Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:15][CH3:16])=[CH:5][C:6]=1[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8].[CH3:17][N:18](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:15]([C:4]1[S:3][C:2]([C:17]#[N:18])=[C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:5]=1)[CH3:16]
Reactant: CCc1cc(C(=O)N2CCCCC2)c(Br)s1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: CCc1cc(C(=O)N2CCCCC2)c(C#N)s1
Temperature: 100 °C

Procedure:
(2-Bromo-5-ethyl-thiophen-3-yl)-piperidin-1-yl-methanone (0.1 g, 0.33 mmol) was dissolved in DMF (3 mL). Zinc cyanide (0.34 mmol) and tetrakis-(triphenylphosphine) palladium (0) (0.017 mmol) were added and the reaction mixture heated at 100° C. for 4 hours. The mixture was cooled to ambient temperature and the reaction quenched with a mixture of 5% aqueous sodium thiosulphate and saturated aqueous potassium carbonate (1:1, 5 mL) and extracted with diethyl ether. The organic solution was dried over magnesium sulphate, filtered and the solvent removed. The product was purified by HPLC, eluting with 20%-95% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum and freeze-dried to give the title compound (0.26 mg). LCMS m/z 249.14 [M+H]+ RT=9.75 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 6.85 (t, 1H), 3.70 (m, 2H), 3.4 (m, 2H), 2.9 (m, 2H), 1.7 (m, 4H), 1.6 (s, 2H), 1.3 (t, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])[C:16]#[N:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O>O1CCCC1>[N:7]1([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[C:21]([F:22])([F:23])[F:24])[CH2:16][NH2:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: N#Cc1ccc(C(F)(F)F)c(N2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(C(F)(F)F)c(N2CCCCC2)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 46.5 %

Procedure:
Next, to a suspension of lithium aluminum hydride (44.8 mg, 1.18 mmol) in tetrahydrofuran (5.0 mL) was added 3-piperidin-1-yl-4-(trifluoromethyl)benzonitrile (100.0 mg, 0.39 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour and at room temperature for 14 hours. To the mixture was added water and extracted with ethylacetate. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (methanol:ethylacetate=1:2) to afford [3-piperidin-1-yl-4-(trifluoromethyl)benzyl]amine (46.8 mg, 46% yield).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[C:14]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[CH:23][C:15]=2[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([SH:41])[CH:38]=[CH:39][CH:40]=1>CN(C)C=O>[N:28]1([CH2:27][C:24]2[CH:25]=[CH:26][C:14]3[C:13]([S:41][C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=4)=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:16][C:15]=3[CH:23]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: CCOC(=O)c1sc2cc(Cn3ccnc3)ccc2c1Cl
Reactant: COc1cccc(S)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(Cn3ccnc3)ccc2c1Sc1cccc(OC)c1
Temperature: 60 °C
Yield: 90.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--0.26 ml, 1.7 mmol) was added to a mixture of ethyl 3-chloro-6-(1H-1-imidazolylmethyl)benzo[b]thiophene-2-carboxylate (Preparation 11, 500 mg, 1.6 mmol) and 3-methoxybenzenethiol (0.29 ml, 2.3 mmol) in dimethylformamide (2 ml) under a nitrogen atmosphere. The solution was heated to 60° C. for 5 hours and then partitioned between ethyl acetate and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using 5% methanol in dichloromethane as eluant to give the title compound as a gum (615 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5](=[CH:9][C:10]=1[Cl:11])[C:6]([OH:8])=O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:11][C:10]1[CH:9]=[C:5]2[C:6](=[O:8])[O:14][C:12](=[O:13])[C:4]2=[CH:3][C:2]=1[Cl:1]
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Yield: 89.9 %

