Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3([OH:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3([OH:16])[CH2:14][CH2:13][CH:12]([N:19]4[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=5)=[O:25])[CH2:20]4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(O)(c2nc3ccc(Br)cc3s2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3nc4ccc(Br)cc4s3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-(6-Bromo-benzothiazol-2-yl)-4-hydroxy-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:7]=1.CO.[NH4+].[Cl-]>[Fe].O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ccncc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(F)cc1Nc1ccncc1
Temperature: 80 °C
Yield: 65.7 %

Procedure:
To a mixture of (5-fluoro-2-nitro-phenyl)-pyridin-4-yl-amine (375 mg, 1.61 mmol) in a 3:1 mixture of MeOH:water (40 mL) were added NH4Cl (516 mg, 9.65 mmol) and iron powder (359 mg, 6.43 mmol) and the reaction mixture heated at 80° C. for 2 h. After cooling to RT, the solid was filtered through a pad of Celite® and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was dried and concentrated in vacuo to afford the title compound as a dark beige solid (215 mg, 66%). LCMS (Method C): RT 1.32 min [M+H]+ 204.09
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([OH:26])=O.Cl.[F:28][C:29]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([N:32]1[CH2:33][CH2:34][C:29]([F:28])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:30][CH2:31]1)=[O:26]
Reactant: FC1(c2ccccc2)CCNCC1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 71.2 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2-chloro-5-methylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (100 mg, 0.27 mmol) obtained in Example 66, step 2 and 4-fluoro-4-phenylpiperidine hydrochloride (86 mg, 0.40 mmol), the title compound (103 mg, 72%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH:16]=[C:17](Br)Br)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.CCCCCC.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]#[CH:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(C=C(Br)Br)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CC1CCN(Cc2cccnc2OC)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2.9 g of 1-[(2-methoxy-3-piridyl)methyl]-4-(2,2-dibromovinyl)piperidine was dissolved in 25 ml of tetrahydrofuran, and 12.3 ml of a 1.50 M n-butyllithium hexane solution was added dropwise at −78° C. After completing the dropwise addition, the mixture was further stirred at −78° C. for one hour. An aqueous saturated ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then the dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound as a yellow oil (quantitatively).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[C:17]([O:21][C:22](=[O:34])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([NH2:32])[C:26]=1[Cl:33])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:21][C:22](=[O:34])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([N:32]=[C:1]=[S:2])[C:26]=1[Cl:33])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N)c1Cl
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (0.42 g, 1.8 mmol) is added to a mixture of (3-amino-2,4-dichloro-benzyl)-carbamic acid tert-butyl ester (0.50 g, 1.7 mmol) and dioxane (25 mL) and stirred at rt for 2 h and at reflux for 2 d. The mixture is concentrated, diluted with DCM and filtered over silica gel. The filtrate is concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([O:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])(=[O:25])[CH3:24]
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCCNC(=O)OCc1ccccc1
Yield: 111 %

