Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([N:18]1[C:24]2=[C:25]3[C:30](=[N:31][C:32]4=[CH:33][CH:34]=[CH:35][C:22](=[C:23]24)[O:21][CH:20]([CH3:36])[C:19]1=O)[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([N:18]1[C:24]2=[C:25]3[C:30](=[N:31][C:32]4=[CH:33][CH:34]=[CH:35][C:22](=[C:23]24)[O:21][CH:20]([CH3:36])[CH2:19]1)[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1Oc2cccc3nc4c(c(c23)N(Cc2ccccc2)C1=O)CCCC4
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CN(Cc2ccccc2)c2c3c(nc4cccc(c24)O1)CCCC3
Reaction time: 0.08 h
Yield: 67 %

Procedure:
To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 12.2 ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.62 g) in portions, with stirring. After five mins, 1-benzyl-3-methyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.38 g) was added and stirring was continued overnight. Ethyl acetate (200 ml) and 10% sodium hydroxide solution (200 ml) were added, and the organic layer was separated, dried over anhydrous sodium magnesium sulfate, and concentrated. Recrystallization of the residue from methanol/diethyl ether gave 2.82 g (67%) of product, mp 151.5°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=O)=[CH:13][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[Br:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.[H-].[Na+]>C1COCC1.C1C=CC=CC=1>[Br:30][C:31]1[CH:37]=[CH:36][C:34]([NH:35][C:23]([C:14]2[C:15]3[O:19][C:18]([CH3:20])=[N:17][C:16]=3[C:21]3[NH:22][C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])=[N:11][C:12]=3[CH:13]=2)=[O:25])=[CH:33][CH:32]=1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Reactant: Nc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(Br)cc1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 15 %

Procedure:
The title compound was prepared following the procedure as described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.276 mmol), benzene (4 mL), thionyl chloride (5.0 mL), 4-bromo aniline (0.142 g, 0.828 mmol), THF (5.0 mL) and 60% NaH (0.033 g, 0.825 mmol). The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.022 g of the desired product. 1HNMR (DMSO-d6): δ 2.70 (s, 3H), 6.54 (s, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.83 (s, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.12-7.26 (m, 2H), 7.33-7.38 (m, 2H), 8.61 (s, 1H), 9.04 (s, 1H); MS [M+H]+: 532.47.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[H-].[Na+].[CH2:19](I)[CH3:20]>C(OCC)(=O)C>[CH2:19]([O:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH3:20]
Reactant: CCI
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(F)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a DMF (10 mL) solution of 4-fluoro-3-nitro-phenol (628 mg), sodium hydride (purity: 55% or higher, 209 mg) was added in small portions at room temperature. After 30 minutes, ethyl iodide (0.38 mL) was added thereto at room temperature. After 2 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and saturated brine, then dried over sodium sulfate, and then concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to obtain the title compound (685 mg, 93%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[OH:3][C@:4]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH:34]=[CH2:35])=[CH:24][CH:23]=2)[CH2:8][N:7]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[C@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]1.[CH3:36]I>CN(C=O)C>[CH3:36][O:3][C@:4]1([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH:34]=[CH2:35])=[CH:26][CH:27]=2)[CH2:8][N:7]([C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[C@H:6]([C:18]([O:20][CH3:21])=[O:19])[CH2:5]1
Reactant: CI
Reactant: C=Cc1ccccc1-c1ccc([C@]2(O)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1ccccc1-c1ccc([C@]2(OC)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 31.1 %

