Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[S:4][C:3]=1[CH:16]1[O:20]CCO1.C[O:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:32])=[C:27](B(O)O)[CH:28]=1>>[OH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:32])=[C:25]([C:2]2[C:6]([CH3:7])=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=3)[S:4][C:3]=2[CH:16]=[O:20])[CH:24]=1
Reactant: COc1ccc(C)c(B(O)O)c1
Reactant: COc1ccc(-c2sc(C3OCCO3)c(Br)c2C)cc1
Product: Cc1ccc(O)cc1-c1c(C=O)sc(-c2ccc(O)cc2)c1C
Yield: 50.4 %

Procedure:
Starting from 2-[3-bromo-5-(4-methoxyphenyl)-4-methylthien-2-yl]-1,3-dioxolane (1.1 g, 3.0 mmol, made in Example 1, Step 1) and substituting 5-methoxy-2-methylphenylboronic acid (0.55 g, 3.3 mmol) in place of 3-methoxyphenylboronic acid (Step 2), the title compound (0.49 g, 89%, m.p. 204-07° C.) was synthesized in essentially the same manner as described in Example 1, Steps 2-4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[C:22]([CH2:26][C:27](Cl)=O)([CH3:25])([CH3:24])[CH3:23].[OH-].[Na+].C(O)C>C(OCC)(=O)C>[CH3:23][C:22]([CH3:25])([CH3:24])[CH2:26][C:27]1[N:14]([CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:9])=[O:10])=[CH:7][C:2]=2[N:1]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(C)S(=O)(=O)c1ccc(NCCN2CCCC2)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 2-amino-4-(isopropylsulfonyl)-1-(N-2-pyrrolidine-1-ylethylamino)benzene (122.9 mg, 0.39 mmol) in ethyl acetate (8 mL) was added tert-butylacetyl chloride (60 μL, 0.43 mmol) at room temperature, and the mixture was stirred for 1 h at room temperature. 2N—NaOH (1 mL) and ethanol (3 mL) were then added to the reaction mixture at room temperature, and stirred for 6 h at 80° C. The reaction was quenched with water, and extracted with three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by amine coated silica gel column chromatography (hexane:ethyl acetate=3:1) to give the title compound as an orange solid (107.9 mg, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:23])[CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1.[ClH:24]>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:23])[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[ClH:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C(F)c2ccc(F)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc(C(F)C2CCNCC2)c(F)c1
Temperature: 45 °C

Procedure:
To a solution of racemic tert-butyl 4-((2,4-difluorophenyl)fluoromethyl)piperidine-1-carboxylate (148 mg, 0.449 mmol) in dioxane (1.50 mL) was added HCl (4 M in dioxane, 337 μL, 1.348 mmol). The mixture was heated at 45° C. for 16 h then concentrated in vacuo to give the title compound as its HCl salt (109 mg, 91%) as a white solid.
Reaction SMILES: Br[C:2]1([C:8]([OH:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.C([O-])([O-])=O.[Na+].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OCC(C)(C)CO2)=[CH:20][CH:19]=1.CCO>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]2[N:3]=[C:2]([C:8]([OH:10])=[O:9])[CH:7]=[CH:6][CH:5]=2)=[CH:20][CH:19]=1
Reactant: CC1(C)COB(c2ccc(F)cc2)OC1
Reactant: O=C(O)C1(Br)C=CC=CN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: O=C(O)c1cccc(-c2ccc(F)cc2)n1
Temperature: 100 °C
Yield: 46 %

