Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[C:11](=O)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[ClH:16].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:16].[ClH:16].[CH3:14][N:12]1[CH2:11][CH2:10][O:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:13]1
Reactant: CN1CC(c2ccc(N)cc2)OCC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1CCOC(c2ccc(N)cc2)C1

Procedure:
6-(4-Aminophenyl)-N-methylmorpholin-3-one was treated in the same manner as the reduction shown in Reference Example 2 and further treated with 4 M hydrogen chloride/ethyl acetate solution in ethyl acetate to obtain 4-(4-methylmorpholin-2-yl)phenylamine dihydrochloride. F: 193.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:25][CH:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>C(#N)C>[CH3:25][CH:26]1[N:31]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:30][CH2:29][NH:28][C:27]1=[O:32]
Reactant: CC1NCCNC1=O
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1C(=O)NCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (200 mg, 0.762 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (3 mL) was added triethylamine (0.318 mL, 2.285 mmol) and 3-methyl-2-piperazinone (87 mg, 0.762 mmol, Sigma-Aldrich). The reaction mixture was heated to 120° C. for 20 min in a microwave reactor. The reaction mixture was concentrated in vacuo. The crude product was purified by silica chromatography (Biotage SP4), eluting with an increasing gradient of (2N NH3 in MeOH) in DCM. The relevant fractions were combined and concentrate to give the title compound as white crystals (151 mg)
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]=[O:27].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Mg]Br>>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH:26]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][CH3:28])[OH:27]
Reactant: COc1ccccc1[Mg]Br
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C=O)cc(OC)c21
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C(O)c3ccccc3OC)cc(OC)c21

Procedure:
The title compound is prepared from 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde (see example 41, step c) and 2-methoxyphenyl-magnesium bromide as described in example 35.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13].C1(C)C=CC=CC=1>C1COCC1>[Cl:8][CH2:9][CH2:10][NH:11][C:12]([NH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)=[O:13]
Reactant: NC1CCOCC1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCCl)NC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A RB flask was charged with 4-aminotetrahydropyran (9.77 g, 97 mmol) in THF (480 mL) and was cooled in an ice bath. To this stirring solution was added 2-chloroethyl isocyanate (11.19 g, 106 mmol) drop-wise and the reaction was brought to RT and stirred at RT overnight. The reaction mixture was concentrated to dryness and the crude product was washed successively with saturated NH4Cl (60 mL) and saturated NaHCO3 (60 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness to afford a white solid. Toluene (20 mL) was added and the residue was concentrated to dryness. The process was repeated a second time (to remove any moisture) to afford 1-(2-chloroethyl)-3-(tetrahydro-2H-pyran-4-yl)urea as a white solid. The product was utilized in the next reaction without purification. 1H NMR (CDCl3): δ 5.34-4.94 (bs, 1 H), 4.93-4.56 (bs, 1 H), 3.94 (dt, J=11.9, 3.2 Hz, 2 H), 3.84-3.71 (m, 1 H), 3.64-3.59 (m, 2 H), 3.49-3.47 (m, 2 H), 1.95-1.83 (m, 2 H), 1.50-1.34 (m, 2 H); MS (ESI) m/z: 207.1 (M+H+).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[CH3:9][S:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:21][C:22]1([CH3:30])[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])[O:23]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>CCO>[CH3:9][S:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][CH:26]2[C:27](=[O:28])[O:29][C:22]([CH3:30])([CH3:21])[O:23][C:24]2=[O:25])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2ccc(S(C)(=O)=O)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Proline (0.126 g, 1.086 mmol) was added to a solution of 4-(methylsulfonyl)benzaldehyde (1.00 g, 5.428 mmol) and Meldrum's acid (1.38 g, 5.428 mmol) in EtOH (10 mL). The mixture was stirred at room temperature for 1 hour and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (1.38 g, 5.428 mmol) was added. Stirring was continued for 3 hours and EtOH removed under reduced pressure. The residue was diluted with i-PrOH and filtered to provide the title compound as a white solid.