Procedure:
In a flask equipped with a stirrer, nitrogen inlet, and DEAN-STARK trap, 10.0 grams of 4,5-dichlorophthalic acid, 150 milliliters of xylene, and several crystals of toluenesulfonic acid were added. The mixture was heated to reflux and water was collected in the DEAN-STARK trap over a period often hours. The xylene was distilled off and the solid was collected in a BÜCHNER funnel and allowed to air dry, yielding 8.3 grams of 4,5-dichlorophthalic anhydride.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].I[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[CH3:12][CH:11]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:13]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
Into a 1000-mL 3-necked round-bottom flask was placed 2-hydroxybenzaldehyde (36 g, 294.79 mmol, 1.00 equiv), 2-iodopropane (100 g, 588.26 mmol, 2.00 equiv), potassium carbonate (122 g, 882.71 mmol, 2.99 equiv) and N,N-dimethylformamide (500 g, 6.84 mol, 23.21 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 1000 mL of water. The resulting solution was extracted with 3×500 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 50 g (crude) of 2-(propan-2-yloxy)benzaldehyde as a yellow oil.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]([F:37])([F:36])[C:8]1[CH:13]=[C:12]([C:14]2([C:28]([F:31])([F:30])[F:29])[CH2:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25]O)=[C:21]([Br:27])[CH:20]=3)=[N:16][CH2:15]2)[CH:11]=[C:10]([C:32]([F:35])([F:34])[F:33])[N:9]=1.C([N:40](CC)CC)C.N>C1COCC1.CO>[F:6][C:7]([F:37])([F:36])[C:8]1[CH:13]=[C:12]([C:14]2([C:28]([F:31])([F:30])[F:29])[CH2:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH2:40])=[C:21]([Br:27])[CH:20]=3)=[N:16][CH2:15]2)[CH:11]=[C:10]([C:32]([F:35])([F:34])[F:33])[N:9]=1
Reactant: CCN(CC)CC
Reactant: OCc1ccc(C2=NCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Br
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(C2=NCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
Methanesulfonyl chloride (0.17 g) was added to (4-{3-[2,6-bis(trifluoromethyl)pyridin-4-yl]-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl}-2-bromophenyl)methanol (0.46 g) and triethylamine (0.26 g) in THF at −10° C. and the resultant mixture was stirred for 30 min. The mixture was poured into ammonia (10 ml), THF (10 ml) and MeOH (10 ml), and the resultant was stirred at room temperature overnight. After the solvents were evaporated under reduced pressure, the residue was diluted with t-BuOMe and H2O, and the organic layer was dried over MgSO4. After the solvents were evaporated under reduced pressure, the residue was purified with column chromatography to get the targeted product (0.4 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:5]=[C:6]2[C@@H:11]([NH:12][CH2:13][C@H:14]([C@@H:16]([NH:20][C:21](=[O:25])[CH2:22][O:23][CH3:24])[CH2:17][CH:18]=[CH2:19])[OH:15])[CH2:10][C:9]3([CH2:28][CH2:27][CH2:26]3)[O:8][C:7]=12.[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[Sn](CCCC)(CCCC)CCCC>C1COCC1.O.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>[CH3:32][C:30]([CH3:31])([CH3:33])[CH2:29][C:4]1[CH:5]=[C:6]2[C@@H:11]([NH:12][CH2:13][C@H:14]([C@@H:16]([NH:20][C:21](=[O:25])[CH2:22][O:23][CH3:24])[CH2:17][CH:18]=[CH2:19])[OH:15])[CH2:10][C:9]3([CH2:28][CH2:27][CH2:26]3)[O:8][C:7]2=[C:2]([C:36]2[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=2)[N:3]=1
Reactant: C=CC[C@H](NC(=O)COC)[C@H](O)CN[C@H]1CC2(CCC2)Oc2c1cc(CC(C)(C)C)nc2Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](NC(=O)COC)[C@H](O)CN[C@H]1CC2(CCC2)Oc2c1cc(CC(C)(C)C)nc2-c1nccn1C
Temperature: 160 °C

Procedure:
A solution of N-((1S)-1-((1R)-2-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-hydroxyethyl)-3-buten-1-yl)-2-methoxyacetamide (225 mg, 469 μmol) and tetrakis(triphenylphosphine)palladium (108 mg, 93.7 μmol) in THF (3.0 mL) is added to a vial with 1-methyl-2-(tributylstannyl)-1H-imidazole (217 mg, 586 μmol). The reaction was heated in the microwave at 160° C. for 20 min. The residue was diluted with H2O (10 mL) and extracted with CH2Cl2 (3×10 ml). The organic layers were dried (MgSO4), concentrated and purified by reverse phase HPLC to give the title compound as a white amorphous solid. MS m/z=526.3 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][CH2:15][C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>FC(C1C=CC=CC=1)(F)F>[S:18]1[CH:19]=[CH:20][C:16]([CH2:15][NH:14][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:17]1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: NCc1ccsc1
Solvent: CCN(C(C)C)C(C)C
Solvent: FC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1NCc1ccsc1
Temperature: 160 °C
Yield: 85.9 %