Procedure:
In 200 ml of methylene chloride was dissolved 21 g of the 3-(benzyloxycarbonylamino)propanol, and 11 g of triethylamine was added thereto, after which 8.6 g of acetyl chloride was added thereto dropwise at -10° C. to -5° C. The resulting mixture was subjected to reaction at the same temperature for 1 hour. Subsequently, at room temperature, the reaction mixture was washed successively with 50 ml of diluted hydrochloric acid, 50 ml of a saturated aqueous sodium hydrogencarbonate solution and 50 ml of water, and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 28 g of oily 1-acetoxy-3-(benzyloxycarbonylamino)propane.
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C1C=C[C:36]2N(O)N=[N:39][C:37]=2[CH:38]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.C1(N)CC1>CN(C=O)C>[CH:37]1([NH:39][C:6]([CH:4]2[CH2:5][C:2]([F:1])([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH2:19][C:18]([C:24]5[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=5)([C:20]([F:21])([F:22])[F:23])[O:17][N:16]=4)=[CH:13][CH:14]=3)[CH2:3]2)=[O:8])[CH2:38][CH2:36]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 6, 0.080 g, 0.156 mmol) in DMF (2 mL) was added HOBt (0.022 g, 0.156 mmol), DIPEA (0.040 g, 0.302 mmol) followed by addition of EDCl.HCl (0.045 g, 0.256 mmol) and cyclopropyl amine (0.009 g, 0.156 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (2×10 mL). Combined organic layer was washed with brine (20 mL), lithium chloride solution (20 mL), water (20 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1% methanol in DCM to afford thick yellow oil, which was re-purified by DCM in pentane (1:9) to afford white solid (0.035 g, 41%. 1H-NMR (400 MHz, CDCl3) δ: 0.48-0.52 (m, 2H), 0.76-0.81 (m, 2H), 2.69-2.77 (m, 2H), 2.83-2.93 (m, 3H), 3.15-3.23 (m, 1H), 3.67 (d, 1H, J=17.2 Hz), 4.07 (d, 1H, J=17.2 Hz), 5.58 (bs, 1H), 7.56-7.58 (m, 2H), 7.64-7.66 (m, 4H). LC-MS (m/z): [M−H] 546.90.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:19][C:20]([C:22]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[C:2]([C@@H:3]([NH:19][C:20]([C:22]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(N)=O)CCOCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(C#N)cc3)cc2)CCOCC1
Temperature: 68 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To a solution of (S)-tert-butyl 4-(1-amino-3-(4′-cyanobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (produced in step (ii), 35 g) in DMF (2.5 rel. vol.) at room temperature was added diisopropylethylamine (4 mol. eq.) and T3P in DMF (50% wt/wt in DMF, 3 mol. eq.) under nitrogen. The resulting mixture was heated to 68° C. for 2 h. The reaction mixture was cooled to room temperature and quenched by dropwise addition of water (3 rel. vol.). The reaction mixture was stirred for 30 min and 2-methyltetrahydrofuran (15 rel. vol.) was added. The organic layer was washed with water (2×5 rel. vol.) followed is by saturated aqueous sodium hydrogen carbonate solution. The separated organic layer was concentrated to 10 rel. vol. under reduced pressure and then heated to 55° C. after which n-heptane (5 rel. vol.) was slowly added over a period of 15 min. The mixture was stirred for 30 min at 55° C. and then filtered, washed with n-heptane (2 rel. vol.) and dried at 50° C. to afford the sub-titled compound (26.2 g).
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:27][CH3:26])[C:11]([C@@H:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])=[CH:10]2
Reactant: CSc1ccccc1B(O)O
Reactant: C[C@@H](c1cc2cccc(F)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccccc1-c1nc2c(F)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 83.5 %

Procedure:
(S)-2-(1-(2-Chloro-8-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione (14.0 g, 39.5 mmol), 2-(methylthio)phenylboronic acid (9.95 g, 59.2 mmol), and potassium carbonate (16.4 g, 118 mmol) were combined in 300 mL of anhydrous DMF under an atmosphere of N2. The solution was sparged with N2 for ˜5 min before adding PdCl2(dppf)CH2Cl2 (3.22 g, 3.95 mmol). The solution was heated at 100° C. for 3 h, and then cooled to 50° C. The solution was concentrated under vacuum to give a brownish residue, which was diluted with EtOAc (600 mL). The organic layers were then washed with H2O (3×80 mL), followed by brine (1×100 mL). The combined aq. layers were extracted with DCM (3×200 mL). The combined organic layers were dried over MgSO4 and then concentrated under vacuum. The residue obtained was purified by silica gel flash chromatography eluting with a gradient of 20% hexane to 40% EtOAc/hexane. The fractions containing the pure product were combined and concentrated under vacuum to give 2-((1S)-1-(8-fluoro-2-(2-(methylthio)phenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (14.6 g, 33.0 mmol, 84% yield) as a light yellow foam. The proton NMR reflects a 53/47 ratio of atropisomers at 25° C. 1H NMR (500 MHz, CDCl3) δ ppm 8.71 (br s, 0.53H), 8.65 (br s, 0.47H), 7.79 (m, 1H), 7.66 (s, 4H), 7.55 (m, 1H), 7.45-7.27 (series of m, 3.6H), 6.87 (m, 1.4H), 5.70 (q J=6.4 Hz, 0.47H), 5.63 (q, J=6.8 Hz, 0.53H), 2.47 (br s, 1.4H), 1.91 (m, 3H), 1.52 (br s, 1.6H). Mass Spectrum (ESI) m/e=443.2 (M+1).
Reaction SMILES: I[CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[N:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=1>>[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:3]1[CH2:2][N:12]1[CH2:13][CH:14]=[C:15]([C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:17]1
Reactant: c1ccc2[nH]c(-c3ccncc3)cc2c1
Reactant: ICC1Cc2ccccc2C1
Product: C1=C(c2cc3ccccc3[nH]2)CCN(CC2Cc3ccccc3C2)C1