Reaction SMILES: Br.Br[C:3]1[CH:14]=[N:13][C:6]2[NH:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]=2[CH:4]=1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17]>>[C:20]([O:19][C:15](=[O:18])[CH:16]=[CH:17][C:3]1[CH:14]=[N:13][C:6]2[NH:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]=2[CH:4]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CN1CCNc2ncc(Br)cc2C1
Agent: Br
Product: CN1CCNc2ncc(C=CC(=O)OC(C)(C)C)cc2C1
Yield: 55 %

Procedure:
7-bromo-4-methyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine hydrobromide (2.0 g, 6.2 mmol) was subjected to Heck coupling with tert-butyl acrylate to give crude product. Purification by silica gel chromatography (CH2Cl2:MeOH:NH4OH/95:4.95:0.05) gave the title compound as a brown oil (970 mg, 55%). 1H NMR (300 MHz, CDCl3) 8.11 (d, J=2.1 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.47 (d, J=16.0 Hz, 1H) 6.22 (d, J=16.0 Hz, 1H), 3.64 (s, 2H), 3.27-3.31 (m, 2H), 2.83-2.88 (m, 2H), 2.44 (s, 3H), 1.52 (s, 9H); MS (ESI) m/e 290 (C16H23N3O2+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]=1[CH2:15][CH2:16][CH3:17].[F:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]([CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[C:25]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[N:24]=2)=[O:26])[C:3]=1[CH2:15][CH2:16][CH3:17]
Reactant: CCCc1c(Cl)ncnc1CNCCC(C)C
Reactant: O=C(O)c1cccc(F)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCc1c(Cl)ncnc1CN(CCC(C)C)C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (6-chloro-5-propyl-pyrimidin-4-ylmethyl)-(3-methyl-butyl)-amine (0.715 g, 2.8 mmol) and 6-fluoro-pyridine-2-carboxylic acid (0.47 g, 3.34 mmol) in DCM (10 ml) is added EDCI (0.61 g) and DMAP (0.153 g). The mixture is stirred at room temperature overnight. DCM (10 ml) is added to dilute the mixture. The mixture is washed with water (5 mL), dried (Na2SO4) and solvent evaporated. Preparative TLC purification of the residue (2:1 of hexane: ethyl acetate) provides the title product. H1 NMR δ (CDCl3) 8.69 and 8.75 (s, 1H), 7.71-7.97 (m,1H), 7.58-60 (m, 1H), 4.79 and 5.07 (s, 2H), 3.50-3.64 (m, 21), 2.59-2.87 (m, 2H), 1.45-1.72 (m,5H), 0.92-1.09 (m, 4H), 0.81 (d, 6H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[CH3:10])=[N+]=[N-].C(N1C(C)=C(C(OCC)=O)C=N1)(C)(C)C>>[C:11]([N:8]1[C:9]([CH3:10])=[C:5]([CH2:4][NH2:1])[CH:6]=[N:7]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1c(CN=[N+]=[N-])cnn1C(C)(C)C
Agent: CCOC(=O)c1cnn(C(C)(C)C)c1C
Product: Cc1c(CN)cnn1C(C)(C)C

Procedure:
4-(azidomethyl)-1-tert-butyl-5-methyl-1H-pyrazole was generated from ethyl 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate according to a procedure similar to that described for the 2,6 dimethyl 3,5-pyridyl derivative, then reduced to the crude primary amine, following procedures described herein.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[N:14][O:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].[BH4-].[Na+]>C(OCC)C.Cl>[CH3:16][O:15][N:14]=[C:4]([CH2:3][OH:2])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13]
Reactant: CON=C(Cc1ccc(Cl)cc1Cl)C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: CON=C(CO)Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
To a stirred solution of 3-(2,4-dichloro-phenyl)-2-(methoxyimino)-propionic acid methyl ester (isomers E/Z) (0.25 g; 0.90 mmol) in diethyl ether (4.0 ml) under argon at 0° C., was added portionwise sodium borohydride (0.14 g; 3.6 mmol). The mixture was stirred for 2 hours at 0° C. and allowed to warm up at 20° C. for 16 h. The mixture was poured carefully in 2 N hydrochloric acid (6 ml) and extracted with ethyl acetate (3×5 ml). Combined organics were dried over sodium sulfate and evaporated under reduced pressure. The crude oil obtained was subject to flash chromatography (eluant: c-hexane/ethyl acetate 7:3) to afford 65 mg (30% of theory) of 1-(2,4-dichloro-phenyl)-3-hydroxy-propan-2-one O-methyl-oxime (mixture of E/Z-isomers) as a clear sticky oil.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C1CSC(=S)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=S)SC1=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