Procedure:
To a solution of 2-fluoro-5-trifluoromethylbenzonitrile 1A (1.11 g, 5.87 mmol) and 3-(aminomethyl)thiophene 1B (1.0 g, 8.85 mmol) in trifluoromethylbenzene (10 mL) was added diisopropylethylamine (2.3 g, 17.8 mmol). The reaction mixture was heated in a microwave reactor at 160° C. for 30 minutes. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to provide 2-[(thiophen-3-yl-methyl)amino]-5-trifluoromethylbenzonitrile 1C (1.42 g, 5.04 mmol) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[C:18](=[O:23])[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:12][CH2:11]1.[BH4-].[Na+].CC(C)=O>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:24])[CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[C:18](=[O:23])[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:12][CH2:11]1
Reactant: O=C(CC1CCN(Cc2ncc[nH]c2=O)CC1)c1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: O=c1[nH]ccnc1CN1CCC(CC(O)c2ccccc2F)CC1
Reaction time: 1 h
Yield: 82 %

Procedure:
After dissolving 217 mg of 3-[4-[2-(2-fluorophenyl)-2-oxoethyl]piperidino]methyl-1H-pyrazin-2-one in 30 ml of methanol, 25 mg of sodium borohydride was added while stirring on ice, and the stirring was continued for 1 hour. Acetone was added to the reaction solution and the mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: ethyl acetate/methanol) to obtain the title compound (179 mg, 82% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].B>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][OH:31])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a solution of 6-bromo-2-(4-carboxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (4.9 g) in tetrahydrofuran (20 ml) was added a solution (1M, 30 ml) of borane in tetrahydrofuran, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by recrystallization from methanol to give the title compound (2.97 g, 62%).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([NH2:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([NH:39][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:23])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:30][CH:31]=1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(c4ccccc4)c4ccc(Cl)cc4)[C@@]3(C)CC[C@@H]12
Yield: 80 %

