Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=O)[CH3:12])[CH:5]=[CH:6][CH:7]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:11]([CH3:12])=[N:10][CH2:9][CH2:8]2
Reactant: CC(=O)NCCc1cccc(Br)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2cc(Br)ccc21

Procedure:
In close analogy to the procedure described above, N-[2-(3-bromo-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[N:28][C:29]([C:32](O)=[O:33])=[CH:30][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:32]([C:29]3[N:28]=[CH:27][C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[CH:31][CH:30]=3)=[O:33])[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)cn1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccccn2)cn1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Yield: 79.2 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 1) (64.7 mg, 0.220 mmol) in DMF (3 ml) was added 2,3′-bipyridine-6′-carboxylic acid (Description 5) (44 mg, 0.220 mmol), HOBT.H2O (33.7 mg, 0.220 mmol), HBTU (83 mg, 0.220 mmol) and DIPEA (0.115 ml, 0.659 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum then DCM was added (5 ml) and washed with saturated NaHCO3 solution (5 ml). The product was concentrated under vacuum then dissolved in MeCN/DMSO 1:1 and purified by MDAP. The desired fractions were combined and evaporated under vacuum to give the title compound (83 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[CH:34][N:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-ethoxy-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M35) (876 mg, 1.35 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (360 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[C:6]([NH:8][S:9]([C:12]2[C:17]3=[N:18]S[N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.CN(C(ON1N=N[C:39]2C=CC=N[C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1SN=C2C(S(NC3C=C(I)C=CC=3C(O)=O)(=O)=O)=CC=CC=12.N1CCOCC1>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[C:6]([NH:8][S:9]([C:12]2[C:17]3[N:18]=[CH:38][CH:39]=[N:20][C:16]=3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)N1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Solvent: C1COCCN1
Product: O=C(c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCOCC1

Procedure:
Benzo[1,2,5]thiadiazole-4-sulfonic acid [5-iodo-2-(morpholine-4-carbonyl)-phenyl]-amide. The title compound was prepared from the HATU-mediated coupling of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid and morpholine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C17H15IN4O4S2, 530.0; m/z found, 531 [M+H]+, 553 [M+Na]+. HPLC (reverse phase): RT=8.50 min. 1H NMR (400 MHz, CDCl3): (rotameric broadening) 8.91 (s, 1H), 8.31 (dd, J=7.0, 0.9 Hz, 1H), 8.27 (dd, J=8.8, 0.9 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.74 (dd, J=8.8, 7.0 Hz, 1H), 7.41 (dd, J=8.1, 1.6 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 3.75-3.05 (br m, 8H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:36](=[O:37])[CH2:35][Cl:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1OCC(O)CNCCNC(=O)OC(C)(C)C
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1OCC(O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 11 (1.0 g, 3.0 mmol) was dissolved in 20 mL DCM and treated with diisopropylethyl amine (0.76 g, 4.5 mmol). The mixture was cooled to ° C. To the cold mixture was added dropwise chloroacetyl chloride in 5 mL DCM. The reaction mixture was allowed to stir at RT for 24 h. The mixture was diluted with 50 mL DCM and washed with 50 mL of water and 10% citric acid. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and the residue was crystallized from ethylether to afford compound 12.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=[O:5].[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[NH:20][N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>[Cu]I.O1CCOCC1>[Br:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:20]2[N:19]=[CH:18][C:17]3[C:22](=[CH:23][CH:24]=[C:15]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:16]=3)[C:21]2=[O:25])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Br)cccc1Br
Reactant: CC(C)(C)c1ccc2c(=O)[nH]ncc2c1
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(Br)c3C=O)ncc2c1
Reaction time: 18 h
Yield: 69.1 %

