])[N:8]2[C:7]3[CH2:6][CH2:5][CH2:4][CH:3]([CH3:2])[C:11]=3[NH:10][C:9]=12)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC1CCCc2[nH]c(CC(=O)c3ccccc3)nc21
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CC1CCCc2c1[nH]c1c(C(=O)c3ccccc3)ccc(=O)n21

Procedure:
The compound is prepared as described in example 20 with 232 mg (0.80 mmol) of 2-(4-Methyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-1-phenylethanone hydrochloride (example XIX), 50 mg (0.92 mmol) of sodium methylate and 67 mg (0.80 mmol) methyl propiolate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[K+].[N+](C1C=CC(S(O[C:18]2[CH2:19][C@@H:20]3[CH2:34][C:33](=[O:35])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])(=O)=O)=CC=1)([O-])=O>C(OCC)C>[N:1]([C:18]1[CH2:19][C@@H:20]2[CH2:34][C:33](=[O:35])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)C1=C(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C[C@@H]2CC(=O)N12
Agent: [K+]
Solvent: CCOCC
Product: [N-]=[N+]=NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Reaction time: 0.17 h
Yield: 35.2 %

Procedure:
Potassium azide (3.2 mg, 39 micromol) was added to a stirred, 0° C. solution of benzyl 2-(p-nitrobenzenesulfonyloxy)-carbapen-2-em-3-carboxylate (5.1 mg, 12 micromol) in anhydrous 5:1 (v/v) acetonitriledichloromethane. After 10 min. the mixture was applied to one 10 cm×20 cm 250 micron silica gel thin layer chromatography plate and developed with diethyl ether. The band centered at Rf 0.5 was eluted with ethyl acetate and the eluate was evaporated under vacuum to provide 1.2 mg (37%) benzyl 2-azidocarbapen-2-em-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH:16](O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:21]([O:23][CH3:24])=[O:22])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26]
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Temperature: 25 °C
Reaction time: 44 h
Yield: 0.1 %

Procedure:
To an ice-cooled mixture of methyl 2-(4-fluoro-3-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (3.39 g, 9.06 mmol) and triethylsilane (3.06 g, 26.3 mmol) in dichloromethane (180 mL) was added a solution of trifluoroacetic acid (4.24 g, 37.1 mmol) in dichloromethane (90 mL) dropwise during 3 hours. After addition, ice-bath was removed and the reaction mixture was stirred at room temperature for 44 hours. Solid sodium carbonate was added and stirred for 15 minutes, filtered, and concentrated. The oil residue was purified by column (silica gel, petroleum ether/ethyl acetate=10:1 to 1:1 due to bad solubility) to afford methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate 2.44 mg (75%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[N:8][NH:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[N:8][N:9]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([C:21]([F:32])([F:31])[F:20])[CH:27]=2)[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1c(-c2cncnc2)n[nH]c1C1CC1
Product: CCOC(=O)c1c(-c2cncnc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1
Yield: 34 %

Procedure:
In analogy to the procedure described in Example 162C], 5-cyclopropyl-3-pyrimidin-5-yl-1H-pyrazole-4-carboxylic acid ethyl ester and 3-(trifluoromethyl)benzeneboronic acid gave the title compound as a yellow oil (34%). MS: 403.2 (MH+).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:37]([N:39]1[N:43]=[C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])[S:41][C@H:40]1[C:48]([O:50]CC1C=CC=CC=1)=[O:49])=[O:38])[NH:17][C@H:18]([C:27]([O:29]CC1C=CC=CC=1)=[O:28])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:44]([C:42]1[S:41][C@@H:40]([C:48]([OH:50])=[O:49])[N:39]([C:37](=[O:38])[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])[NH:17][C@H:18]([C:27]([OH:29])=[O:28])[CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:43]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: [H][H]
Reactant: CC(C)(C)C1=NN(C(=O)[C@H](CCCCNC(=O)OCc2ccccc2)N[C@@H](CCc2ccccc2)C(=O)OCc2ccccc2)[C@H](C(=O)OCc2ccccc2)S1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C1=NN(C(=O)[C@H](CCCCN)N[C@@H](CCc2ccccc2)C(=O)O)[C@H](C(=O)O)S1