Procedure:
Sodium hydride (60% in oil) (0.08 g, 1.925 mmol) was added to a solution of (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-hydroxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (0.5 g, 1.069 mmol) and methyl iodide (0.12 mL, 1.925 mmol) at 0° C. in DMF. This was stirred at 0° C. for 3 hrs. The reaction was then quenched with a saturated NH4Cl solution and ether. The ether layer was washed with brine, dried over MgSO4, filtered and evaporated to give crude material. The crude material was purified by flash chromatography on the Biotage (20-40% EtOAc in hexanes) to give (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (160 mg, 31% yield) as a clear oil. LCMS: rt=2.11 min. [M+Na]+=504; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm −0.04-0.13 (m, 9H) 0.95-1.02 (m, 1H) 1.03-1.08 (m, 1H) 2.55 (dd, J=13.12, 8.85 Hz, 1H) 2.76-2.89 (m, 1H) 3.00 (s, 3H) 3.68-3.77 (m, 1H) 3.78 (s, 3H) 3.96-4.09 (m, 1H) 4.20-4.31 (m, 2H) 4.64 (dd, J=8.70, 1.98 Hz, 1H) 5.22 (d, J=11.90 Hz, 1H) 5.72 (d, J=17.40 Hz, 1H) 6.69 (ddd, J=17.40, 10.99, 2.44 Hz, 1H) 7.29 (d, J=7.32 Hz, 1H) 7.32-7.45 (m, 6H) 7.66 (d, J=7.32 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[C:20]([CH2:22][C:23]([NH:25][NH2:26])=O)#[N:21]>CO>[Cl:1][C:2]1[S:19][C:5]2[N:6]3[C:23]([CH2:22][C:20]#[N:21])=[N:25][N:26]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)sc2N1
Reactant: N#CCC(=O)NN
Solvent: CO
Product: N#CCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
1.2 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione are refluxed for 1.5 hours together with 2 g of cyanoacetic acid hydrazide in 80 ml of absolute methanol, a dry nitrogen stream being conducted through the solution. The solution is concentrated to 10 ml and left to crystallize. The 7-chloro-5-(o-chlorophenyl)-2-(2-cyanoacetylhydrazino)-3H-thieno[2,3-e]-1,4-diazepine, which is filtered off under a vacuum and dried, is refluxed for 2 hours in 150 ml of absolute xylene. The solution is evaporated and the residue recrystallized from ethyl acetate containing active carbon to yield 2-chloro-4-(o-chlorophenyl)-9-cyanomethyl-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, melting point 217°-220° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([CH2:19]Cl)[C:6]=2[N:7]=1.Cl.[F:29][C:30]([F:34])([F:33])[CH2:31][NH2:32].C(N(CC)C(C)C)(C)C>[Br-].C([N+](CC)(CC)CC)C.[I-].C([N+](CC)(CC)CC)C.CS(C)=O>[F:16][C:15]([F:18])([F:17])[CH2:14][O:13][CH2:12][CH2:11][N:10]1[C:5]2[C:4]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[C:8]([CH2:19][NH:32][CH2:31][C:30]([F:34])([F:33])[F:29])=[N:9]1
Reactant: FC(F)(F)COCCn1nc(CCl)c2nc(Cl)nc(Nc3ccncn3)c21
Reactant: NCC(F)(F)F
Agent: CC[N+](CC)(CC)CC
Agent: Cl
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: FC(F)(F)CNCc1nn(CCOCC(F)(F)F)c2c(Nc3ccncn3)nc(Cl)nc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-Chloro-3-(chloromethyl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-amine (610 mg, 1.5 mmol), trifluoroethylamine hydrochloride (390 mg, 2.9 mmol) and N,N-diisopropylethylamine (410 mg, 3.2 mmol) along with tetraethylammonium bromide (1 mg) and tetraethylammonium iodide were mixed in dimethyl sulfoxide (10 ml) in a reaction vial. The reaction mixture was stirred for two days at room temperature and a second quantity of trifluoroethylamine hydrochloride (390 mg, 2.9 mmol) and N,N-diisopropyl-ethylamine (410 mg, 3.2 mmol) were added and the reaction allowed to proceed for another two days. The reaction mixture was partitioned between ethyl acetate (70 mLs) and water (2×25 mLs) and the organic layer dried (Na2SO4) and concentrated to an oil that solidified on standing. This intermediate was used without further purification. MS ES+ [MH]+m/z (relative intensity): 485.1 (100), 486.1 (10), 487.1 (20).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH2:18]2.CO[Na].Cl>C1C=CC=CC=1>[CH2:18]1[C:19]2[C:15](=[C:14]([NH:13][C:4](=[O:6])[C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=3[CH3:1])[CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: Nc1cccc2c1CCC2