Procedure:
A solution of 2-bromo-picolinic acid (2.02 g, 10 mmol, Aldrich) in DME containing 4 mL of 10% aq. Na2CO3 was purged with Ar gas, treated with Pd(PPh3)4 followed by 2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2.40 g, 11.5 mmol, Aldrich) and EtOH (20 mL). This mixture was then also purged with Ar gas. The reaction mixture was heated at 100° C. for 2.5 h in a sealed tube. Additional 2-bromo-picolinic acid (900 mg) and Pd(PPh3)4 was added, and after purging with Ar gas it was heated at 100° C. for 4.5 h. Trifluoroacetic acid (20 mL) was added to the reaction and the mixture was concentrated in vacuo. MeOH (150 mL) was added to the residue and the insoluble material was filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica gel eluting with EtOAc/MeOH (9:1) followed by EtOAc/MeOH/HOAc (14:30:1) to afford the desired product (1.0 g, 40% based on borinane starting material) as a white solid. 1H NMR (CD3OD) δ 8.01 (d, 1H, J=7.7 Hz), 7.94–7.87 (m, 3H), 7.73 (d, 1H, J=7.7 Hz), 7.13 (t, 2H, J=8.8 Hz); MS(ESI+) m/z 234 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[O:15][C:14](=[NH:23])[C:13]=2[C:24]#[N:25])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].NC1C=C2C(C(C3C=C(OC)C(OC)=C(Br)C=3)=C(C#N)C(=N)O2)=CC=1.C(ON=O)(C)(C)C>>[NH2:23][C:14]1[O:15][C:16]2[C:21]([CH:12]([C:4]3[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=3)[C:13]=1[C:24]#[N:25])=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2
Reactant: COc1cc(-c2c(C#N)c(=N)oc3cc(Cl)ccc23)cc(Br)c1OC
Agent: CC(C)(C)ON=O
Agent: COc1cc(-c2c(C#N)c(=N)oc3cc(N)ccc23)cc(Br)c1OC
Product: COc1cc(C2C(C#N)=C(N)Oc3cc(Cl)ccc32)cc(Br)c1OC

Procedure:
4-(3-bromo-4,5-dimethoxy-phenyl)-7-chloro-3-cyano-2-imino-2H-chromene: The title compound was prepared from 7-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-2H-chromene (82 mg, 0.205 mmol), t-butyl-nitrite (0.8 mL, 6 mmol) and CuCl2 (104 mg, 0.774 mmol) by a procedure similar to Example 62b and isolated as a yellow solid (16 mg). 1H NMR (CDCl3): 7.82 (s, 1H), 7.22–7.16 (m, 4H), 6.94 (d, J=1.8 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: [C:1]1([P:7]2(=[O:16])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]=[C:19]=[O:20]>C(#N)C>[C:1]1([P:7]2(=[O:16])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]2[C:19]([NH:18][CH3:17])=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN=C=O
Reactant: O=P1(c2ccccc2)NCc2ccccc21
Solvent: CC#N
Product: CNC(=O)N1Cc2ccccc2P1(=O)c1ccccc1
Temperature: 26 °C
Yield: 86 %

Procedure:
A mixture of 1-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.5 g, 0.0065 mol) and methylisocyanate (1.92 g, 0.0337 mol) in 15 ml. of acetonitrile was heated with constant stirring at reflux for 16 hours. The mixture was allowed to air cool to 26° C. and was then cooled to 0° C. in an ice bath. The mixture was filtered and the precipitate washed with anhydrous ether to yield 1-phenyl-2-methylaminocarbonyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.6 g, 86% yield) as a white solid having a melting point of 219°-221° C. and the following analysis:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[CH2:21][CH2:20]2)=[O:18])=[C:11]([N+:33]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:33][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[CH2:23][CH2:24]1)=[O:18]
Reactant: COc1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c(N)cc1OCc1ccccc1
Yield: 91.3 %

Procedure:
[4-(Benzyloxy)-5-methoxy-2-nitrophenyl][4-(2-methoxyphenyl)piperazino]methanone (7a) (500 mg, 1.04 mmol) was dissolved in methanol (10 mL), SnCl2.2H2O (706 mg, 3.14 mmol) was added and refluxed until the TLC indicated the completion of the reaction. The methanol was evaporated by vacuum and the aqueous layer was then adjusted to pH 8 with 10% NaHCO3 solution and extracted with ethyl acetate (2×30 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (8a) (425 mg, 91% yield). 1H NMR (CDCl3) δ 3.20-3.30 (m, 4H), 3.45-3.55 (m, 4H), 3.85 (s, 3H), 3.98 (s, 3H), 5.20 (s, 2H), 6.19 (s, broad NH2) 6.80-7.00 (m, 5H), 7.30-7.50 (m, 5H), 7.70 (s, 1H); FABMS: 447 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]2([O:17][CH2:18][CH3:19])[CH2:14][C:13]2([F:16])[F:15])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1)[NH2:25].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:18]([O:17][C:12]1([C:4]2[N:3]=[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([N:29]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]4)=[C:22]([O:21][CH3:20])[CH:23]=3)[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=2)[CH2:14][C:13]1([F:16])[F:15])[CH3:19]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CCOC1(c2cc(C(C)(C)O)nc(Cl)n2)CC1(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC1(c2cc(C(C)(C)O)nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)n2)CC1(F)F
Temperature: 120 °C