Procedure:
A solution of the product from step d) (1.lg) in ethanol (90ml) was treated with 10% palladium on carbon (0.9g) and the mixture stirred under 1 atmosphere of hydrogen for 1 hour. The catalyst was removed by filtration and the filtrate evaporated. The residue was recrystallised from a mixture of tetrahydrofuran and ethanol to give the title product as a white solid (0.24g)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C@@H:8]1[C:13]([OH:15])=O.[NH2:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]([OH:28])[C:25]([NH2:27])=[O:26].O[NH-].O=[N-]>>[NH2:27][C:25](=[O:26])[C:24](=[O:28])[CH:23]([NH:22][C:13]([C@H:8]1[CH2:9][CH2:10][C:11](=[O:12])[N:7]1[CH2:6][C:5]1[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=1[O:3][C:2]([F:1])([F:21])[F:20])=[O:15])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1OC(F)(F)F
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1OC(F)(F)F

Procedure:
Coupling of (R)-1-(2-trifluoromethoxy-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([C:13]2C=CC=CC=2)[C:7]=1[CH2:19][Br:20])=[O:5])[CH3:2].C(OC(C1C=CN(C)C=1C)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([CH3:13])[C:7]=1[CH2:19][Br:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Br)c(Br)n(-c2ccccc2)c1CBr
Agent: CCOC(=O)c1ccn(C)c1C
Product: CCOC(=O)c1c(Br)c(Br)n(C)c1CBr

Procedure:
Prepared in analogy to that of 4,5-dibromo-2-bromomethyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 1,2-Dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester; the title product, 1H NMR (200 MHz, CDCl3): δ (ppm)=4.93 (s, 2H), 4.34 (q, 2H, J=7.1 Hz), 3.69 (s, 3H), 1.40 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([C:13](OC)=[O:14])[CH2:5]2.[BH4-].[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]([CH2:13][OH:14])[CH2:5]2
Reactant: COC(=O)C1Cc2cc(Br)cnc2NC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2ncc(Br)cc2CC1CO
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a suspension of methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (285 mg, 1 mmol) in THF (10 mL) under Argon at room temperature was added sodium borohydride (151 mg, 4 mmol). The reaction mixture was stirred at 60° C. for 4 h, then diluted in EtOAc and washed four times with a NH4Cl solution (pH=6.5). The white organic phase was filtered to give the title compound contamined by impurities as a white solid (59 mg). The filtrate was dried over sodium sulphate, filtered and concentrated in vacuo to give a yellow solid (143 mg). The crude was purified by preparative TLC (eluent: dichloromethane/MeOH 93/7) to give the title compound (10 mg, 4%) as a white solid.
Reaction SMILES: [ClH:1].C(OC([N:7]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:8]1[CH2:9][CH:10]([CH2:16][C:17]([OH:19])=[O:18])[CH2:11]2)=O)C>>[ClH:1].[CH:8]12[NH:7][CH:12]([CH2:13][CH2:14][CH2:15]1)[CH2:11][CH:10]([CH2:16][C:17]([OH:19])=[O:18])[CH2:9]2
Reactant: CCOC(=O)N1C2CCCC1CC(CC(=O)O)C2
Agent: Cl
Product: O=C(O)CC1CC2CCCC(C1)N2
Temperature: 25 °C
Yield: 95 %

Procedure:
Concentrated HCl (36%, 73.5 ml) was added to [9-(ethoxy carbonyl)-9-azabicyclo[3.3.1]-non-3-yl]-acetic acid (4.9 g, 19.2 m mol) under stirring at room temperature. The reaction mixture was heated at 100° C. for 8 hours and progress of reaction was monitored by mass spectroscopy. After the completion of reaction, the reaction mixture was evaporated to dryness under reduced pressure and traces of water was removed by evaporating with dichloromethane (3×50 ml) the crude product was dried under high vacuum to yield the title compound (4.01 g, 95%) and subjected to further reaction without purification
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=[O:5].[C:11]12[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=1[S:18][C:17]1[C:16](=[O:24])[NH:15][N:14]=[CH:13][C:12]2=1.C(=O)([O-])[O-].[Cs+].[Cs+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>O1CCOCC1>[Br:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]([N:15]2[C:16](=[O:24])[C:17]3[S:18][C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:11]=4[C:12]=3[CH:13]=[N:14]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Br)cncc1Br
Reactant: O=c1[nH]ncc2c3c(sc12)CCCC3
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=Cc1c(Br)cncc1-n1ncc2c3c(sc2c1=O)CCCC3
Temperature: 100 °C
Yield: 27 %

