Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:18]1([CH:23]=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>CCCCCC.C1COCC1>[CH:18]1([CH:23]([OH:24])[C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]#[N:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=CC1CCCC1
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CC1(c2ccc(C(O)C3CCCC3)cc2)CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-bromophenyl)cyclopropanecarbonitrile (2.01 g, 0.00905 mol) in tetrahydrofuran (30 mL, 0.4 mol) was added 2.5 M of n-butyllithium in hexane (4.0 mL) at −78° C. and the mixture was stirred at −30° C. for 30 minutes. A solution of cyclopentanecarbaldehyde (0.972 g, 0.00990 mol) in THF (2 mL) was added to the above mixture and the resulting mixture was stirred at −78° C. for 2 hours. The reaction was then quenched with a small amount of saturated aqueous NH4Cl solution followed by extraction with ethyl acetate, drying with MgSO4, and concentrating under reduced pressure. The crude product was purified by flash chromatography, eluting with 30% AcOEt in hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH:14]([CH3:17])[CH2:15][OH:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O>CN(C=O)C>[C:25]([O:24][C:22]([CH2:21][O:16][CH2:15][CH:14]([NH:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[Cl:1])[CH3:17])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1ccc(NC(C)CO)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(NC(C)COCC(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1.12 g (4.35 mmol) ethyl 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate are combined in 10 ml DMF with 0.21 g (4.78 mmol) 55% sodium hydride dispersion and stirred for 5 min at ambient temperature. Then 0.67 ml tert.-butyl bromoacetate are added and the mixture is stirred for a further 16 h at ambient temperature. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=95:5->80:20)
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:24][C:25]1[C:29](C(B(O)O)=O)=[C:28]([CH3:35])[O:27][N:26]=1>C(=O)([O-])[O-].[Na+].[Na+].COCCOC.C(OCC)(=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>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20]([C:29]5[C:25]([CH3:24])=[N:26][O:27][C:28]=5[CH3:35])=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1noc(C)c1C(=O)B(O)O
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
A mixture of 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (252 mg, 0.6 mmol), 3,5 dimethyl-4-isoxazoyl boronic acid (168 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium(0) in 2M sodium carbonate solution (5 ml) and ethylene glycol dimethyl ether (10 ml) was stirred at reflux for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of sodium bicarbonate, water, brine and dried (sodium sulfate). The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title compound (E222); MS (ES+) m/e 390 [M+H]+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Br:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>O.C(O)(=O)C>[OH:3][N:1]=[C:8]([C:7]([CH2:6][Br:5])=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)CBr
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)CBr
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A solution of sodium nitrite (12.4 g.) in water (150 ml.) was dropwise added with stirring at 5° to 7° C. to a solution of ethyl 4-bromoacetoacetate (30 g.) in acetic acid (200 ml.) and the mixture was stirred for 2 hours at 10° C. Water (200 ml.) was added to the reaction mixture and the resultant mixture was extracted with ether (500 ml.). The extract was washed twice with water (200 ml.) and with a sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give yellowish brown crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (32.6 g.).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[N:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCCc1nc(CC)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 144 h
Yield: 55.3 %

Procedure:
A mixture of 4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.5 g), phenylboronic acid (0.99 g), copper(II) acetate (1.5 g), pyridine (1.6 mL), triethylamine (2.8 mL), molecular sieves 4 A (1.5 g) and dichloromethane (30 mL) was stirred for 6 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.0 g, 55%) as a colorless liquid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][OH:20])([CH3:18])[CH2:13]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].[OH-].[Na+]>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][S:22]([CH3:21])(=[O:24])=[O:23])([CH3:18])[CH2:13]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1(COS(C)(=O)=O)CCCN(CC2COc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol (0.92 g, 3.31 mmol) in DCM (40 ml) at 0° C. was added methanesulfonyl chloride (0.51 ml). The reaction mixture was stirred at RT for 12 h. The reaction mixture was made basic with 2 M NaOH and then extracted with DCM (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:15])=O>>[CH:4]1([CH2:7][CH2:8][CH2:9][C:10]([Cl:15])=[O:12])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCC1CCCCC1
Product: O=C(Cl)CCCC1CCCCC1