Procedure:
From 22c and 27a. 1H NMR (CDCl3) d 2.50-2.55 (m, 2H), 2.65 (broad s, 2H), 2.70-2.85 (m, 5H), 3.00-3.15 (m, 2H), 3.25 (d, 2H), 6.05 (broad s, 1H), 6.45 (s, 1H), 7.05 (t, 1H), 7.10-7.25 (m, 5H), 7.30 (d, 1H), 7.55 (d, 1H), 8.10 (broad s, 1H). MS m/z (%): 329 (MH+, 5%), 160 (4%), 131 (4%), 91 (6%), 44 (100%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([NH:29][CH:30]3[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]3)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(NC3CCC(O)CC3)nc21
Yield: 89.2 %

Procedure:
3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-(4-hydroxy-cyclohexylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 5 using 0.5 g (1.21 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.42 g (3.64 mmol) of trans-4-aminocyclohexanol. The crude product was purified using medium-pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.50 g (89%) of the title compound: mp 198° C.–202° C. MS (APCI) (m+1)/z 464.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[C:28]1([C@@H:34]2[CH2:38][O:37][C:36](=[O:39])[NH:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:35]3[C@H:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:38][O:37][C:36]3=[O:39])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4c4ccccc4)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 15.3 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 9 and (R)-(−)-4-phenyloxazolidin-2-one (326 mg), the title compound (163 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:4]([Cl:27])[CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)Cl>[Cl:27][C:4]1[CH:3]=[C:2]([NH:1][C:36]([O:38][CH3:39])=[O:37])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)COc1ccc(C(F)(F)F)cc1-c1ccc(N)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccc(-c2cc(C(F)(F)F)ccc2OCC(=O)OC(C)(C)C)c(Cl)c1
Reaction time: 20 h

Procedure:
The product from step (iii) (0.07 g) was dissolved in DCM (5 ml), triethylamine (0.024 ml) added, followed by methyl chloroformate (0.013 ml) and stirred for 20 h. Further triethylamine (0.024 ml) and methyl chloroformate (0.013 ml) were added three times over to achieve complete reaction. The solvent was removed by evaporation to give the crude product which was carried forward to step (v) without characterisation.
Reaction SMILES: [SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8])=[O:4].[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].Cl>[OH-].[Na+]>[C:14]([S:8][CH2:7][C@@H:6]([C:9]([OH:11])=[O:10])[NH:5][C:3](=[O:4])[C:2]([S:1][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(S)C(=O)N[C@@H](CS)C(=O)O
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)C(=O)SC[C@H](NC(=O)C(C)(C)SC(=O)C(C)(C)C)C(=O)O
Yield: 16.3 %

Procedure:
N-(2-Mercapto-2-methylpropanoyl)-L-cysteine (11.2 g, 0.05 mol) is dissolved in N sodium hydroxide (50 ml) and pivaloyl chloride (17.0 g, 0.13 mol) and aqueous N sodium hydroxide (150 ml) are added dropwise at 0° C. with stirring under a nitrogen atmosphere. After the addition, the mixture is stirred for 1 hour at room temperature and acidified with 6 N hydrochloric acid. The produced oil is extracted with ethyl acetate and the organic layer is washed with water, dried and concentrated to dryness under reduced pressure to yield 3.2 g (16.4%) of S-pivaloyl-N-(S-pivaloyl-2-mercapto-2-methylpropanoyl)-L-cysteine.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH:3]1[CH2:6][N:5]([C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)[C:20]([CH3:33])=[CH:19][N:18]=3)=[C:9]([O:34][CH3:35])[CH:8]=2)[CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:36][N:2]([CH3:1])[CH:3]1[CH2:4][N:5]([C:7]2[CH:8]=[C:9]([O:34][CH3:35])[C:10]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH3:32])[CH:24]=4)[C:20]([CH3:33])=[CH:19][N:18]=3)=[CH:11][C:12]=2[NH2:13])[CH2:6]1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Yield: 68.6 %