Procedure:
To a 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (15 mL), 3,5-dibromoisonicotinaldehyde (200 mg, 0.76 mmol), 8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-6-one 191d (160 mg, 0.76 mmol), and cesium carbonate (176 mg, 1.5 mmol). Cuprous iodide CuI (100 mg, 0.76 mmol) and 4,7-dimethoxy-1,10-phenanthroline (127 mg, 0.52 mmol) were added, and the reaction mixture was heated at 100° C. for 5 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on flash column eluting with EtOAC/PE (1:2) to afford 116a (80 mg, 30%). MS: [M+H]+ 390.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].Br[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23]>>[NH2:1][C:2]1[C:3]([C:4]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Reactant: Fc1cccc(F)c1Br
Product: Nc1nc(Cl)ccc1C(=O)c1c(F)cccc1F

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 2-bromo-1,3-difluorobenzene (Aldrich) using the procedure described in Example 7. HRMS, observed: 268.0217, Calcd for M+: 268.0215.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([O:12]C)=[O:11].[CH:15]12[O:20][CH:16]1[CH2:17][CH2:18][CH2:19]2.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[OH:20])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(C)c1ccc(O)cc1F
Reactant: C1CC2OC2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(O[C@H]2CCC[C@@H]2O)cc1F
Temperature: 70 °C
Reaction time: 14 h
Yield: 54.8 %

Procedure:
To a solution of compound (8) (3.50 g, 17.7 mmol) in dry DMF (35 mL), cyclopentene oxide (2.3 mL, 26.6 mmol) and sodium hydride (0.64 g, 26.6 mmol) were added and stirred at 70° C. for 14 hours. After completion of the reaction, the obtained mixture was cooled to room temperature and concentrated under reduced pressure. The residue was extracted with ethyl acetate (300 mL) followed by washing with water and drying (over sodium sulfate). The solvent was distilled off, and the residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (8:1) solution followed by conventional hydrolysis to give 2.60 g (52%) of compound (13) of interest as yellow oil.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[N:6]=1)[CH3:3].C(O)(=O)C.C(N(CC)C(C)C)(C)C.C([BH3-])#N.[Na+].[O:33]=[C:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[C:40]1[C:45]([CH2:46][CH:47]=O)=[CH:44][CH:43]=[CH:42][N:41]=1.Cl.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>CO.CC(C)=O>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[CH3:3][CH:2]([O:4][C:5]1[N:6]=[C:7]([CH:11]2[CH2:15][CH2:14][N:13]([CH2:47][CH2:46][C:45]3[C:40]([N:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:34]4=[O:33])=[N:41][CH:42]=[CH:43][CH:44]=3)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: CC(C)Oc1cccc(C2CCNC2)n1
Reactant: O=CCc1cccnc1N1CCCCC1=O
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CC(C)Oc1cccc(C2CCN(CCc3cccnc3N3CCCCC3=O)C2)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 12.5 %

