Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][NH:23]2)=[CH:18][CH:17]=1>C(C#N)(C)=O>[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][N:23]2[C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)=[CH:18][CH:17]=1
Reactant: Clc1ccc2c(c1)NCCC2
Reactant: Clc1ncnc(Cl)n1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2c(c1)N(c1ncnc(Cl)n1)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of the compound 2,4-dichloro-1,3,5-triazine (1.0 g, 5.97 mmol) and solid K2CO3 (4.0 g, 29 mmol) was suspended in AcCN (20 mL) under nitrogen at 0° C., followed by slow addition of 7-chloro-1,2,3,4-tetrahydro-quinoline (Step 1) (1.1 g, 6.56 mmol) as a solution in AcCN (20 mL) over 15 min. The mixture was stirred at 0° C. for 1 h. The solids were removed by suction filtration and washed with AcCN. The organics were concentrated under reduced pressure and the crude compound was purified via column chromatography to give 7-chloro-1-(4-chloro-[1,3,5]triazin-2-yl)-1,2,3,4-tetrahydro-quinoline).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH2:37]([N:44]1[CH2:49][CH2:48][O:47][CH:46](NC)[CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CS(C)=O.[CH2:56]([N:58](CC)CC)C>C(#N)C>[CH2:37]([N:44]1[CH2:49][CH2:48][O:47][CH:46]([CH2:56][NH:58][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:22]=[CH:23][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH3:34])=[CH:25][CH:26]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH2:45]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCN(CC)CC
Reactant: CNC1CN(Cc2ccccc2)CCO1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCC4CN(Cc5ccccc5)CCO4)n3Cc3ccccc32)cc1

Procedure:
The title compound was prepared according to the procedure of Example 2 starting from 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 1 (0.619 g, 1.15 mmole), (4-benzyl-1,4-oxazinan-2-yl)-methylamine (01.97 g, 0.955 mmole), dimethylsulfoxide (0.374 g, 4.8 mmole), and triethylamine (0.213 g, 2.1 mmole) in 15 mL of acetonitrile. The residue was adsorbed on silica Merck-60 and purified by flash chromatography (0-75% ethyl acetate in dichloromethane) to provide an off white solid (0.241 g), m.p. 180-182° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][N:11]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([O:34][CH3:35])[CH:28]=2)[N:21]([CH2:36][C:37](O)=[O:38])[C:20]3=[O:40])[CH2:10][CH:9]1[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:42]([NH2:45])([CH3:44])[CH3:43].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][N:11]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([O:34][CH3:35])[CH:28]=2)[N:21]([CH2:36][C:37](=[O:38])[NH:45][CH:42]([CH3:44])[CH3:43])[C:20]3=[O:40])[CH2:10][CH:9]1[CH3:41])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(-c2nc3ccc(N4CC(C)N(C(=O)OC(C)(C)C)CC(C)(C)C4)cc3c(=O)n2CC(=O)O)ccc1F
Reactant: CC(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(-c2nc3ccc(N4CC(C)N(C(=O)OC(C)(C)C)CC(C)(C)C4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Yield: 56 %

Procedure:
4-[3-Carboxymethyl-2-(4-fluoro-3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2,6,6-trimethylperhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (200 mg, 0.352 mmol), isopropylamine (208 mg, 299 uL, 3.52 mmol), 1-propanephosphonic acid cyclic anhydride (336 mg, 320 uL, 0.528 mmol) and DIPEA (135 mg, 186 uL, 1.06 mmol) were stirred at room temperature in DCM (15 mL) for 2 h. NaHCO3 (aq.) (15 mL) was added, the organic layer separated, dried (Na2SO4) and evaporated under reduced pressure. Crude product was purified by chromatography on silica gel with a gradient of DCM to DCM:MeOH (4:1, v/v) as eluent to afford 4-[2-(4-fluoro-3-methoxyphenyl)-3-(isopropylcarbamoylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2,6,6-trimethylperhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (120 mg, 0.197 mmol, 56%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][CH2:10][CH2:11][CH2:12][SnH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17].[Cl:22][C:23]1[N:28]=[C:27]([Cl:29])[CH:26]=[CH:25][N:24]=1>C1COCC1>[Cl:22][C:23]1[N:28]=[C:27]([Sn:13]([CH2:12][CH2:11][CH2:10][CH3:9])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH:26]=[CH:25][N:24]=1.[Cl:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([Sn:13]([CH2:12][CH2:11][CH2:10][CH3:9])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[N:28]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: Clc1ccnc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccnc(Cl)n1
Product: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 5.5 %
Yield: 24 %