Procedure:
The title compound was prepared in a yield of 80% in a similar manner to that described in Example 2 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and α-(4-chlorophenyl)benzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:17]=[C:18]=S.[NH2:20][C:21]1[C:22]([NH:37][CH3:38])=[CH:23][C:24]([O:32][CH2:33][CH:34]([F:36])[F:35])=[C:25]([CH:31]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27].CC(C)N=C=NC(C)C>CN(C=O)C>[CH2:29]([O:28][C:26]([C:25]1[C:24]([O:32][CH2:33][CH:34]([F:35])[F:36])=[CH:23][C:22]2[N:37]([CH3:38])[C:18]([NH:17][C:3]3[CH:4]=[C:5]([CH2:6][NH:7][C:8]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:14])[CH:15]=[CH:16][C:2]=3[Cl:1])=[N:20][C:21]=2[CH:31]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)c1cc(N)c(NC)cc1OCC(F)F
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(Nc3cc(CNC(=O)OC(C)(C)C)ccc3Cl)n(C)c2cc1OCC(F)F
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 4-chloro-3-isothiocyanatobenzylcarbamate ((see Example 2, step (c)) 974 mg; 3.26 mmol) and ethyl 5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)benzoate ((see Example 59, step (g)) 894 mg; 3.26 mmol) in DMF (10 mL) was stirred over night at rt. DIC (411 mg; 3.26 mmol) was added and the mixture was heated at 90° C. for 1.5 h. The mixture was concentrated and the residue was recrystallized from EtOAc/petroleum ether and washed with Et2O to give the sub-title compound. Yield: 1.75 g (99%).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([N:16]1[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][C@H:17]1[C:25]([OH:27])=[O:26])=[O:15])[CH3:13])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]([C:14]([N:16]1[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][C@H:17]1[C:25]([OH:27])=[O:26])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
Dissolve 1.70 g of 1-[N-Benzyloxycarbonyl-(S)-alanyl]octahydroindole-2(S)-carboxylic acid in 100 ml of methanol. Add 0.40 g 10% palladium-on-charcoal and hydrogenate the mixture at atmospheric pressure. Filter the mixture and concentrate in vacuo to give 1-[(S)-alanyl ]octahydroindole-2(S)-carboxylic acid, a white solid [α]D26 -18.5° (ethanol), m.p. 163°-165°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([CH3:29])[C:27]=1[OH:28])[NH2:24]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:24][C:23]3[CH:25]=[C:26]([CH3:29])[C:27]([OH:28])=[C:21]([Cl:20])[CH:22]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N)cc(Cl)c1O
Reactant: CC(C)(C)c1cccc(Nc2nc(Cl)ncc2F)c1
Product: Cc1cc(Nc2ncc(F)c(Nc3cccc(C(C)(C)C)c3)n2)cc(Cl)c1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of N4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidineamine with 3-chloro-4-hydroxy-5-methylaniline gave N4-(3-tert-butylphenyl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 25.46 min.; purity: 100%; MS (m/e): 400 (M+); 1H NMR (DMSO-d6): δ 9.63 (1H, s), 9.30 (1H, s), 8.82 (1H, s), 8.20 (1H, d, J=3.9 Hz), 7.92 (1H, d, J=8.8 Hz), 7.58 (2H, m), 7.40-7.20 (3H, m) 2.22 (3H, s), 1.35 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16]C)=[CH:9][CH:10]=3)[C:5]3([CH2:21][O:20][C:19]([NH2:22])=[N:18]3)[C:4]=2[C:3]=1[F:23].B(Br)(Br)Br>C(Cl)Cl>[NH2:22][C:19]1[O:20][CH2:21][C:5]2([N:18]=1)[C:4]1[C:3]([F:23])=[C:2]([Br:1])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:16])=[CH:9][CH:10]=1
Reactant: COc1ccc2c(c1)C1(COC(N)=N1)c1c(ccc(Br)c1F)O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC1=NC2(CO1)c1cc(O)ccc1Oc1ccc(Br)c(F)c12
Temperature: 0 °C