Procedure:
A mixture of N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 115, 210 mg, 0.43 mmol), iron (144 mg, 2.58 mmol) and NH4Cl (16.13 mg, 0.30 mmol) in ethanol (6 mL) and water (2 mL) were heated at reflux for 2 h. The crude mixture was purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave a brown foam after concentration of appropriate fractions in vacuo. Further purification by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia provided material that was concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-4% CH3OH in CH2Cl2 gave the title compound (135 mg, 69%) as a brown foam; 1H NMR: 2.11 (6H, s), 2.35 (3H, s), 3.04 (1H, p), 3.44 (2H, t), 3.89 (3H, s), 3.92 (2H, s), 3.9-3.97 (2H, m), 6.28 (1H, s), 7.12 (1H, dd), 7.2-7.26 (1H, m), 7.28 (1H, s), 7.48 (1H, d), 7.55 (1H, s), 8.00 (1H, s), 8.15 (1H, s), 8.43 (1H, d); m/z: ES+ MH+ 458.31.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][N:31]=1)[C:26](O)=[O:27]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][N:31]=[C:23]([N:22]([CH3:21])[CH3:32])[CH:24]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: CN(C)c1cc(C(=O)O)ccn1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: CN(C)c1cc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)ccn1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-2-dimethylamino-iso-nicotinamide was prepared starting from intermediate D and 2-dimethylamino-isonicotinic acid. MS calcd. for C24H22ClN4O2 [(M+H)+] 433.1, obsd. 432.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[C:11](=[CH:20]N(C)C)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH:25]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)[C:26]([NH2:28])=[NH:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[N:28]=[C:26]([NH:25][CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)[N:27]=[CH:20][C:11]=3[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C=C1CC(c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=N)N)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc3c(n2)-c2ccccc2C(c2ccc(Cl)c(Cl)c2)C3)CC1

Procedure:
This was prepared from 4-(3,4-dichlorophenyl)-2-((dimethylamino)methylene)-3,4-dihydronaphthalen-1(2H)-one and tert-butyl 4-guanidinopiperidine-1-carboxylate hydrochloride salt under the condition described in the general procedure 1 to afford tert-butyl 4-(6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)piperidine-1-carboxylate (0.68 g) as a light yellow solid. M.p.=94-96° C. 1H NMR 400 MHz (DMSO-d6) δ 8.27-8.25 (m, 1 H), 8.13 (s, 1 H), 7.52 (d, J=8.4 Hz, 1 H), 7.47-7.40 (m, 3 H), 7.08-7.00 (m, 3 H), 4.40 (t, J=6.4 Hz, 1 H), 3.94 (bd, 2 H), 3.22-3.03 (m, 2 H), 2.90-2.85 (m, 2 H), 1.89-1.86 (m, 2 H), 1.42-1.34 (m, 12 H). LCMS m/e 525 (M+H).
Reaction SMILES: [C:1]1([NH:7][C:8]2([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23]OCCOCCOC>>[CH3:23][O:22][CH2:21][C:8]1([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: OCC1(Nc2ccccc2)CCN(CCc2cccs2)CC1
Reactant: COCCOCCOC
Product: COCC1(Nc2ccccc2)CCN(CCc2cccs2)CC1

Procedure:
Residual alcohol (2), diglyme and mineral oil are reduced/eliminated by either of the following methods:
Reaction SMILES: [OH-].[NH4+:2].C(O)C.[CH3:6][Si:7]([CH3:22])([CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:15][O:14]1>O>[NH2:2][CH2:15][CH:13]([OH:14])[CH2:12][O:11][CH2:10][CH2:9][CH2:8][Si:7]([CH3:22])([CH3:6])[CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CN
Temperature: 50 °C

Procedure:
Aqueous ammonium hydroxide (25%; 10 g, 150 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 50° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 50° C. for an additional 8 hours. Ethanol and water were stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.