Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg+].[Br-].CCOCC.[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].[C:16](#[N:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH:9]([N:12]([CH:13]([CH3:15])[CH3:14])[C:16](=[NH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:11])[CH3:10]
Reactant: CC(C)NC(C)C
Reactant: N#Cc1ccccc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)N(C(=N)c1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.9 %

Procedure:
A solution of MeMgBr in ether (50.0 mL, 3.0 M, 0.15 mol) was added to a solution of diisopropylamine (16.17 g, 0.16 mol) in toluene (250 mL) at 50° C. The mixture was stirred for 1.5 h and a white precipitate formed. Next, the mixture was cooled to 0° C. and benzonitrile (15.4 g, 0.15 mol) was added. The mixture was allowed to warm to room temperature and stirred for 16 h subsequently. The conversion, determined by GC, appeared to be 90%. The mixture was quenched with water (100 mL). The organic phase was separated from the aqueous phase and the latter was extracted with diethylether (50 mL) twice. The combined organic phases were dried over Na2SO4, filtered and the solvents were removed under reduced pressure. The crude product was distilled at 145° C. at reduced pressure (0.52 mbar) resulting in 15.3 g (50%) of pure product. The ligand was characterized by 1H NMR (300 MHz) (CDCl3) δ (ppm): 7.2 (m, 5H), 5.7 (bs, 1H), 3.5 (p, 2H), 1.2 (d, 12H) and by 13C-NMR (75.5 MHz) (CDCl3) δ (ppm) 168.4, 141.8, 128.8, 128.5, 126.2, 48.6, 21.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH2:16][CH2:17][CH2:18][S:19][C:20]1[N:24]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]=1)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O.ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH2:16][CH2:17][CH2:18][S:19][C:20]1[N:24]([CH2:25][C:26]([OH:28])=[O:27])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1c2ccccc2c(=O)n1CCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)n1c2ccccc2c(=O)n1CCCSc1nc2ccccc2n1CC(=O)O
Yield: 13.2 %

Procedure:
tert-Butyl {2-[3-(2,3-dihydro-1-ethyloxycarbonyl-3-oxo-indazol-2-yl)-propylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor G-01b, 63.8 mg, 0.1 mmol) is stirred in TFA/dichloromethane (1:1, 2 ml) at rt overnight. The solvents are removed in vacuo. The crude is taken up in chloroform (1 ml) and filtered over cotton wool. The solvent is removed in vacuuo and the residue is dried under high vacuum. This yields the title compound (6 mg) in 11% as a colourless oil: tR=2.24 min (LC-2), ESI-MS (pos.): m/z 455.11 [M+H]+, ESI-MS (neg.): m/z 453.22 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 1.31 (t, 3H, CH3), 2.03 (quint., 2H, CH2CH2N), 3.18 (m, 2H, SCH2), 4.23 (t, 2H, CH2N), 4.36 (q, 2H, OCH2), 4.94 (s, 2H, CH2CO2), 7.10-7.15 (m, 2H, m), 7.39 (t, 1 Harom), 7.46 (m, 2Harom), 7.70-7.78 (m, 2Harom), 7.87 (d, 1Harom)
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C1C=CC=CC=1.Cl[CH:31]([C:37]([CH3:39])=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(Cl)(Cl)(Cl)Cl>[CH2:35]([O:34][C:32]([C:31]1[O:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=3)=[CH:10][C:11]=2[C:37]=1[CH3:39])=[O:33])[CH3:36]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccc3oc(C(=O)OCC)c(C)c3c2)cc1
Reaction time: 2 h

Procedure:
To a solution of 0.25 mole of sodium ethoxide is added 64 g. (0.25 mole) of ethyl 4-(4-hydroxyphenyl)phenylacetate. After stirring two hours the solution is evaporated, benzene is added, and the solution is further evaporated. The residue is dissolved in 800 ml. of benzene, 0.25 mole of ethyl α-chloroacetoacetate is added, and the mixture is stirred at room temperature, then heated at its reflux temperature for 16 hours and filtered hot. Evaporation provides a residue which is dissolved in carbon tetrachloride and filtered through silica gel. This intermediate is treated with concentrated sulfuric acid at 0° C. After stirring one hour, ice is added and the mixture is extracted with benzene. The benzene layer is dried, then evaporated. The residue is recrystallized from a dichloromethanehexane mixture, then carbon tetrachloride, to provide ethyl 4-(2-ethoxycarbonyl 3-methylbenzofuran-5-yl)phenylacetate, m.p. 110°-112° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.ON1C(=O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:31][C:32]1[C:33]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([I:57])=[CH:53][C:52]=2[F:58])=[C:34]([CH:42]=[C:43]([CH2:46][NH:47][O:48][CH3:49])[C:44]=1[F:45])[C:35]([NH:37][O:38][CH2:39][CH2:40][OH:41])=[O:36].C(N(CC)CC)C>C(Cl)Cl.C1COCC1.C(OCC)(=O)C>[F:31][C:32]1[C:33]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([I:57])=[CH:53][C:52]=2[F:58])=[C:34]([CH:42]=[C:43]([CH2:46][N:47]([O:48][CH3:49])[C:4](=[O:6])[CH2:3][O:2][CH3:1])[C:44]=1[F:45])[C:35]([NH:37][O:38][CH2:39][CH2:40][OH:41])=[O:36]
Reactant: COCC(=O)O
Reactant: CONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCC(=O)N(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)OC
Reaction time: 3 h
Yield: 32.7 %