Procedure:
50 g of 4-cyclohexanebutyric acid are refluxed for 4 hours in 160 ml of thionyl chloride. After evaporation of the excess thionyl chloride, the expected product is distilled off. b.p.=70-80° C. at 400 Pa.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:32]Br>C(#N)C>[F:27][C:28]([F:41])([F:42])[C:29]1[CH:30]=[C:31]([CH2:32][NH:1][C@H:2]2[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@H:3]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COC(=O)[C@H]1CC[C@H](N)[C@@H]1c1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1CC[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccc(F)cc1
Yield: 71.7 %

Procedure:
A solution of 20 mg of amine from Example 63, 0.050 mL of DIPEA and 30 mg of 3,5-bis(trifluoromethyl)benzyl bromide in 1 mL of acetonitrile was stirred for 20 h in a sealed vial and evaporated. The residue was purified on a 1 mm preparative silica gel plate eluted with 20% ethyl acetate in hexanes to obtain 28 mg of title compound as an oil. Mass spec (NH3 /CI): 464 (M+1).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]=[CH:12][C:11]=2[CH:15]=1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].O>C1COCC1>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:15][C:11]=2[CH:12]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1ccc2occc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cc2cc(F)ccc2o1
Temperature: 25 °C
Yield: 22.5 %

Procedure:
Butyllithium (1.5 mL, 2.4 mmol, 1.6 M) was added at −75° C. to a solution of 5-fluorobenzofuran (0.3 g, 2.2 mmol) in THF (10 mL). Tributyltin chloride (0.98 g, 1 mL) was added at −75° C. and the mixture was allowed to warm to 25° C. over a period of 2 hours. Water (25 mL) was added and the aqueous layer was extracted with diethyl ether (2×25 mL). The combined organic extracts were dried over Na2SO4 and concentrated. Silica gel chromatography (pentane) provided tributyl-(5-fluorobenzofuran-2-yl)-stannane (210 mg).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11].[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][CH2:8][N:34]2[CH2:35][CH2:36][CH:31]([C:27]3[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH:30]=[CH:29][CH:28]=3)[CH2:32][CH2:33]2)=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1ccc(C(=O)CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 3-chloro-1-(4-methoxyphenyl)-1-propanone and 0.2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([O:15][CH2:22][CH3:23])=[O:14])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: COc1cc(C(=O)O)c(I)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC)c(OCc2ccccc2)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-benzyloxy-2-iodo-5-methoxybenzoic acid (reference example 5-1) (2 g), 2-iodoethane (0.5 mL), potassium carbonate (1.08 g) and N,N-dimethylformamide (17 mL) was stirred at room temperature for 2 hours. Water was added to the mixture. Insoluble materials were collected by filtration to give the title compound (2.07 g).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2cccc3c2c2ccccc2n3Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Cn2c3ccccc3c3c(OCCN4CCNCC4)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture of tert-Butyl 4-{2-[(9-Benzyl-9H-carbazol-4-yl)oxy]ethyl}-1-piperazinecarboxylate (0.0450 g, 0.0927 mmol), trifluoroacetic acid (2.5 mL), and CH2Cl2 (2.5 mL) is stirred at room temperature for 1 h. Trifluoroacetic acid and CH2Cl2 are then removed in vacuo and the residue is partitioned between CH2Cl2 and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and taken to dryness to give 0.0326 g (91%) of the title compound; IR (drift) 2935, 2821, 1584, 1456, 1353, 1342, 1332, 1271, 1245, 1154, 1145, 1112, 783, 750, 715 cm−1; 1H NMR (CDCl3) δ2.70, 2.95, 3.04, 4.41, 5.50, 6.69, 6.99, 7.12, 7.2-7.4, 8.39. Anal. Calcd for C25H27N3O: C, 77.89; H, 7.06; N, 10.90. Found: C, 76.35; H, 7.20; N, 10.30.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:15]3([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][O:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=2)O1.I[C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:37]=[C:38]([C:39]([F:42])([F:41])[F:40])[C:31]=12.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(OCC)(=O)C>[F:40][C:39]([F:42])([F:41])[C:38]1[C:31]2[C:32](=[N:33][CH:34]=[CH:35][C:30]=2[C:9]2[CH:10]=[C:11]([C:15]3([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:16][O:17][CH2:18]3)[CH:12]=[CH:13][CH:14]=2)[N:36]([C:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:37]=1
Reactant: CC(C)(C)OC(=O)NCC1(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)COC1
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2nccc(I)c12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC1(c2cccc(-c3ccnc4c3c(C(F)(F)F)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)COC1
Temperature: 60 °C
Yield: 50.3 %