A solution containing 2.1 g (0.0157 mol) of rhodanine, 2.76 g (0.0151 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.15 ml of piperidine in 10 ml of acetic acid was heated for 7-8 h at 100° C. After cooling the crystals were filtered and washed with 2-propanol. Yield 4.0 g (89%), mp >350° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH:41]1[CH2:44][CH2:43][CH2:42]1.C(=O)(O)[O-].[Na+]>ClCCl>[N:41]1([CH2:19][C:18]([CH3:21])([CH3:22])[O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[N:7]=[C:2]([Cl:1])[CH:3]=3)=[N:16][CH:15]=2)[CH2:44][CH2:43][CH2:42]1
Reactant: C1CNC1
Reactant: Cn1nc(Cl)cc(Nc2ccc(OC(C)(C)C=O)cn2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1nc(Cl)cc(Nc2ccc(OC(C)(C)CN3CCC3)cn2)c1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
A pressure flask containing 2-[6-(6-chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-pyridin-3-yloxy]-2-methyl-propionaldehyde (188 mg, 0.582 mmol) was taken up in dichloromethane (2.5 ml). Sodium triacetoxyborohydride (309 mg, 1.46 mmol) and acetic acid (0.1 ml, 1.75 mmol) were added and the flask was next cooled in an ice bath under nitrogen atmosphere. Azetidine (0.24 ml, 3.49 mmol) was added and the flask was sealed. The flask was placed in an oil bath heated to 50° C. and stirred for 16 hours. The mixture was cooled to ambient and taken up in dichloromethane (50 ml) and a saturated solution of aqueous sodium bicarbonate (50 ml). The material was transferred to a separatory funnel and shaken. The organic phase was collected and washed with a solution of 50% diluted brine (50 ml). The dichloromethane phase was collected and the aqueous phases were back extracted with methylene chloride (2×40 ml). The combined organic phase was dried (magnesium sulfate), filtered and concentrated in vacuo. The crude residue was loaded onto two preparatory TLC plates and eluted with 8% methanol/dichloromethane. The product band was collected to provide the desired product as a light white-brown powder (139 mg). (M+H)+=364 m/e.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C:6]2=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:33][CH2:2][C:3]1[CH:4]=[C:5]2[C:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:23]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])[C:6]2=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CO)cc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CBr)cc12
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-(hydroxymethyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (441 mg, 0.98 mmol) was dissolved in methylene chloride (10 mL). Thereafter, carbon tetrabromide (359 mg, 1.08 mmol) and triphenylphosphine (310 mg, 1.18 mmol) were added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at the same temperature as above for 2.5 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-(bromomethyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (390 mg, 77%) in the form of a colorless amorphous product.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].C([Li])CCC.CCCCCC.[CH2:16]([S:24]C#N)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:16]([S:24][C:3]#[C:2][CH2:1][OH:4])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C#CCO
Reactant: CCCCCCCCSC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCCCCSC#CCO