Procedure:
5.90 g (22.4 mmol) of 2,6-dibromobenzaldehyde, 1.80 g (8.90 mmol) of 6-tert-butyl-2H-phthalazin-1-one, 6.02 g (18.5 mmol) of cesium carbonate, 179 mg (0.940 mmol) of copper(I) iodide, and 428 mg (1.87 mmol) of 4,7-dimethoxy-1,10-phenanthroline were weighed into a 100 ml, reaction flask fitted with a stir bar and septum cap. Added 50 mL of anhydrous dioxane. Purged the reaction mixture with nitrogen for 15 min. Stirred at 100° for 18 h. Partitioned the reaction mixture between 200 mL of 10% MeOH/CH2Cl2 and 200 mL of water. Separated phases and extracted the aqueous phase with 2×100 mL of 10% MeOH/CH2Cl2. The combined organic extracts were washed with 200 mL of brine, dried over Na2SO4, and the solvent was removed on rotavap. Purified the crude by flash chromatography on silica gel to obtain 2.37 g of the title compound as an off-white solid. MS (ESI) doublet 385, 387 (M+H)+.
Reaction SMILES: [Si]([O:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([CH2:25][O:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[OH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([CH2:25][O:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]1
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@H]1CCC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(C)(C)OC[C@H]1CCC[C@@H](O)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
16 g of tert-butyl 2-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexylmethoxy]-2-methylpropionate are dissolved in 100 ml of acetonitrile, and 62 ml of tetrabutylammonium fluoride (1 N solution in tetrahydrofuran) are added. After 2 h of stirring at 60° C., the reaction has ended and the mixture is concentrated under reduced pressure. The residue is extracted from water/ethyl acetate. The combined org. phases are extracted with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent is removed under reduced pressure. The crude product is purified on silica gel (heptane/ethyl acetate 15:1→1:1). This gives 16 g of the product tert-butyl 2-(cis-3-hydroxycyclohexylmethoxy)-2-methylpropionate as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[N:12]=[CH:11][N:10]=1.O.C(O)(=O)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(OCC)C>[N:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:11]1[N:12]=[C:13]([Cl:15])[CH:14]=[C:9]([Cl:8])[N:10]=1
Reactant: Brc1ccncc1
Reactant: Clc1cc(Cl)ncn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: Clc1cc(Cl)nc(-c2ccccn2)n1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
nButyllithium (1.5 M in hexanes/1.53 mL, 2.3 mmol) was added dropwise to a solution of 4-bromopyridine (200 μL, 2.08 mmol) and in diethyl ether (20 mL)−78° C. After 30 minutes, the reaction mixture was warmed to −30° C. and 4,6-dichloropyrimidine (283 mg, 1.9 mmol) was added. The reaction mixture was allowed to warm to 0° C. over 60 min after which water (2 mmol) and acetic acid (4 mmol) were added followed by DDQ (431 mg, 1.9 mmol). After 30 minutes, the reaction mixture was diluted with diethyl ether (30 mL) and washed three times with aqueous 3M NaOH. the organic layer was dried over MgSO4. Filtration and removal of volatiles under reduced pressure yielded a brown gummy solid which was purified by flash chromatography to afford 2-pyridyl-4,6-dichloropyrimidine as a white solid (0.261 mg, 61%). 1H NMR: (CDCl3) δ 7.40, 1H, s; 8.23, 2H, d; 8.80, 2H, d.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH3:25])[CH2:5][CH2:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[CH:16]([C:18]1[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=1)O>C(O)(C(F)(F)F)=O>[F:24][C:19]1[C:18]([CH2:16][C:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:7]=2[CH2:6][CH2:5][N:4]([CH3:3])[CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CN(C)CCc1sc2ccccc2c1C(O)c1cccnc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCc1sc2ccccc2c1Cc1cccnc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.3 %

Procedure:
A suspension of NaBH4 (0.11 g, 2.9 mmol) in 7 mL TFA was stirred at room temperature for 15 minutes. A solution of [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-(2-fluoro-pyridin-3-yl)-methanol (0.12 g, 0.36 mmol) in 6 mL TFA was added slowly. The mixture was stirred at room temperature for 48 h. The solvent was evaporated and water and ammonium hydroxide were added at 0° C. until pH=9. The solution was extracted with EtOAc (3×) and washed with water/ammonium hydroxide (30/1 v/v). The combined organic layers were concentrated and 0.12 g of crude material was obtained. Purification by Mass triggered HPLC afforded 32 mg of {2-[3-(2-fluoro-pyridin-3-ylmethyl)-benzo[b]thiophen-2-yl]-ethyl}-dimethyl-amine (Compound 24-2) (MH+=315.0, tR=4.50, Method 2).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>>[F:31][C:28]([F:29])([F:30])[C:24]1[CH:23]=[C:22]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[NH:15][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(F)(F)F)c2)C(N)C1
Product: NC(=O)c1ccnc2c(NC3CNCCC3c3cccc(C(F)(F)F)c3)ncnc12