Procedure:
To a mixture of THF (300 mL) and LDA (100 mL, 20.1 mmol) at −20° C. was added Bu3SnH (50 mL, 17.4 mmol) dropwise and stirred for 15 min. The reaction mixture was cooled to −78° C. and treated with 2,4-dichloro pyrimidine (20 g, 134 mmol) portionwise. The reaction mixture was stirred at −78° C. for 5 h with constant stirring under argon atmosphere. The cooling bath was removed and the reaction mixture was warmed up to 0° C. within 30 min. The resulting mixture was poured into 10% NH4Cl aqueous solution, and extracted the compound with Et2O. The organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (1% EtOAc: 99% n-Hexane) to obtain 2-chloro-4-tributylstannanyl-pyrimidine 20a (3 g, 5.5% yield) as a pale yellow color syrup and 4-chloro-2-tributylstannanyl-pyrimidine 24a (13 g, 24% yield) as a pale yellow color syrup. Compound 24a: MS (ESI, pos. ion) m/z: 405.3 (M+1).
Reaction SMILES: Cl[C:2]#[C:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]([F:16])([F:15])[F:14].[OH2:17]>C(O)CO>[F:14][C:13]([F:16])([F:15])[O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[O:5][CH2:4][CH2:3][C:2]2=[O:17]
Reactant: O
Reactant: FC(F)(F)Oc1ccccc1OCC#CCl
Solvent: OCCO
Product: O=C1CCOc2c(OC(F)(F)F)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
A solution of the product of Example 66B (12.8 g, 51.2 mmol) in ethylene glycol (200 mL) was heated at reflux for 6 hours, cooled to ambient temperature, stirred for 16 hours at ambient temperature, then heated at reflux for an additional 3 hours. After cooling, the reaction mixture was poured into water (100 mL) and extracted with diethyl ether (250 mL). The mixture was partitioned and the organic portion was concentrated. The resulting residue was purified by silica gel chromatography (gradient elution, 0%-20% EtOAc/hexanes) to obtain the title compound (3.62 g, 28% for three steps). 1H NMR (300 MHz, CDCl3) δ 7.86 (dd, J=8.1, 1.7 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.05-6.98 (m, 1H), 4.66-4.60 (m, 2H), 2.90-2.84 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[C:4]([CH3:19])[N:3]=1.O=P(Cl)(Cl)[Cl:22]>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:22])[C:5]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[C:4]([CH3:19])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(N)nc(O)c1Sc1ccc(CC#N)cc1
Product: Cc1nc(N)nc(Cl)c1Sc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of the product from step (iii) (2.3 g) and POCl3 (25 ml) was heated under reflux for 8 h. The mixture was evaporated under reduced pressure and ice/water added to the residue. The mixture was stirred at rt for 15 min then neutralised with aq. 2M NaOH solution and heated at 40° C. for 2 h then extracted with DCM. The organics were dried, evaporated under reduced pressure and the residue purified by column chromatography (2% MeOH/DCM), to give the subtitle compound as a solid, 530 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:8]=3[S:7][C:6]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][O:37][C:36]1=[O:40]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][O:37][C:36]4=[O:40])[CH2:14][CH2:13]3)[C:9]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:8]=3[S:7][C:6]=2[CH:23]=1
Reactant: O=C1OCCN1CCCl
Reactant: Fc1ccc2c(c1)C(N1CCNCC1)Cc1ccc(Cl)cc1S2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C1OCCN1CCN1CCN(C2Cc3ccc(Cl)cc3Sc3ccc(F)cc32)CC1