Reactant: CCOC(=O)c1ccccc1C
Agent: CO[Na]
Agent: Cl
Solvent: c1ccccc1
Product: Cc1ccccc1C(=O)Nc1cccc2c1CCC2
Reaction time: 10 h
Yield: 65.4 %

Procedure:
A mixture of 2.0 g of ethyl o-methylbenzoate (12.2 m mol), 1.62 g of 4-aminoindan (12.2 m mol), 0.72 g of CH3ONa and 30 ml of benzene is stirred for 10 hours under reflux. After ice-cooling, the mixture is added to dilute hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and concentrated. The resulting crystals are washed with n-hexane to give 2.0 g of N-4-indanyl-o-methylbenzamide (yield: 65.4%).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([O:30][CH3:31])[CH:22]=1.ClC1C=CC(C(O)=O)=C(OC)C=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][CH:2]2[C:8]3=[N:9][C:10]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)=[CH:11][C:12](=[O:13])[N:7]3[CH2:6][CH2:5][O:4][CH2:3]2)=[O:26])=[C:23]([O:30][CH3:31])[CH:22]=1
Reactant: COc1cc(F)ccc1C(=O)O
Reactant: NC1COCCn2c1nc(-c1ccncc1)cc2=O
Agent: COc1cc(Cl)ccc1C(=O)O
Product: COc1cc(F)ccc1C(=O)NC1COCCn2c1nc(-c1ccncc1)cc2=O

Procedure:
By analogy with the method described in example 1 (step 1.4), using (+/−) 9-amino-2-pyridin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one and 4-fluoro-2-methoxy benzoic acid in place of (+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one and 4-chloro-2-methoxy-benzoic acid, the compound, 0.068 g (71%), was obtained as a powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25](OC)=O)[N:19]=[CH:18]3)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH2:33])[CH2:31][NH2:32].[Al](C)(C)C.[ClH:38]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.CCOCC>[ClH:38].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][C:25]2[NH:32][CH2:31][CH2:30][N:33]=2)[N:19]=[CH:18]3)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: COC(=O)Cn1ncc2cc(-n3ccc(OCc4ccccc4)cc3=O)ccc21
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CC2=NCCN2)c1
Yield: 14 %

Procedure:
A solution of methyl 2-(5-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1H-indazol-1-yl)acetate (100 mg, 0.217 mmol) in toluene (0.5 mL) was treated with ethane-1,2-diamine (24 mg, 0.40 mmol) and Al(CH3)3 (0.2 mL, 2 M in toluene, 0.4 mmol) at 0° C. under nitrogen. Then, the reaction mixture was heated to reflux. After stirring at reflux for 16 h, the reaction mixture was diluted with H2O (20 mL) and extracted with CH2Cl2 (2×25 mL). The organics were dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH/NH4OH, 40:1:0.05 to 20:1:0.15) provided the free base. This was dissolved in ethyl acetate (0.3 mL) and treated with 1 equivalent of 1 M HCl in Et2O. The resulting mixture was filtered to provide the title compound (13.5 mg, 14%) as a yellow solid melting point (mp) 164-166° C.; 1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.31 (d, J=0.7 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 7.82 (d, J=16 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.49-7.36 (m, 6H), 6.12 (dd, J=7.6, 2.7 Hz, 1H), 5.99 (d, J=2.7 Hz, 1H), 5.70 (s, 2H), 5.16 (s, 2H), 3.87 (s, 4H); ESI MS m/z 400 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C@H:11]2[CH2:12][CH2:13][C@@H:8]([NH2:7])[CH2:9][CH2:10]2)=[N:16][CH:17]=1