Procedure:
Compound 24 was prepared following general synthesis scheme 9 wherein 4-hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylic acid amide was reacted with tert-butyl 3-amino-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate to give the title compound. LC-MS [417 (M+H)], 1H NMR (400 MHz, DMSO-d6) δ 9.78 (d, 1H), 9.06 (d, 1H), 9.03-8.95 (m, 1H), 8.90 (d, 1H), 8.88-8.73 (m, 1H), 8.50 (s, 1H), 8.32 (d, 1H), 8.16 (d, 1H), 7.62 (s, 1H), 7.56 (q, 1H), 7.43 (d, 2H), 5.22-5.02 (m, 1H), 3.60-3.38 (m, 3H), 3.14 (q, 1H), 2.99 (q, 1H), 2.54 (d, 1H), 2.08 (dt, 2H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)=[O:3].[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([F:17])[F:16])[CH3:12]>[Cu].CS(C)=O>[CH2:11]([O:13][C:14](=[O:19])[C:15]([C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)([F:17])[F:16])[CH3:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(=O)c1ccc(I)cc1
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(C(C)=O)cc1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
According to the Kumadaki method (supra) and the above-described scheme, 4-iodoacetophenone (Compound 1e; 1.23 g, 5.0 mmol), bromodifluoroacetic acid ethyl ester (1.22 g, 6.0 mmol), copper powder (768.0 mg, 12.0 mmol) and DMSO (10.0 mL) were put into a two-neck reaction tube, and the mixture was stirred under argon atmosphere at 55° C. for 24 hours. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(4-acetylphenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2e) was obtained with a yield of 82%.
Reaction SMILES: [Br:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=3[CH:9]=[N:10][C:4]=2[CH:3]=1.[C:19]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20]1>C(OCC)(=O)C>[Br:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=3[C@H:9]3[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][CH2:20][C:19](=[O:26])[N:10]3[C:4]=2[CH:3]=1
Reactant: Fc1cc2c(cc1Br)N=Cc1c(F)cccc1O2
Reactant: O=C1CCCC(=O)O1
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1CCC(=O)N2c3cc(Br)c(F)cc3Oc3cccc(F)c3[C@@H]12
Yield: 99.6 %

Procedure:
Preparation analogous to Example 5, step e, from 8-bromo-1,7-difluorodibenz[b,f][1,4]oxazepine (8 g, 25.8 mmol) and glutaric anhydride (5.9 g, 51.6 mmol). After cooling down, the reaction mixture was dissolved in ethyl acetate, washed with water, dried (Na2SO4) and evaporated to afford the title carboxylic acid (10.9 g, 100%)
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[CH:19]([OH:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=C1CCCc2nc3ccccc3c(NCc3ccccc3C(F)(F)F)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCc3ccccc3C(F)(F)F)c21
Temperature: 10 °C
Yield: 79.4 %

Procedure:
In 100 ml of dry THF was dissolved 4.31 g of 3,4-dihydro-9-(2-trifluoromethylbenzylamino)acridin-1(2H)-one and the mechanically stirred solution was cooled to 10° C. under nitrogen. To it was added 5.8 ml of 1M LiAlH4 in THF dropwise over 15 minutes. Within 0.5 hours of addition the reaction was complete by TLC, so it was quenched with 1 ml of saturated ammonium chloride and the salts were filtered. The filtrate was evaporated to a solid which was dissolved in dichloromethane. The dichloromethane solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was refluxed and pentane was added to effect crystallization. The crystals were collected from the cooled mother liquor to yield 3.44 g of solid, mp 158°-160° C.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:19][N:18]=2)=[C:12]([CH3:36])[CH:11]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:12]1[CH:11]=[C:10]([NH:2][CH3:1])[CH:15]=[CH:14][C:13]=1[O:16][C:17]1[N:18]=[CH:19][C:20]([NH:23][C:24](=[O:35])[C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)=[CH:21][CH:22]=1
Reactant: Cc1cc(N(C)C(=O)OC(C)(C)C)ccc1Oc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(Oc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cn2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl methyl{3-methyl-4-[(5-{[4-(trifluoromethyl)benzoyl]amino}pyridin-2-yl)oxy]phenyl}carbamate (0.60 g) in CH2Cl2 (1 mL) was added TFA (3.32 mL) in three portion at 0° C. After stirring at 0° C. for 30 min, the mixture was evaporated under reduced pressure and the residue was dissolved in AcOEt. Ice cold 2 M NaOH (10 mL) was added, the mixture was extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. After addition of Et2O (20 mL), the solution was stirred vigorously. The resulting precipitate was collected and the precipitate was recrystallized from Et2O/AcOEt/Hexane to afford the title compound (0.44 g) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7]([CH3:18])([CH3:17])[C:4]=2[NH:5][N:6]=1.C(N(C(C)C)CC)(C)C.[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32][CH2:33]Cl>>[NH2:1][C:2]1[C:3]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7]([CH3:18])([CH3:17])[C:4]=2[N:5]([CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[N:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N1Cc2c(N)n[nH]c2C1(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2c(N)nn(COCC[Si](C)(C)C)c2C1(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
To a suspension of tert-butyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (8.5 g, 33.9 mmol) and diisopropyl ethylamine (18 mL, 3.0 equiv) in dichloromethene (200 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (6.0 mL, 1.0 equiv) dropwise at 0° C. under nitrogen. The mixture was been stirred at 0° C. under nitrogen for two hours then warmed to room temperature and stirred over night. The reaction mixture was concentrated and purified by column chromatography to give the title compound as a white solid (2.27 g, 18%). 1H NMR (400 MHz, METHANOL-d4): δ ppm 0.81-0.97 (m, 2H) 1.45-1.59 (m, 9H) 1.72 (d, J=5.29 Hz, 13H) 3.53-3.67 (m, 2H) 4.26 (d, J=7.55 Hz, 2H) 5.17 (s, 2H). 2D-NOESY NMR showed proton at 5.17 ppm is correlated with proton at 1.72 ppm.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][N:25]2[C:29]([CH:30]([C:36](OCC)=[O:37])[C:31](OCC)=[O:32])=[N:28][N:27]=[N:26]2)=[CH:22][CH:21]=1>BrC1C=CC=CC=1>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]3[C:31](=[O:32])[C:30]([C:29]4[N:25]([CH2:24][C:23]5[CH:41]=[CH:42][C:20]([O:19][CH3:18])=[CH:21][CH:22]=5)[N:26]=[N:27][N:28]=4)=[C:36]([OH:37])[N:17]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1nnnn1Cc1ccc(OC)cc1
Reactant: CC(C)c1csc(CCc2ccnc(N)c2)n1
Solvent: Brc1ccccc1
Product: COc1ccc(Cn2nnnc2-c2c(O)nc3cc(CCc4nc(C(C)C)cs4)ccn3c2=O)cc1
Reaction time: 4 h
Yield: 71.7 %