Procedure:
To a solution of 2′-bromo-1′-fluoro-7′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine (0.575 g, 1.516 mmol) in 15 mL of CH2Cl2 at −15° C. was added boron tribromide (1.0 M in CH2Cl2, 4.55 mL, 4.55 mmol). The mixture was slowly allowed to warm to 0° C. over the course of 1.25 hours at which point the reaction was carefully quenched with 2 mL of MeOH and saturated sodium bicarbonate (100 mL). This mixture was poured into a separatory funnel containing EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide 2-amino-2′-bromo-1′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-7′-ol as a glassy red solid. MS m/z=365.1 [M+H].
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:24][C:23]([NH:25][CH:26]5[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]5)=[N:22][N:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl>O1CCOCC1.O.[OH-].[Na+]>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:24][C:23]([NH:25][CH:26]5[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]5)=[N:22][N:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(NC5CCCN(C(=O)OC(C)(C)C)C5)s4)ccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1cccc(-c2c[nH]c3ccc(-c4nnc(NC5CCCNC5)s4)cc23)n1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
An orange solution of tert-butyl 3-(5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-ylamino)piperidine-1-carboxylate (38.6 mg, 0.056 mmol) and aq. NaOH (2.0 M, 0.1 mL, 0.200 mmol) in dioxane (1.0 mL) was heated at 100° C. for 30 min. Additional aq. NaOH (2.0 M, 0.1 mL, 0.200 mmol) was added, and the resulting mixture was stirred at 100° C. for 1.5 h. The mixture was then concentrated in vacuo, and the residue was taken up in HCl (4.0 M in dioxane; 1.0 mL, 4.00 mmol). The resulting yellow-orange mixture was stirred at 25° C. for 1 h, diluted with H2O (4 mL) and 1 N aq NaOH (3.5 mL). The resulting mixture was partitioned between DCM (30 mL) and saturated aq NaHCO3 (20 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide crude 5-(3-(6-isopropoxypyridin-2-yl)-1H-indol-5-yl)-N-(piperidin-3-yl)-1,3,4-thiadiazol-2-amine as a light-yellow solid, which was taken up in DMSO (2.0 mL) and purified by reverse phase HPLC (10-100% AcCN/H2O+0.1% TFA) to provide 5-(3-(6-isopropoxypyridin-2-yl)-1H-indol-5-yl)-N-(piperidin-3-yl)-1,3,4-thiadiazol-2-amine 2,2,2-trifluoroacetate (12.0 mg, 0.022 mmol, 39%) as a yellow oil: MS (ESI, pos. ion) m/z: 435.2 (M+1). 1H NMR (400 MHz, MeOH-d4) δ ppm 11.38 (br s, 1H), 8.80 (d, J=1.2 Hz, 1H), 7.98 (s, 1H), 7.75-7.79 (m, 1H), 7.71-7.75 (m, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.43 (d, J=7.4 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H), 5.53 (dt, J=12.2, 6.1 Hz, 1H), 4.07-4.16 (m, 1H), 3.68 (dd, J=12.2, 3.6 Hz, 1H), 3.34-3.35 (obsc m, 1H), 3.09-3.15 (m, 1H), 3.02-3.08 (m, 1H), 2.18-2.27 (m, 1H), 2.10 (dt, J=15.0, 5.1 Hz, 1H), 1.83-1.92 (m, 1H), 1.73-1.82 (m, 1H), 1.49-1.51 (m, 3H), 1.49 (s, 3H).
Reaction SMILES: [Cl-].C(O[C:5](=[NH2+:22])[CH2:6][N:7]1[C:17]2[C:18]3[N:9]([CH2:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]=3[CH:14]=[CH:15][CH:16]=2)[C:8]1=[O:21])C.N[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:41](=[CH:42][C:43]=1[N+:44]([O-])=O)[CH2:40][C@:30]1([C:38]3[C:33](=[N:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]1=[O:39])[CH2:29]2.C([O-])(O)=O.[Na+]>CCO>[CH3:19][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[N:7]([CH2:6][C:5]4[NH:44][C:43]5[CH:42]=[C:41]6[C:28](=[CH:27][C:26]=5[CH2:25][CH2:24][N:22]=4)[CH2:29][C@@:30]4([C:38]5[C:33](=[N:34][CH:35]=[CH:36][CH:37]=5)[NH:32][C:31]4=[O:39])[CH2:40]6)[C:8](=[O:21])[N:9]([C:18]=23)[CH2:10][C:11]1=[O:20]
Reactant: NCCc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Reactant: CCOC(=[NH2+])Cn1c(=O)n2c3c(cccc31)N(C)C(=O)C2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CN1C(=O)Cn2c(=O)n(CC3=NCCc4cc5c(cc4N3)C[C@]3(C5)C(=O)Nc4ncccc43)c3cccc1c32
Temperature: 100 °C

Procedure:
A mixture of 1-ethoxy-2-(6-methyl-2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)ethaniminium chloride from Step B (72 mg, 0.22 mmol) and (2S)-5-(2-aminoethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (73 mg, 0.25 mmol, described in Intermediate 15) in EtOH (7 mL) was heated to 100° C. for 5 min then allowed to cool. The reaction was poured into dilute aqueous NaHCO3 (50 mL) and the mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 80:20, to give the title compound. MS: 71/Z=520 (M+1) HRMS: m/z=520.2081; calculated m/z=520.2092 for C29H26N7O3.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:23])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([C:20](O)=[O:21])[CH:11]=[CH:10][C:9]1=2.[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[CH3:7][C:8]1([CH3:23])[CH2:17][CH2:16][C:15]([CH3:18])([CH3:19])[C:14]2[CH:13]=[C:12]([CH2:20][OH:21])[CH:11]=[CH:10][C:9]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(CO)ccc21

Procedure:
3.8g (0.1 mol) of lithium aluminium hydride and 100 ml of THF are introduced into a round-bottomed flask. Under a stream of nitrogen, a solution of 11.6 g (0.05 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoic acid in 100 ml of THF is added dropwise and the mixture is heated to reflux for four hours. The excess hydride is hydrolyzed with 7.2 ml of a 10% solution of sodium potassium tartrate, the precipitate is filtered off and the organic phase is evaporated. 10.6 g (97%) of the expected alcohol, melting point 74°-75° C., are collected.