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-propynol (0.65 g/0.68 ml, 11.7 mmol) in 25 ml of tetrahydrofuran (THF), cooled to -60°, is slowly added butyllithium in hexane (14.6 ml, 23.3 mmol) over 5 min. About 5 ml of HMPA is added and the mixture is warmed to -20° and stirred for 5 min. The mixture is then cooled again to -60° and octylthiocyanate (2.0 g, 11.7 mmol) in 3 ml of THF is added over 1 min. The mixture is allowed to warm to RT over 1 hour and is stirred at RT for an additional hour. It is then cooled to -10° and quenched with water. The reaction mixture is diluted with ether, washed with water and brine and dried to give 3-octylthio-2-propynol.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[C:10]2/[CH:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][CH2:13][CH2:14]/2)=[N:7][CH:8]=1.[OH-].[Na+].[H][H]>CO.[Pd]>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[N:7][CH:8]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1CCC/C1=C\c1ccc(C(F)(F)F)cn1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCCC1Cc1ccc(C(F)(F)F)cn1

Procedure:
To a solution of tert-butyl N-[(2E)-2-{[5-(trifluoromethyl)pyridin-2-yl]methylidene}cyclopentyl]carbamate (1.5 g, 4.38 mmol) in methanol (5 ml) was added palladium on carbon (10% wt, 50% wet, 300 mg) and 2M NaOH (5 ml). The resulting reaction was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound. The resulting residue was purified by column chromatography (silica, 0-70% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl.Cl[CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][CH:53]([C:56]([O:58]C)=[O:57])[CH2:52][CH2:51]1>>[C:32]([C:31]1[CH:30]=[CH:29][C:28]([C:15]2[C:16]([CH3:27])([CH3:26])[C@H:17]3[C@:12]([CH3:37])([CH2:13][CH:14]=2)[C@@H:11]2[C@:20]([CH3:25])([C@@:21]4([CH3:24])[C@H:8]([CH2:9][CH2:10]2)[C@H:7]2[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]2([NH:5][CH2:48][CH2:49][N:50]2[CH2:51][CH2:52][CH:53]([C:56]([OH:58])=[O:57])[CH2:54][CH2:55]2)[CH2:23][CH2:22]4)[CH2:19][CH2:18]3)=[CH:36][CH:35]=1)([OH:34])=[O:33]
Reactant: COC(=O)C1CCN(CCCl)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(C(=O)O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using methyl 1-(2-chloroethyl)piperidine-4-carboxylate hydrochloride (prepared as described below) as the alkylating reagent in Step 1. The product was isolated as a white solid (8 mg, 83%). LCMS: m/e 685.6 (M+H)+, 2.33 min (method 10). 1H NMR (400 MHz, METHANOL-d4) δ 7.94 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 5.31 (d, J=4.5 Hz, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 3.48-3.36 (m, 5H), 3.12-2.88 (m, 2H), 2.79-2.69 (m 1H), 2.68-2.60 (m, 1H), 2.24-2.11 (m, 4H), 2.11-2.00 (m, 4H), 1.97-1.81 (m, 3H), 1.77 (s, 3H), 1.81-1.71 (m, 2H), 1.70-1.46 (m, 10H), 1.45-1.27 (m, 4H), 1.21 (s, 3H), 1.12 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: C(O)=O.[Cl:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=2)[O:13][CH2:14][CH2:15][CH:16]2[CH2:19][NH:18][CH2:17]2)=[CH:7][CH:6]=1.CC#N.C1([O:34][C:35](=O)[NH:36][C:37]2[N:41]3[N:42]=[CH:43][CH:44]=[CH:45][C:40]3=[N:39][CH:38]=2)C=CC=CC=1>CCOC(C)=O>[N:39]1[CH:38]=[C:37]([NH:36][C:35]([N:18]2[CH2:17][CH:16]([CH2:15][CH2:14][O:13][C:12]3[CH:20]=[CH:21][CH:22]=[C:10]([O:9][C:8]4[CH:7]=[CH:6][C:5]([Cl:4])=[CH:24][CH:23]=4)[CH:11]=3)[CH2:19]2)=[O:34])[N:41]2[C:40]=1[CH:45]=[CH:44][CH:43]=[N:42]2
Reactant: Clc1ccc(Oc2cccc(OCCC3CNC3)c2)cc1
Reactant: O=C(Nc1cnc2cccnn12)Oc1ccccc1
Solvent: CC#N
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=C(Nc1cnc2cccnn12)N1CC(CCOc2cccc(Oc3ccc(Cl)cc3)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a solution consisting of 3-{2-[3-(4-chloro-phenoxy)-phenoxy]-ethyl}-azetidine formic acid salt (0.040 g, 0.13 mmol), TEA (0.018 mL, 0.13 mmol) and CH3CN (1.0 mL) was added imidazo[1,2-b]pyridazin-3-yl-carbamic acid phenyl ester (0.034 g, 0.13 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with EtOAc (40 mL) and washed with saturated aq. NaHCO3 (40 mL). The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (0.035 g, 57%). MS (ESI+): calcd. for C24H22ClN5O3, 463.14. m/z found, 464.1 (M+H)+. 1H NMR (d6-DMSO): 8.55 (s, 1H), 8.52 (d, J=4.4 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.64 (s, 1H), 7.43 (d, J=7.3 Hz, 2H), 7.29 (t, J=8.2 Hz, 1H), 7.19-7.15 (m, 1H), 7.04 (d, J=7.4 Hz, 2H), 6.75 (d, J=8.3 Hz, 1H), 6.61-6.55 (m, 2H), 4.09 (t, J=8.1 Hz, 2H), 3.99 (t, J=6.1 Hz, 2H), 3.77-3.66 (m, 2H), 2.83-2.69 (m, 1H), 2.10-2.01 (m, 2H).