Reactant: Cc1ccc(N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(N[C@H]2CC[C@@H](N)CC2)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a round bottomed flask was added tert-butyl(cis-4-((5-methylpyridin-2-yl)amino)cyclohexyl)carbamate (0.2795 g, 0.915 mmol) and hydrogen chloride, 4.0M solution in 1,4-dioxane (1.144 ml, 4.58 mmol, Sigma-Aldrich Chemical Company, Inc.) to stir at room temperature for 6 h. Solvent was evaporated in vacuo to provide the title compound, which was carried on without further work up. LCMS showed product peak at 0.357 min (m+1=206.0).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH:23]([C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[N:35]([CH2:39][CH:40]1[CH2:42][CH2:41]1)[CH2:36][CH2:37][CH3:38])[CH3:24])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+]>C(O)C>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:43]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:50])[F:51])[CH:45]=1)[CH2:6][N:7]([CH:23]([C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[N:35]([CH2:39][CH:40]1[CH2:41][CH2:42]1)[CH2:36][CH2:37][CH3:38])[CH3:24])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C(C)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C(C)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[2-(Cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethanol (500 mg) is dissolved in methylene chloride (5 ml) and thereto is added thionyl chloride (133 μl) under ice-cooling and the mixture is stirred at room temperature for 15 minutes. To the reaction solution are added methylene chloride and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue and ethyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxy]-butyrate (749 mg) are dissolved in N,N-dimethylformamide (5 ml) and thereto is added sodium hydride (62%) (64 mg) under ice-cooling and the mixture is stirred for 1 hour. Thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:14:1) to give ethyl 4-[2-((3,5-bis-trifluoromethyl-benzyl)-{1-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethyl}-amino)-pyrimidin-5-yloxy]-butyrate (144 mg) as a crude product. The resulting ester is dissolved in ethanol (2 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (500 μl) and the mixture is stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue is added ethyl acetate and a dilute hydrochloric acid and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→24:1) to give 4-[2-((3,5-bis-trifluoromethyl-benzyl)-{1-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethyl}-amino)-pyrimidin-5-yloxy]-butyric acid (11 mg). MS (m/z): 707 [M+H]+
Reaction SMILES: O[C@:2]1([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:7][C:6](=[O:8])[C@H:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:3]1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>C(Cl)Cl>[CH2:26]([O:25][C@H:3]1[C@H:4]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:5]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6](=[O:8])[CH:7]=[C:2]1[CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1C[C@](O)(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=C1C=C(COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of (3S,4S,5S,2R)-5-hydroxy-5-[(phenylmethoxy)methyl]-2,3,4-tris(phenyl methoxy)cyclohexan-1-one (580.0 g, 1.051 mol) in anhydrous methylene chloride (3.6 L) was added trifluoroacetic anhydride (331.1 g, 222 mL, 1.577 mol) followed by addition of pyridine (149.7 g, 153 mL, 1.892 mol) at room temperature under argon. The mixture was stirred at room temperature for 24 h and quenched by addition of ice water (1.0 L). The organic layer was separated and the aqueous layer was extracted with methylene chloride (3×2 L). The combined organic layers were washed with sodium bicarbonate (sat. aq. 3×0.5 L), brine (sat. aq. 3×1.0 L), dried over sodium sulfate, filtered and concentrated to give a yellow oil (476.7 g, purity of 90%, yield 85%). 1H NMR (CDCl3, 400 MHz): δ 7.26-7.48 (m, 20H), 6.26 (s, 1H), 5.15 (d, J=11.2 Hz, 1H), 5.05 (d, J=10.8 Hz, 1H), 4.95 (d, J=10.8 Hz, 1H), 4.77-4.81 (m, 2H), 4.72 (d, J=11.2 Hz), 4.55 (S, 2H), 4.40-4.42 (m, 1H), 4.31 (d, J=16 Hz, 1H), 4.03-4.13 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](O)[C:5]2[C:6]([N:19]=1)=[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[N:8]=[N:9][CH:10]=2.[OH-].[Na+].P(Cl)(Cl)([Cl:25])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]2[C:6]([N:19]=1)=[C:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[N:8]=[N:9][CH:10]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)c2cnnc(-c3ccc(Cl)c(Cl)c3)c2n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Cl)c2cnnc(-c3ccc(Cl)c(Cl)c3)c2n1