Procedure:
25 g. of 1-[3-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]-thiepin-10-yl]-piperazine are heated together with 20 g. of pulverized potassium carbonate, 0.4 g. of potassium iodide and 25.6 g. of N-(β-chloro-ethyl)oxazolidinone under reflux conditions over a period of 25 hours. The reaction mixture is poured onto water and equilibrated with benzene. The organic phase is washed with aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure. One obtains 3-{2-[4-(3-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone which is treated with maleic acid to yield the corresponding maleate which after recrystallization from ethanol and ether melts at 143.5°-146° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][CH:9]=[CH2:10].[CH3:11][CH:12]=[CH2:13].[CH3:14][CH:15]=[CH2:16].[CH3:17][CH:18]=[CH2:19].[CH3:20][CH:21]=[CH2:22].[H-].[Ca+2:24].[H-].[Ca]>>[Ca:24].[CH2:10]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH2:9][CH2:8][CH2:13][CH2:12][CH2:11][CH2:16][CH2:15][CH2:14][CH2:19][CH2:18][CH2:17][CH2:20][CH2:21][CH3:22]
Reactant: [Ca+2]
Reactant: Oc1ccccc1
Reactant: C=CC
Agent: [Ca]
Agent: [H-]
Product: CCCCCCCCCCCCCCCc1ccccc1O
Temperature: 13 °C
Reaction time: 18 h

Procedure:
Branched pentadecylphenol calcium salt was prepared from the alkylation of phenol with a branched chain C14-C18 olefin derived primarily from propylene pentamer. To a 2-liter round bottom flask equipped with a mechanical stirred, Dean Stark trap fitted with a condenser under an atmosphere of dry nitrogen was charged with 705 gm (2.32 moles) of a C15 branched alkylphenol followed by 500 gm of Chevron RLOP 100N oil. This mixture was cooled to approximately 13° C. using an ice bath and then 48.8 gm (1.16 moles) of calcium hydride (98% obtained from Aldrich Chemical Company) was added in approximately 10 gram portions with stirring. The reaction was then heated to 100° C. over 50 minutes and then heated to 200° C. for over 140 minutes and held at 200° C. for approximately 18 hours and then heated to 280° C. over 1 hour and held at 280° C. for 8.5 hours and then cooled to 230° C. and held at 230° C. for approximately 14 hours. The reaction was then cooled to 150° C. and filtered through a dry, hot (150° C.) 600 mL Buchner funnel containing a filter bed of Celite and maintained between 110° C. and 120° C. with the aid of a vacuum to afford a product containing 3.51 wt % calcium.
Reaction SMILES: CC(O)=O.C([N:12]1[CH2:16][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)[C@H:14]([NH:28][C:29](=[O:37])[O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:13]1)C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CCO.[Pd]>[F:27][C:24]([F:25])([F:26])[O:23][C:19]1[CH:18]=[C:17]([C@@H:15]2[CH2:16][NH:12][CH2:13][C@H:14]2[NH:28][C:29](=[O:37])[O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[CH:22]=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)CCOC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1c1cccc(OC(F)(F)F)c1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOC(=O)N[C@@H]1CNC[C@H]1c1cccc(OC(F)(F)F)c1
Yield: 83.2 %

Procedure:
AcOH (2 mL) was added to a solution of 2-(trimethylsilyl)ethyl [trans-benzyl-4-(3-trifluoromethoxyphenyl)pyrrolidin-3-yl]carbamate (2.50 g; 6.03 mmol) in EtOH (150 ml). Pd/C (1.25 g, wet, 10% Pd) was then added, and the reaction mixture was put on a par shaker (60 Psi), and reacted for 2 h. The reaction mixture was filtered, and the filtrate was concentrated to provide the title compound (1.96 g, quantitative yield).
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1.[CH2:12](I)[CH3:13]>C(Cl)Cl>[Cl:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([CH2:10][O:11][CH2:12][CH3:13])[N:9]=1
Reactant: CCI
Reactant: OCc1coc(CCl)n1
Agent: N#N
Solvent: ClCCl
Product: CCOCc1coc(CCl)n1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(chloromethyl)oxazol-4-yl)methanol (500 mg, 3.39 mmol) in CH2Cl2 (2.0 mL) was treated with EtI (0.28 mL, 3.39 mmol) followed by Ag2O (1.18 g, 5.08 mmol) and the resulting mixture (protected from light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as a yellow oil: TLC: rf (7:3 hept-EA)=0.29. LC-MS-conditions 07: tR=0.62 min, [M+H]+=176.26.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]=O.Cl.[CH3:23][NH:24][CH3:25].Cl>C(O)(C)C.C(O)C>[C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH2:13][CH2:23][N:24]([CH3:20])[CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: C=O
Reactant: CC(=O)c1c(-c2ccccc2)oc2ccc(C)cc12
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: Cc1ccc2oc(-c3ccccc3)c(C(=O)CCN(C)C)c2c1