Procedure:
tert-Butyl N-[[3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl]methyl]carbamate (65 mg, 0.1670 mmol) was dissolved in dioxane (3 mL) and 4-iodo-3-(trifluoromethyl)-1-trityl-pyrazolo[3,4-b]pyridine (92.74 mg, 0.1670 mmol) was added followed by sodium carbonate (250.5 μL of 2 M, 0.5010 mmol). The reaction was degassed and filled with nitrogen 5 times then Pd[P(tBu)3]2 (12.80 mg, 0.02505 mmol) was added. The reaction was heated at 60° C. overnight. After cooling, water was added followed by ethyl acetate. The aqueous layer was extracted three times with ethyl acetate, the combined organics washed with brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude product was purified on silica (Companion, 12 g) eluting with 2.5-50% EtOAc:Pet.ether to give tert-butyl N-[[3-[3-[3-(trifluoromethyl)-1-trityl-pyrazolo[3,4-b]pyridin-4-yl]phenyl]oxetan-3-yl]methyl]carbamate as a white foam (58 mg, 50%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([C:16]3([NH2:20])[CH2:19][O:18][CH2:17]3)[CH3:15])[NH:12][CH:13]=2)=[CH:5][CH:4]=1>C(O)C>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@@H:14]([C:16]3([NH2:20])[CH2:17][O:18][CH2:19]3)[CH3:15])[NH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(c1nc(-c2ccc(C(F)(F)F)cc2)c[nH]1)C1(N)COC1
Solvent: CCO
Product: C[C@@H](c1nc(-c2ccc(C(F)(F)F)cc2)c[nH]1)C1(N)COC1

Procedure:
Racemic 3-(1-{4-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}ethyl)oxetan-3-amine (Example 12, 0.410 g, 1.32 mmol) was dissolved in ethanol (8.2 mL). Enantiomers were separated by chiral preparative HPLC under basic conditions at ambient temperature on a Chiralpak AD-H column (250*, 21.2 mm i.d) supplied by Daicel Chemical Industries. A flow rate of 18 mL/min was used with a mobile phase of: 70% heptane+30% IPA+0.3% diethylamine (v/v) supplied by an Agilent 1200 prep pump. An injection volume of 1 mL was used per run.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH2:6])[CH3:2].[NH2:15][C:16]1[NH:25][C:24](=[O:26])[C:23]2[C:22]3[CH:27]=[C:28]([NH:31][S:32]([C:35]4[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[CH:29]=[CH:30][C:21]=3[CH:20]=[CH:19][C:18]=2[N:17]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH2:15][C:16]1[NH:25][C:24](=[O:26])[C:23]2[C:22]3[CH:27]=[C:28]([NH:31][S:32]([C:35]4[CH:43]=[CH:42][C:38]([C:39]([NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:40])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[CH:29]=[CH:30][C:21]=3[CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: Nc1nc2ccc3ccc(NS(=O)(=O)c4ccc(C(=O)O)cc4)cc3c2c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(S(=O)(=O)Nc2ccc3ccc4nc(N)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of L-glutamic acid diethyl ester (0.81 g, 4.0 mmoles) and 4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoic acid (0.43 g, 0.9 mmoles) in dry dimethylformamide (20 ml) was added 1-hydroxybenzotriazole monohydrate (0.43 g, 3.2 mmoles) and dicyclohexylcarbodiimide (0.66 g, 3.2 mmoles). The solution was stirred at room temperature under a nitrogen atmosphere for 20 hrs, after which time the solvent was removed under reduced pressure. The residue was recrystallized successively from methylene chloride:methanol/9:1 and methanol to give diethyl N-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoyl)-L-glutamate as a white solid. (0.215 9, 36%). 1HNMR(DMSO-d6, 300 MHz) δ: 1.12(t, J=7 Hz, 3H, ester-CH3); 1.15(t, J=7 Hz, 3H, ester-CH3); 1.89-2.13(m, 2H, glu-CH2); 2.40(t, J=7.6 Hz, 2H, glu-CH2); 4.00(q, J=7 Hz, 2H, ester-CH2); 4.08(q, J=7 Hz, 2H, ester-CH2); 6.55(br s, 2H, NH2); 7.16(d, J=8.9 Hz, 1H, Ar); 7.23(dd, J=8.7, 2 Hz, 1H, Ar); 7.73(d, J=8.7 Hz, 1H, Ar); 7.89(d, J=8.9 Hz, 1H, Ar); 7.96(m, 4H, Ar); 8.89(d, J=7.4 Hz, 1H, glu-NH); 9.48(d, J=2 Hz, 1H, Ar); 10.67(s, 1H, NH); 11.08(s, 1H, NH). Anal. Calculated for C28H29N5O8S: C, 56.46; H, 4.91; N, 11.76; S. 5.38. Found: C, 56.45; H, 4.94; N, 11.75; S, 5.43.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=O)[C:7]2=1.Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[N:18][OH:19])[C:7]2=1
Reactant: NO
Reactant: Cn1c2c(c3cccc(F)c31)C(=O)CCC2
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c2c(c3cccc(F)c31)C(=NO)CCC2
Yield: 56.1 %