Procedure:
Reflux a mixture of 2-methyl-4-hydroxy-8-(3,4-dichlorophenyl)pyrido[2,3-d]pyridazine (3) (4.5 g, 15 mmol) in phosphorous oxychloride (15 mL) for 2 hrs. Cool the reaction mixture, pour onto cracked ice and neutralize the solution with 1N NaOH. Extract the solution with ethyl acetate (2×100 mL) and wash the combined organic layers with brine. Dry the solution (Na2SO4) and evaporate in vacuo to obtain 4.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([NH:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21])[N:6]=[CH:7]2.C[Si]([C:29]#[CH:30])(C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.CO.ClCCl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[C:5]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[N:6]=[CH:7]2)=[C:2]([C:29]#[CH:30])[N:11]=1
Reactant: O=C(Nc1cc2c(Cl)nc(-c3ccccc3Cl)cc2cn1)C1CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C#Cc1nc(-c2ccccc2Cl)cc2cnc(NC(=O)C3CC3)cc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A mixture of N-(5-chloro-7-(2-chlorophenyl)-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (110 mg, 0.31 mmol), (trimethylsilyl)acetylene (45 mg, 0.46 mmol), N,N-diisopropylethylamine (0.1 mL, 0.61 mmol), copper(I) iodide (6 mg, 0.03 mmol), and bis(triphenylphosphine)palladium(II) chloride (15 mg, 0.02 mmol) in 1,4-dioxane (2 mL) was heated at 50° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was redissolved in methanol (4 mL) and treated with potassium carbonate (210 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 1 h, and then diluted with dichloromethane (100 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid (50 mg, 50%), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].CCN(C(C)C)C(C)C.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])(=[O:24])=[O:23]
Reactant: C[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Reaction time: 66.5 h

Procedure:
To a 500 mL round-bottomed flask were added a stirbar, (S)-2-aminopropan-1-ol (2.151 g, 28.65 mmol), dry DCM (100 mL), and DIPEA (14.0 mL, 81.2 mmol). The mixture was then treated with 2-bromobenzene-1-sulfonyl chloride (6.981 g, 27.32 mmol) and stirred for 66.5 hours before concentrating to dryness and subjecting the residue to FCC to give the title compound. (7.31 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:13][NH2:14])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Si:15]([O:22][CH2:23][C:24]1([CH3:33])[S:30][CH2:29][CH2:28][N:27]=[C:26](SC)[CH2:25]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(O)CCC>[Si:15]([O:22][CH2:23][C:24]1([CH3:33])[S:30][CH2:29][CH2:28][N:27]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:13][N:14]=[C:26]2[CH2:25]1)([C:18]([CH3:21])([CH3:19])[CH3:20])([CH3:16])[CH3:17]
Reactant: CSC1=NCCSC(C)(CO[Si](C)(C)C(C)(C)C)C1
Reactant: NNC(=O)C1(c2ccc(Cl)cc2)CC1
Solvent: CCCCO
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A solution of the compound (2.03 g, 10 mmol) obtained in Example 1-1) and 7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-methyl-5-(methylthio)-2,3,6,7-tetrahydro-1,4-thiazepine (WO2008078725) (3.2 g, 10 mmol) in n-butanol (50 mL) was stirred at 140° C. for 7 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Isco Combiflash, 40 g, hexane:ethyl acetate=0:100 to 100:0, gradient) to obtain the title compound (2.27 g, 49%) as a light yellow oily substance.