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[CH:9]=[C:10]([CH:14]2[O:18][CH2:17][CH2:16][O:15]2)[CH:11]=[CH:12][CH:13]=1.CN(C)C=O.C(N(CC)CC)C>[Cu](I)I.O>[O:15]1[CH2:16][CH2:17][O:18][CH:14]1[C:10]1[CH:9]=[C:8]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc(C2OCCO2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
A mixture of ethynyl(trimethyl)silane (36 g, 367 mmol), 2-(3-bromophenyl)-1,3-dioxolane (78 g, 342 mmol), N,N-dimethylformamide (400 mL), and triethylamine (1.1 81 mL, mmol) was bubbled with anhydrous argon for 5 minutes, treated with copper iodide (0.94 g, 4.96 mmol) and dichlorobis(triphenylphosphine) palladium(II) (7.7 g, 11.01 mmol), stirred at 60° C. for 3 hours, cooled to room temperature, poured into water and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo to give {[3-(1,3-dioxolan-2-yl)phenyl]ethynyl}-(trimethyl)silane as a yellow oil (63 g, 256 mmol). The yellow oil was dissolved in MeOH (600 mL) and CH2Cl2 (600 mL), treated with cesium carbonate (91.8 g, 281.6 mmol), stirred at room temperature for 10 h, poured into water and extracted with ethyl ether. The ether extracts were combined, dried over MgSO4, concentrated in vacuo and distilled to give 2-(3-ethynylphenyl)-1,3-dioxolane as a yellow oil (42 g, 71% yield), MS m/e M+ 174; 1H NMR (400 MHz, DMSO-d6) 3.9-4.05 (m, 4H), 4.15 (s, 1H), 5.7 (s, 1H), 7.35-7.45 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[N:24][C:23]([CH:26]2[CH2:28][CH2:27]2)=[CH:22][N:21]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[N:24][C:23]([CH:26]3[CH2:28][CH2:27]3)=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Reactant: Brc1cnc(C2CC2)cn1
Product: Cc1cc(-c2cnc(C3CC3)cn2)cc(C)c1Cl

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-5-cyclopropyl-pyrazine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 11): tR=1.28 min; Mass spectrum (ESI+): m/z=259/261 (Cl) [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[O:25])=[CH:22][C:21]=4[O:35][CH3:36])=[N:18][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:51]1[CH2:56][CH2:55][C:54](=O)[CH2:53][CH2:52]1.C(O)(=O)C>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]5[CH2:32][CH2:31][N:30]([CH:54]6[CH2:55][CH2:56][O:51][CH2:52][CH2:53]6)[CH2:29][CH2:28]5)=[O:25])=[CH:22][C:21]=4[O:35][CH3:36])=[N:18][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCOCC1
Reactant: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C3CCOCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Yield: 24.7 %

Procedure:
4-(9-Cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide (Intermediate 12) (35 mg, 0.07 mmol, 1 eq) and sodium triacetoxyborohydride (18 mg, 0.084 mmol, 1.2 eq) in DCM (0.5 mL) were reacted with tetrahydropyran-4-one (6.5 μL, 0.07 mmol, 1 eq) at rt for 2 days. Further and sodium triacetoxyborohydride (18 mg, 1.2 eq), tetrahydropyran-4-one (6.5 μL, 1 eq) were added and acetic acid (4 μL, 1 eq). After two days the RM was diluted with DCM, washed with water and the organic layer concentrated in vacuo. The resulting residue was purified by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-[1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]-benzamide (10 mg, 25%).