Procedure:
A mixture of 2-(2-chloro-6-(1-ethoxy-2,2-difluorocyclopropyl)pyrimidin-4-yl)propan-2-ol (8 mg, 0.03 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (6 mg, 0.03 mmol), cesium carbonate (17.81 mg, 0.05 mmol), palladium acetate (1 mg, 4 μmol) and 2-(dicyclohexylphosphino)biphenyl (1.5 mg, 4 μmol) in dioxane (1.5 mL) was heated under argon atmosphere at 120° C. for 90 minutes in microwave reactor. The crude mixture was filtered through a short silica plug which was washed with 10% MeOH in EtOAc (35 mL). The residue was purified by preparative HPLC to give the title compound as a dry film, 6 mg (48%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccc1Cl
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Into a 500 mL round bottom flask was placed a solution of 2-chlorobenzoic acid (20 g, 127.80 mmol) in toluene (150 mL). To the mixture was added SOCl2 (16 g, 134.45 mmol). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 75° C. in a bath of oil. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 22.3 g (100%) of 2-chlorobenzoyl chloride as yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].C([Sn](CCCC)(CCCC)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)CCC.C(Cl)(Cl)Cl.Cl>O1CCOCC1.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>[S:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(-c2nccs2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 126 %

Procedure:
4-Bromoacetophenone (500 mg, 2.51 mmol) and 2-(tributylstannyl)thiazole (0.948 ml, 3.014 mmol) were dissolved in 1,4-dioxane (8 ml), and bis(triphenylphosphine)palladium dichloride (176 mg), was added to the solution under an argon gas atmosphere. The mixture was stirred at 90° C. for 8 hours. After the reaction solution was cooled to room temperature, chloroform and 1 N—HCl were added to the solution, and the extraction/separation step was carried out. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified on silica gel column chromatography (EtOAc:hexane=1:3) to yield the title compound (643 mg) as an opaque white solid.
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([CH2:7][N:8]([CH2:20][C@@H:21]2[C@@H:28]3[C@@H:24]([O:25][C:26]([CH3:30])([CH3:29])[O:27]3)[C@H:23]([N:31]3[C:35]4[N:36]=[CH:37][N:38]=[C:39]([NH:40][CH2:41][C:42]5[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=5[O:50][CH3:51])[C:34]=4[CH:33]=[CH:32]3)[CH2:22]2)[CH:9]2[CH2:12][CH:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH2:10]2)[CH2:6][CH2:5]1.Cl>O1CCCC1.CO>[CH:4]1([CH2:7][N:8]([CH2:20][C@@H:21]2[C@@H:28]3[C@@H:24]([O:25][C:26]([CH3:30])([CH3:29])[O:27]3)[C@H:23]([N:31]3[C:35]4[N:36]=[CH:37][N:38]=[C:39]([NH:40][CH2:41][C:42]5[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=5[O:50][CH3:51])[C:34]=4[CH:33]=[CH:32]3)[CH2:22]2)[CH:9]2[CH2:12][CH:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:10]2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)CCC1CC(N(CC2CC2)C[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC3CC3)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Lithium hydroxide, monohydrate (0.62 g, 15 mmol) added to a solution of ethyl 3-(3-((cyclopropylmethyl)(((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (0.98 g, 1.5 mmol) in Tetrahydrofuran (13 ml) and Methanol (3 ml). The reaction was stirred for 24 hours at RT, acidified with 1 N HCl to pH=6. The volatiles removed in vacuo and remaining water removed by azeotropic distillation with ethanol followed by 18 hours on lyophilizer. The resulting off white solid was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C[O:20][C:21]1[CH:26]=[C:25]([O:27]C)C=C[C:22]=1CCC(C1CCCC1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[O:13][C:25](=[O:27])[CH2:26][C:21](=[O:20])[CH2:22]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC(=O)C2CCCC2)c(OC)c1
Reactant: COc1ccc(CCC(=O)C2CCCC2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(86), Step 2 substituting 3-(3-chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one from Step 1 above in place of 3-(2,4-dimethoxyphenyl)-1-cyclopentylpropan-1-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[C:17](O)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]>>[OH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:25]
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C(O)c1ccccc1O
Product: O=C(Nc1ccccc1-c1cc2ccccc2[nH]1)c1ccccc1O
Yield: 46 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and salicylic acid in 46% yield following procedure 1. The compound was chromatographed on silica using an ethylacetate/hexane gradient. % Purity by LC/MS (230 DAD), Mass-spec (M+H+)=329, 1H NMR (MeOH-d4): 6.66 s (1H), 6.86 dd,
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[CH3:1][CH:2]1[N:7]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:20]3[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=3)[CH:24]=2)[CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1
Reactant: CC1CN(c2ccc(C#N)cn2)CCN1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC1CN(c2ccc(C#N)cn2)CCN1C(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 39 %