Procedure:
A mixture of 8-fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (3.0 g) and hydroxylamine hydrochloride (2.92 g) in pyridine (ca. 35 ml) was heated at 60° for 3 h. The solution was concentrated in vacuo then azeotropically dried with toluene (2×10 ml). The residue was treated with 8% sodium bicarbonate solution (125 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were filtered and concentrated in vacuo to give the title compound (1.8 g) as a solid, t.l.c. (System A, 100:8:1) Rf 0.66.
Reaction SMILES: C([O:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][C@@H:10]1[CH3:23])C1C=CC=CC=1>CO.[Pd]>[OH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:11][C@H:10]1[CH3:23]
Reactant: C[C@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1O
Yield: 84.6 %

Procedure:
tert-Butyl [(1R*,3S*,4R*)-4-(benzyloxy)-3-methylcyclohexyl]carbamate (example C7; 14.0 g; 43.8 mmol) dissolved in MeOH (440 mL) is pressure hydrogenated over Pd (10% on charcoal; 1.4 g) at 50 bar and ambient temperature for 72 hours. The catalyst is removed by filtration through a pad of celite. The filtrate is concentrated under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/AcOEt—70:30 to 50:50) to yield 8.5 g of the tile compound as colourless oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:17][C:16]([CH2:20][OH:21])([CH2:18]Cl)[CH2:15]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:17][C:16]3([CH2:20][O:21][CH2:18]3)[CH2:15]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CC(CO)(CCl)C2)c2nn[nH]c2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Temperature: 25 °C

Procedure:
A mixture of (1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-3-(chloromethyl)azetidin-3-yl)methanol (284 mg, 915 μmol) (example 179, step 2) and potassium tert-butoxide (205 mg, 1.83 mmol) in THF (3 mL) at 0° C. was stirred to room temperature and stirred for 20 h. The mixture was filtered, concentrated in vacuo and used without further purification in the consecutive step.
Reaction SMILES: [BH4-].[Li+].[CH3:3][C:4](=[CH2:24])[CH2:5][C:6]1([C:19](OCC)=[O:20])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C1(C)C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.O>[OH:20][CH2:19][C:6]1([CH2:5][C:4]([CH3:24])=[CH2:3])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][CH2:7]1
Reactant: C=C(C)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Yield: 67.2 %

Procedure:
Lithium borohydride (0.44 g, 20 mmol) was added to a solution of 1-(1,1-dimethylethyl) 4-ethyl 4-(2-methyl-2-propenyl)-1,4-piperidinedicarboxylate (Description 89, 3.11 g, 10 mmol) in tetrahydrofuran and the mixture was stirred under reflux for 18 hours. The mixture was cooled, toluene (20 mL) and lithium borohydride (0.44 g, 20 mmol) were added and the mixture was stirred under reflux for 6 hours. The mixture was cooled and saturated aqueous ammonium chloride (20 mL) and water (50 mL) were added. The mixture was extracted with ethyl acetate (3×500 mL) and the combined organic fractions were washed with aqueous citric acid (10%, 50 mL), saturated aqueous sodium hydrogen carbonate (50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (70:30) to give the title compound as a colorless foam (1.81 g, 67%). 1H NMR (400 MHz, CDCl3) shows two slowly equilibrating tautomers; major: δ 4.92 (1H, s), 4.77 (1H, s), 3.86–3.20 (10H, m), 2.14 (2H, s), 1.82 (3H, s), and 1.46 (9H, s); minor; δ 4.87 (1H, s), 4.66 (1H, s), 3.86–3.20 (10H, m), 2.11 (2H, s), 1.76 (3H, s), and 1.46 (9H, s). m/z (ES+) 270 (M+1).