Procedure:
To a solution of methoxyacetic acid (9.0 μL, 0.12 mmol) in methylene chloride (1 ml) were added 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (18.9 mg, 0.12 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.5 mg, 0.12 mmol), and the mixture was stirred for 3 hours. This solution was added dropwise to a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-benzamide (50.0 mg, 0.10 mmol) obtained in Example 15 in THF (3 ml), and triethylamine (40.9 μl, 0.29 mmol) was added thereto. The mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate (45 ml), and washed with saturated aqueous ammonium chloride (20 ml), and then with saturated brine (2×20 ml). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by preparative TLC (CH2Cl2/MeOH (10:1)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-{[methoxy-(2-methoxy-acetyl)-amino]-methyl}-benzamide (Compound F-6, 19.1 mg, 34%) as a colorless oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.O1CCOCC1.CC(C)([O-])C.[K+].Cl[C:27]1[N:28]=[C:29]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][CH:49]([N:52]4[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]4)[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)[C:30]([C:36]([NH2:38])=[O:37])=[N:31][C:32]=1[CH:33]1[CH2:35][CH2:34]1>O>[C:36]([C:30]1[N:31]=[C:32]([CH:33]2[CH2:35][CH2:34]2)[C:27]([O:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[N:28][C:29]=1[NH:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:47][CH2:48][CH:49]([N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]3)[CH2:50][CH2:51]2)=[CH:42][CH:41]=1)(=[O:37])[NH2:38]
Reactant: CN1CCN(C2CCN(c3ccc(Nc4nc(Cl)c(C5CC5)nc4C(N)=O)cc3)CC2)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(C2CCN(c3ccc(Nc4nc(O[C@@H]5CCN(C(=O)OC(C)(C)C)C5)c(C5CC5)nc4C(N)=O)cc3)CC2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 75.3 %

Procedure:
To a mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (151 mg) and dioxane (4 mL) were added potassium tert-butoxide (91 mg) and 5-chloro-6-cyclopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (190 mg), followed by stirring at 100° C. for 16 hours. After leaving to be cooled, water was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-cyclopropyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (189 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([O:7][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])=[O:6]
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cc1cc(C(=O)ON2C(=O)CCC2=O)cc(C)c1O