Procedure:
This compound was synthesized from 6-(3-methylpiperazin-1-yl)nicotinonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (75 mg, yield 39%). 1H NMR (400 MHz, MeOD) δ 8.41 (d, J=2.0 Hz, 1H), 8.27-8.25 (m, 1H), 8.18 (s, 1H), 7.77-7.72 (m, 3H), 6.89 (d, J=9.0 Hz, 1H), 4.39 (m, 3H), 3.48 (m, 2H), 3.22-3.15 (m, 1H), 1.29 (m, 3H). MS (ESI) m/z: Calculated for C21H17F3N6O2: 442.14. found: 443.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[C:16]=2[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:34][C:35]1[CH:36]=[N:37][C:38](Cl)=[N:39][CH:40]=1.[Cl-].[NH4+]>O1CCCC1.CN(C)C(=O)C.O>[Br:34][C:35]1[CH:36]=[N:37][C:38]([O:24][CH2:23][CH2:22][O:21][C:17]2[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=3)=[C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=3)(=[O:13])=[O:12])[N:19]([CH3:20])[N:18]=2)=[N:39][CH:40]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1cccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-1-methyl-4-(3-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Preparation 61) (101 mg) in tetrahydrofuran (2 ml) and N,N-dimethylacetamide (0.5 ml) at 0° C. was added sodium hydride (20 mg of a 60% dispersion in oil) followed by the 5-bromo-2-chloropyrimidine (66 mg) The reaction was stirred for one hour at 0° C. and then at room temperature overnight. Water (3 ml) was then added to the reaction followed by saturated aqueous ammonium chloride (3 ml) and the mixture was extracted with ethyl acetate (3×5 mls). The combined organics were then washed with 1:1 saturated ammonium chloride and water (4×15 ml) and dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the crude material (130 mg). The crude material was purified by HPLC on a 5μ ODS Phenomenex Magellen™ column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an off white solid (12 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:5]([OH:7])=[O:6].[CH2:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=2)=[CH:23][CH:22]=1)[CH2:18][CH:19]=[CH2:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CCOCC>[CH2:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:6][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([O:11][CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])=[C:2]([F:1])[CH:3]=3)=[CH:33][CH:34]=2)=[CH:23][CH:22]=1)[CH2:18][CH:19]=[CH2:20]
Reactant: C=CCCc1ccc(CCc2ccc(O)cc2)cc1
Reactant: CC[C@H](C)COc1ccc(C(=O)O)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C=CCCc1ccc(CCc2ccc(OC(=O)c3ccc(OC[C@@H](C)CC)c(F)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.2 %