Procedure:
4-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-aminopyridine (50 mg) and diethyl 2-[1-(4-methoxybenzyl)tetrazol-5-yl]malonate (141 mg) were heated to 150° C. in bromobenzene with stirring for 4 hours. After the solvent was evaporated, the residue was purified by silica gel column chromatography to obtain the title compound (73 mg) as cream solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:18])[N:3]=1.CC(C)([O-])C.[Na+].[CH3:25][CH:26]([CH3:29])[CH2:27][OH:28]>>[CH3:25][CH:26]([CH3:29])[CH2:27][O:28][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:18])[N:3]=1
Reactant: CC(C)CO
Reactant: Nc1nc(Cl)nc2c1ncn2CC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CC(C)COc1nc(N)c2ncn(CC3CCOCC3)c2n1
Temperature: 105 °C

Procedure:
2-Chloro-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (0.20 g) was added to a suspension of 2-methyl-1-propanol (2 mL) and sodium tert-butoxide (0.288 g). The mixture was heated in a microwave for 30 minutes at 105° C. The reaction mixture was washed with water after diluting with ethyl acetate (50 mL). The organic was separated and dried by passing through a hydrophobic frit before volatiles were stripped off under reduced pressure to give a pinkish solid. This material was triturated with diethyl ether and filtered to give the title compound as a pinkish solid (91.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[CH:17]=3)[CH2:12][CH2:11][C@@H:10]2[OH:32])=[O:7])=[CH:4][CH:3]=1.[ClH:35]>O1CCOCC1>[ClH:35].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)[CH:17]=3)[CH2:12][CH2:11][C@@H:10]2[OH:32])=[O:7])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)[C@H](NC(=O)c2ccc(F)cc2)[C@@H](O)CC3)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N[C@H]1c2cc(N3CCNCC3)ccc2CC[C@@H]1O)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
To a solution of tert-butyl 4-[(3S,4S)-4-[(4-fluorobenzoyl)amino]-3-hydroxy-tetralin-6-yl]piperazine-1-carboxylate (19.4 g, 41.3 mmol) in 1,4-dioxane (430 mL) add 4 M hydrogen chloride in dioxane (135 mL) at room temperature. Stir the resulting slurry mechanically at 50° C. for 13 hr. Concentrate the reaction in vacuo to obtain the title compound (24.8 g, quantitative). LC-ES/MS m/z 370 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=1[OH:28].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:28][C:21]2[C:22]([F:27])=[CH:23][CH:24]=[C:25]([F:26])[C:20]=2[F:19])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: Oc1c(F)ccc(F)c1F
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2c(F)ccc(F)c2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 65.2 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.19 g of 2,3,6-trifluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.21 g of 4-(2-butynyloxy)-6-(2,3,6-trifluorophenoxy)pyrimidine (the present compound (46)).