Procedure:
2-(Propan-2-yloxy)-6-(pyrrolidin-3-yl)pyridine a1-61 (0.302 g, 1.464 mmol, 1 eq) is dissolved in methanol (15 ml) and the solution is cooled at 0° C. Acetic acid (0.527 g, 8.784 mmol, 6 eq), N,N,-diisopropylethylamine (0.378 g, 2.928 mmol, 2 eq) and sodium cyanoborohydride (0.552 g, 8.784 mmol, 6 eq) are added. The reaction mixture is stirred for 5 min, and then poured on crude [2-(2-oxopiperidin-1-yl)pyridin-3-yl]acetaldehyde a4-3 (1.46 mmol, 1 eq) cooled at 0°. After 10 min at 0° C., the reaction mixture is warmed up to room temperature. Hydrochloric acid 1N is added until acidic pH. The solution is catched over an acidic column, washed with methanol and then released with ammonia 1M in methanol. The solvent is evaporated under reduced pressure. The residue is purified by LC-MS basic reverse phase (gradient CH3CN/H2O/NaHCO3 from 5/95/0.5 to 95/5/0.5). The residue of evaporation is dissolved in a minimum of acetone and oxalic acid (1 eq) is added to form the salt. The solvent is removed under reduced pressure. The residue is taken in diethyl ether, the mixture is stirred, sonicated and filtered. The precipitate is washed with diethyl ether (2 times) to afford 75 mg of 1-[3-(2-{3-[6-(propan-2-yloxy)pyridin-2-yl]pyrrolidin-1-yl}ethyl)pyridin-2-yl]piperidin-2-one oxalate 94.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[S:7](=[O:11])(=[O:10])[CH2:8][CH2:9][C:5]=2[CH:4]=1.[NH2:14][C:15]1[C:16]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[N:17][O:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:10]=[S:7]1(=[O:11])[CH2:8][CH2:9][C:5]2[CH:4]=[C:3]([CH2:2][O:26][C:23]3[CH:22]=[CH:21][C:20]([C:16]4[C:15]([NH2:14])=[CH:19][O:18][N:17]=4)=[CH:25][CH:24]=3)[CH:13]=[CH:12][C:6]1=2
Reactant: O=S1(=O)CCc2cc(CBr)ccc21
Reactant: Nc1conc1-c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1conc1-c1ccc(OCc2ccc3c(c2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
To a solution of 5-bromomethyl-2,3-dihydro-benzo[b]thiophene 1,1-dioxide (55 mg, 0.21 mmol), 4-(4-amino-isoxazol-3-yl)-phenol (37 mg, 0.21 mmol) in DMF (2 mL) was added tetrabutylammonium iodide (8 mg, 0.021 mmol) and K2CO3 (58 mg, 0.42 mmol). After stirring for 4 h at rt, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed three times with water, once with brine and dried over Na2SO4. Filtration followed by removal of volatiles under reduced pressure gave crude product from which 3-[4-(1,1-dioxo-2,3-dihydro-1H-1lambda*6*-benzo[b]thiophen-5-ylmethoxy)-phenyl]-isoxazol-4-ylamine (42 mg, 56%) was isolated by chromatography (66-80% ethyl acetate in hexane. M+1=356.9
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][O:9]C2CCCCO2)[CH:6]=1.[CH:16]([N:19]1[C:23]([C:24]2[S:25][C:26]3[CH2:27][CH2:28][O:29][C:30]4[CH:37]=[C:36](B5OC(C)(C)C(C)(C)O5)[CH:35]=[CH:34][C:31]=4[C:32]=3[N:33]=2)=[N:22][CH:21]=[N:20]1)([CH3:18])[CH3:17]>>[CH:16]([N:19]1[C:23]([C:24]2[S:25][C:26]3[CH2:27][CH2:28][O:29][C:30]4[CH:37]=[C:36]([C:2]5[N:3]=[CH:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=5)[CH:35]=[CH:34][C:31]=4[C:32]=3[N:33]=2)=[N:22][CH:21]=[N:20]1)([CH3:18])[CH3:17]
Reactant: Brc1cn(CCOC2CCCCO2)cn1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(B3OC(C)(C)C(C)(C)O3)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cn(CCO)cn3)ccc1-2

Procedure:
Following the procedure for 258, 4-Bromo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-imidazole was reacted with 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene to give 486. MS(ESI+) 423.1. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3, 1H), 8.11 (s, 1H), 7.73 (d, J=1.0, 1H), 7.68 (d, J=0.9, 1H), 7.58 (dd, J=8.3, 1.7, 1H), 7.44 (d, J=1.7, 1H), 5.95-5.74 (m, 1H), 5.00 (t, J=5.2, 1H), 4.39 (t, J=5.0, 2H), 4.03 (t, J=5.4, 2H), 3.70 (q, J=5.3, 2H), 3.44 (t, J=5.0, 2H), 1.56 (d, J=6.6, 6H)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 471 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[CH:21]=[C:22]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:23]=[C:24]([CH3:26])[CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:22]3[CH:21]=[C:20]([CH3:19])[CH:25]=[C:24]([CH3:26])[CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cc(C)cc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cc(C)cc(C)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3,5-dimethyl-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:27][CH2:26][C:20]3([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:19][CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:15])=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:27][CH2:26][C:20]3([CH2:25][CH2:24][N:23]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:22][CH2:21]3)[CH2:19][CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:15])=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CCC3(CCNCC3)CC2)n1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(NC2CCC3(CC2)CCN(C(=O)CC#N)CC3)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 5-chloro-N2-(1,3-dimethyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (238.1 mg, 0.6107 mmol) and 2-cyanoacetic acid (132.3 mg, 1555 mmol) in DCM (10 mL) and DMF (3 mL) were added HATU (703.4 mg, 17.94 mmol) and Et3N (225 mg, 2.201 mmol). The mixture was stirred at room temperature for 3 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V)=1/5) to give the title compound as a light yellow solid (203.1 mg, 72.8%).