Procedure:
treating 3,5-dimethyl-4-hydroxybenzoic acid with N-hydroxysuccinimide and 1,3-dicyclohexylcarbodiimide to produce succinimidyl 3,5-dimethyl-4-hydroxybenzoate;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[F:30][CH:31]([F:41])[C:32]1[N:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=1>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:20])([F:18])[F:19])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:38]([C:35]3[CH:34]=[N:33][C:32]([CH:31]([F:41])[F:30])=[CH:37][N:36]=3)=[O:39])[CH:3]=[CH:4][C:5]=2[F:29])[N:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(C(F)F)cn4)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-difluoromethyl-pyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.80 (dd, J=13.8, 3.7 Hz, 1H), 3.11 (dd, J=13.6, 2.8 Hz, 1H), 3.31-3.41 (m, 1H), 3.86 (d, J=8.3 Hz, 1H), 4.57 (d, J=8.3 Hz, 1H), 4.64 (dt, J=14.7, 7.1 Hz, 1H), 4.75 (br s, 2H), 6.69 (t, J=56.3 Hz, 1H), 7.07 (dd, J=11.6, 8.8 Hz, 1H), 7.57 (dd, J=7.1, 2.8 Hz, 1H), 7.87 (dt, J=8.5, 3.6 Hz, 1H), 8.85 (s, 1H), 9.45 (s, 1H), 9.58 (br. s., 1H)
Reaction SMILES: [CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12](=[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)[CH2:13]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH4+:33].[OH-]>>[CH2:1]([N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12](=[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:33])=[O:23])=[CH:20][CH:19]=1)[CH2:13]2)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1.5 g (0.0034 mole) sample of 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzoyl chloride was cooled in an ice bath. 30 mL of NH4OH was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for 2 h. The solid was filtered off and dried. The product was passed through a Biotage Flash 40 L (silica gel, 9:1; CH2Cl2:MeOH). Conversion to the HCl salt and recrystallization from EtOH/Et2O gave 0.45 g of 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzamide; mp. 210-212° C. MS m/z (MH+) 423. 1H NMR (DMSO-d6) δ 7.95 (s, 1H); 7.9 (d, 2H); 7.4-7.2 (ar, 12H); 4.05 (bs, 1H); 3.6 (q, 2H); 2.9 (d, 2H); 2.4-2.1 (m, 5H); 1.8 (m, 3H); 1.1 (t, 3H).
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][C:15](=[O:20])[C:14]=2[CH:13]=[N:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[BH4-].[Na+]>CCO.C1COCC1>[S:1]([N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH:15]([OH:20])[C:14]=2[CH:13]=[N:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c2CCCC3=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ncc3c2CCCC3O)cc1
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 1-tosyl-6,7-dihydro-1H-indazol-4(5H)-one (5 g, 17.22 mmol) in EtOH/THF (30 mL/30 mL)) was added NaBH4 (1.3 g, 34.44 mmol) under ice-bath. The mixture was stirred for 1 h at this temperature and quenched with aqueous NH4Cl solution. Removed the solvent under reduced pressure and extracted with DCM and the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo and the residue 1-tosyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (4.94 g, yield 98.2%) was used directly to next step. MS-ESI (m/z): 293 (M+1)+ (Acq Method: 10-80AB_2 min; Rt: 1.01 min)
Reaction SMILES: [N+](=[CH:3][C:4]([CH:6]1[O:12][CH:11]2[C:8]([C:34](=[O:42])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:9](=[O:33])[N:10]2[C:13](=[C:30]([CH3:32])[CH3:31])[C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[NH:7]1)=[O:5])=[N-].B(F)(F)F.CCOCC.[C:52]([OH:55])(=[O:54])[CH3:53]>>[C:52]([O:55][CH2:3][C:4]([CH:6]1[O:12][CH:11]2[C:8]([C:34](=[O:42])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:9](=[O:33])[N:10]2[C:13](=[C:30]([CH3:31])[CH3:32])[C:14]([O:16][CH:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[NH:7]1)=[O:5])(=[O:54])[CH3:53]
Reactant: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)C=[N+]=[N-])OC12
Reactant: CC(=O)O
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)OCC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Temperature: 0 °C
Yield: 30 %

Procedure:
To a solution of 200 mg of diphenylmethyl α-(3ξ-diazoacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 2 ml of acetic acid is added 0.045 ml of boron trifluoride etherate. After the termination of gas evolution, the reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is washed with water, an aqueous solution of sodium hydrogencarbonate and then water, dried on sodium sulfate and evaporated. The residue (205 mg) is purified by thin-layer chromatography to yield 65 mg of diphenylmethyl α-(3ξ-acetoxyacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 30% yield.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH2:17][CH:12]2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>Cl.C(O)C.[Pd]>[O:1]([CH2:8][CH:9]1[CH2:25][N:13]2[CH2:14][CH2:15][N:16]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)[CH2:17][CH:12]2[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccc(N2CCN3CC(COc4ccccc4)CCC3C2)n1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(OCC2CCC3CN(c4ccncn4)CCN3C2)cc1
Yield: 20.1 %