Procedure:
A suspension in 60 milliliters of isopropanol of 21.3 grams of the 2-phenyl-3-acetyl-5-methylbenzofuran that was thus prepared, 3.9 grams of paraformaldehyde, 10.4 grams of dimethylamine hydrochloride, and 8 milliliters of a saturated solution of hydrogen chloride in ethanol was heated under reflux for a period of 8 hours, after which the solvent was evaporated therefrom under vacuum and the remaining residue was treated with 20 milliliters of a 10% aqueous hydrochloric acid solution. The undissolved portion was extracted from the solution in which it was suspended with ethyl ether and the aqueous phase was then separated and made alkaline by the addition thereto of a 5% aqueous solution of sodium hydroxide. The oily base that precipitated was then extracted with ethyl ether, washed with water and dried over anhydrous sodium sulfate. A solution of hydrogen chloride in ethanol was then added to the dried ether extract and the precipitate consisting of the hydrochloride of the compound named in the heading of this example was separated therefrom by suction filtration. The precipitate, after recrystallization from a mixture of ethyl ether and ethanol, had a melting point of 148°-149° C and weighed 22.5 grams.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[C:22]([F:24])([F:23])[F:25]
Reactant: Cc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2(O)CCNCC2)cc1C(F)(F)F

Procedure:
According to Preparation 2: Tert-butyl 4-[4-methyl-3-(trifluoro-methyl)phenyl]-4-hydroxypiperidine-1-carboxylate (5.5 g, 15.3 mmol, methylen chloride (30 ml), trifluoroacetic acid (4.5 ml). Yield: 1.97 g. MS m/z (rel. intensity, 70 eV) 259 (M+, 14), 241 (84), 240 (43), 187 (19), 56 (bp).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([OH:10])=O)=[C:5]([CH3:11])[O:4][N:3]=1.CN(C=O)C.C(Cl)(C(Cl)=O)=O.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([CH:36]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]2)=[C:26]([F:50])[CH:25]=1>ClCCCl.O>[CH3:1][C:2]1[C:6]([CH2:7][C:8]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][CH:33]([CH:36]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:37]([N:39]([CH2:40][CH3:41])[CH2:42][CH3:43])=[O:38])[CH2:32][CH2:31]3)=[C:26]([F:50])[CH:25]=2)=[O:10])=[C:5]([CH3:11])[O:4][N:3]=1
Reactant: CCN(CC)C(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2F)CC1
Reactant: Cc1noc(C)c1CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CCN(CC)C(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)Cc3c(C)noc3C)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A mixture of (3,5-dimethyl-isoxazol-4-yl)-acetic acid (1.0 mmol) and DMF (0.050 mL) in DCE (10 mL) was treated with (COCl)2 (10 mmol), dropwise. The mixture was stirred at rt for 1 h and was concentrated. The residue was diluted with DCE (10 mL) and treated with 2-[1-(4-amino-2-fluoro-phenyl)-piperidin-4-yl]-N,N-diethyl-2-phenyl-acetamide (0.30 mmol) and TEA (2.0 mmol). After 16 h, the mixture was diluted with H2O (10 mL) and extracted. The organic layer was concentrated and the residue was purified by PTLC to provide the title compound (87 mg, 56%). MS (ESI): mass calcd. for C30H37FN4O3, 520.28; m/z found, 521.4 [M+H]+. 1H NMR (CDCl3): 7.40-7.20 (m, 6H), 6.96 (dd, J=8.6, 1.6, 1H), 6.83 (t, J=9.0, 1H), 3.50-3.10 (m, 9H), 2.70-2.60 (m, 1H), 2.52-2.42 (m, 1H), 2.38 (s, 3H), 2.30-2.20 (m, 4H), 2.08-1.98 (m, 1H), 1.50-1.15 (m, 3H), 1.15-1.03 (m, 6H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([NH:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@H:24]3[C@H:34]([CH2:35][CH2:36][C@:19]12[CH3:20])[C@:32]1([CH3:33])[C:27]([CH:28]=[C:29]([C:37]#N)[CH2:30][CH2:31]1)=[CH:26][CH2:25]3)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C(C(C(O)=O)O)[OH:41]>C1(C)C=CC=CC=1>[C:11]([NH:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@H:24]3[C@H:34]([CH2:35][CH2:36][C@:19]12[CH3:20])[C@:32]1([CH3:33])[C:27]([CH:28]=[C:29]([CH:37]=[O:41])[CH2:30][CH2:31]1)=[CH:26][CH2:25]3)=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2 ml of a 1M solution of diisobutyl aluminum hydride in toluene were added at 0° C. to 10 ml of a dry solution of toluene containing 380 mg of N-t-butyl-3-cyanoandrosta-3,5-diene-17β-carboxamide (prepared as described in Preparation 2). The reaction mixture was then stirred at 0° C. for 30 minutes, after which 30 ml of an aqueous solution of 1.5 g of tartaric acid were added to the mixture. The reaction mixture was then stirred at room temperature for 2 hours, and then extracted with methylene chloride three times. The combined organic extracts were washed with water and with a saturated aqueous solution of sodium chloride, in that order. They were then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 50 g of silica gel and using a gradient elution method, with mixtures of acetone and methylene chloride in ratios ranging from 1:99 to 4:96 by volume as the eluent, to give 325 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][OH:9])[CH2:3]1.CCN(C(C)C)C(C)C.[Cl:19][C:20](OC1C=CC([N+]([O-])=O)=CC=1)=[O:21].Cl.Cl.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1.Cl.CCOCC>C(Cl)Cl>[ClH:19].[ClH:34].[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([N:41]2[CH2:46][CH2:45][N:44]([C:20]([O:9][CH2:8][CH:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[O:21])[CH2:43][CH2:42]2)=[CH:39][CH:40]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CN1CCOC(CO)C1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCOC(COC(=O)N2CCN(c3ccc(Cl)cc3)CC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 119.5 %