Procedure:
About 4.5 g (0.02 mol) of 3-fluoro-4-[(S)-2-methylbutoxy]benzoic acid (which can be prepared, for example, as described in EP-A 255 962 ), 5.0 g (0.02 mol) of 4-[4-(3-butenyl)phenylethyl]phenol, 4.1 g (0.02 mol) of dicyclohexylcarbodimide and 0.1 g of 4-dimethylaminopyridine were mixed in 40 ml of ether at room temperature. The mixture was first heated to reflux for 4 hours and then stirred at room temperature for 14 hours, and the resulting urea was filtered off. Washing was carried out first with 2N hydrochloric acid and then with NaHCO3 solution, and the ether phase was worked up. Column chromatography on Al2O3 with methyl tert-butyl ether/petroleum ether (1:2) as mobile phase resulted in 4.9 g of [4-[4-(3-butenyl)phenyl]ethylphenyl]-3-fluoro-4-[(S)-2-methylbutoxy]benzoate (yield 53.9%) which showed the following phase behavior: C 77 N* 86 I.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH:17]([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:9]3)[CH:7]=1.[CH3:29][O:30][C:31]1[N:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+]>C(Cl)Cl>[F:18][CH:17]([F:19])[C@@H:14]1[C@@H:13]2[C@@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:37]([C:34]4[CH:33]=[N:32][C:31]([O:30][CH3:29])=[CH:36][N:35]=4)=[O:38])[CH:3]=[CH:4][C:5]=3[F:28])([N:9]=[C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[S:11][CH2:12]2)[CH2:16][O:15]1
Reactant: COc1cnc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)F)[C@H]2CS1
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C(F)F)[C@H]3CSC(NC(=O)OC(C)(C)C)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a stirred solution of tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (2.70 g) and 5-methoxypyrazine-2-carboxylic acid (1.25 g, described in WO2009/091016), in DCM (30 mL) was added N,N-diisopropylethylamine (3.5 mL) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (4.2 g). The reaction mixture was stirred at RT for 18 h, concentrated under vacuum to circa 20 mL, and sodium bicarbonate (sat., aq., 100 mL) was added. The mixture was extracted with EtOAc (2×150 mL), the combined organic portions were dried over MgSO4, evaporated and purified by silica gel chromatography (0% to 25% EtOAc in DCM gradient) to afford the title compound (1.74 g) as a white solid. NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 9H), 2.76-2.88 (m, 1H), 2.95-3.28 (m, 1H), 3.34-3.53 (m, 1H), 3.83-3.93 (m, 1H), 4.10 (s, 3H), 4.46-4.68 (m, 2H), 5.98 (dt, J=3.6, 56.8 Hz, 1H), 7.07-7.20 (m, 1H), 7.36-7.48 (m, 1H), 7.96-8.04 (d, J=7.8 Hz, 1H), 8.20 (d, J=1.0 Hz, 1H), 9.04 (d, J=1.3 Hz, 1H), 9.53 (br. s., 1H)
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:8]=[N:7]1.[Cl:20][C:21]([Cl:26])([Cl:25])[C:22](Cl)=[O:23]>ClC(Cl)C>[Cl:20][C:21]([Cl:26])([Cl:25])[C:22]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([C:9]3[CH:8]=[N:7][N:6]([CH3:5])[CH:10]=3)[CH:12]=2)[NH:17][CH:18]=1)=[O:23]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cn1cc(-c2cnc3[nH]cc(C(=O)C(Cl)(Cl)Cl)c3c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
76.3 g of AlCl3 are suspended in 600 ml of dichloroethane under argon, and 22.7 g of the product 2 prepared above are incorporated in portions. During this addition, the orange solution changes colour to dark brown. After 10 min, 19.2 ml of trichloroacetyl chloride are slowly added dropwise. The reaction batch is cooled here using a water bath. When the addition is complete, the mixture is stirred at RT for a further 6 h before the suspension is filtered off with suction and the filter cake is washed with dichloromethane and water. The filter cake is transferred into a flask, and water is carefully added with ice-water cooling. The beige solid is filtered off with suction, likewise rinsed and subsequently dried at 70° C. in a vacuum drying cabinet for 3 h, giving 20.6 g. The acidic mother liquor is poured into ice-water, the suspension is likewise filtered off with suction as described above and dried, giving 10.3 g. The mother liquor is left to stand for 12 h, and precipitated product is filtered off with suction and dried, giving 0.4 g. The solids are combined; HPLC-MS: Rt=2.132 min; [M+H+]: 345.0.