Procedure:
A mixture of 0.110 g (0.307 mmol) of (7RS,9aSR)-7-phenoxymethyl-2-(2-chloropyrimidin-4-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Example 29), 20 mg of 10% Pd/C, and several drops of conc. hydrochloric acid in 30 mL of ethanol were shaken under 50 psi of hydrogen gas at room temperature for 6 h. The mixture was filtered through Celite and the filtrate was evaportated. The residue was basified with conc. ammonium hydroxide, extracted with chloroform, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with a solvent gradient from 100% chloroform to 95:5 chloroform:methanol gave 0.020 g (20%) of the title compound. mp (—HCl) >265° C. (dec). HRMS calc for C19H24N4O: 324.1945, found: 324.1970.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]1[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([Li])CCC.IC.O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[C:13]([CH3:20])=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]1[CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1C=CC(Cl)=CC1C1CCCC1
Solvent: O
Solvent: CI
Solvent: CCOCC
Product: CC1=CC(Cl)=CC(C2CCCC2)N1C(=O)OC(C)(C)C
Temperature: -42 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-4-chloro-2-cyclopentyl-1,2-dihydropyridine (3.69 g, 12.99 mmol) in 180 ml of THF at −42° C. was added n-butyllithium (6.25 mL, 15.59 mmol) dropwise via syringe. After the mixture had stirred at −42° C. for 1 h, iodomethane (2.4 mL, 38.97 mmol) was added and stirring was continued at −42° C. for 1 h and then at room temperature for 1 h. Water (50 mL) and ether (100 mL) were added, the layers were separated, the aqueous phase was extracted with ether (2×15 mL), and the combined organic extracts were washed with brine. The organic phase was dried over K2CO3 filtered through silica gel/Celite, and concentrated in vacuo to give the crude product. Purification by column chromatography with 5% EtOAc in hexanes afforded 2.60 g (69%) of the product as an orange oil that was homogeneous by TLC analysis. 1H NMR (250 MHz) δ5.68-5.61 (d, 1 H), 5.37 (br s, 1 H), 4.86-4.73 (q, 1 H), 2.21 (m, 1 H), 2.14 (s, 3 H), 1.76-1.20 (m, 17 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](O)=[N:9][CH:8]=[N:7][C:6]=2[N:12]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:10]1[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:12][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Oc1ncnc2nc(Cl)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(Cl)ncnc2n1
Yield: 73 %

Procedure:
A mixture of Example 140C (1 g, 5.5 mmol) in phosphorus oxychloride (40 mL) was refluxed for 2 h then cooled and evaporated. The residue was taken into ethyl acetate (75 ml), washed with saturated sodium bicarbonate (50 ml) water (50 ml) and brine (50 ml). The ethyl acetate was evaporated to yield 0.8 g of product (73%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=2)[N:10]=1.S(Cl)([Cl:24])=O>>[Cl:24][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:9]2[N:10]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:7][C:8]=2[CH3:21])=[N:18][CH:17]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of 6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethanol (1.87 g) and thionyl chloride (15 ml) was stirred at room temperature for 1 hr. After concentration under reduced pressure, ice water was added to the residue. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]pyridine (1.41 g, yield 71%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 95–96° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)=[O:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1cccc(C)n1
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH:7]1([C:13]([CH3:17])([CH3:16])[CH:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(CO)C1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C=O)C1CCCCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
Oxalyl chloride (7.8 g, 61.42 mmol) in methylene chloride (60 mL) at −78° C. was treated with dimethylsufoxide (8.4 g, 107.5 mmol). After stirring at −78° C. for 10 minutes, the mixture was treated with 2-cyclohexyl-2-methylpropanol (4.8 g, 36.86 mmol) in 15 ml of methylene chloride. The mixture was allowed to stir at −78° C. for 30 minutes and then treated with triethylamine (15.54 g, 153.6 mmol). The reaction mixture was stirred for 10 minutes and then stirred an additional 5 minutes at 0° C. The mixture was quenched with saturated aqueous ammonium (10 mL) chloride and extracted with diethyl ether (2×50 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate and concentrated under vacuo. The crude product was redissolved in diethyl ether and the resulting precipitate was filtered through a pad of Celite. The solution was concentrated under reduced pressure to provide 4.5 g of 2-cyclohexyl-2-methylpropanal as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[N:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:28]4[N:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1ncc(F)c(N2CCC(C3CCNCC3)CC2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ncc(F)c(N2CCC(C3CCN(c4ncc(F)cn4)CC3)CC2)n1
Temperature: 70 °C

Procedure:
1-(5-fluoro-2-methylpyrimidin-4-yl)-4,4′-bipiperidine (16 mg, 0.058 mmol) and cesium carbonate (57 mg, 0.17 mmol) were stirred in NMP (0.6 ml) and 2-chloro-5-fluoropyrimidine (0.014 mL, 0.116 mmol) was added. The mixture was heated at 70° C. for 1 h. The reaction was cooled down to r.t. and diluted with ethyl acetate (5 mL) and was washed with water 2 mL (×1) and brine 2 mL (×1). The organic phase was dried over magnesium sulfate, filtered, and concentrated on rotavapor. The crude material was purified by preparative TLC with 30% acetone: hexane to yield the titled compound. LC-MS: 375.06 (M+H). Examples reported in Table 14 are prepared in accordance with Procedure 14.1.