Procedure:
(4-Methyl-morpholin-2-yl)-methanol (1.05 g, 8.0 mmol) and DIPEA (2.79 ml, 16.0 mmol were dissolved in DCM (80 mL) and the reaction mixture was cooled to 0° C. and p-nitrophenyl chloroformate (3.23 g, 16.0 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was divided into 4 batches and concentrated in vacuo. One portion was dissolved in DMF (20 mL) and 1-(4-chlorophenyl)-piperazine dihydrochloride (539 mg, 2 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo and the residue was dissolved in DCM (30 mL). The organic layer was washed with 1.0M Na2CO3 solution (3×30 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, 20 mL/min, gradient 0% to 5% MeOH in DCM, residue dry loaded). The solvents were removed in vacuo and the residue was dissolved in DCM (50 mL), filtered and 2M HCl in Et2O (2 mL, 4 mmol) added. The solvents were removed in vacuo and the resulting solid was dried in a vacuum oven overnight to give the (4-methylmorpholin-2-yl)methyl 4-(4-chlorophenyl)piperazine-1-carboxylate dihydrochloride salt (0.510 g, 60%) as a white solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].CO.O>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][OH:20]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1CO
Reaction time: 1 h
Yield: 82.8 %

Procedure:
Sodium borohydride (325 mg) was added to a solution of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (5.00 g) in tetrahydrofuran (30 ml)-methanol (30 ml) at 0° C. After stirring for 1 hour, the reaction mixture was poured into water to give crystals. Recrystallization from acetone-ethyl acetate gave 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (4.17 g, yield 83%) as colorless prisms. m.p. 155-156° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:23]=1[NH2:24]>>[NH2:24][C:23]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:28][C:22]=1[F:21]
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)c(F)c3)ccn2c1=O
Yield: 76.7 %

Procedure:
Methyl 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (200 mg, 0.68 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (195 mg, 0.82 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (191 mg, 76%). ESI-MS m/z: 367 (M+H)+.