Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[C:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[C:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:19]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1C(=O)CBr
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2ncccc2CO[Si](C)(C)C(C)(C)C)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 employing 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromoacetyl-3-(tert-butyldimethylsilyloxymethyl)pyridine (step 2).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12]([O:21][CH2:22][CH3:23])(=[O:20])[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:14]>>[O:11]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:13]([OH:14])([C:12]([O:21][CH2:22][CH3:23])=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: O=C1CCCc2ccccc21
Product: CCOC(=O)C(O)(C(=O)OCC)C1CCc2ccccc2C1=O
Temperature: 100 °C
Yield: 70.4 %

Procedure:
A mixture of the required tetralone (0.01 mol) and diethyl mesoxalate (0.014 mol) was heated at 100° C. for 12 h. After cooling, the reaction mixture was purified by silica gel chromatography, eluting with cyclohexane/ethyl acetate (8/2), to give the white crystals. Yield 70.4%. ESI-MS: m/z 321.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[C:34]([NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH2:48])([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>C(Cl)CCl.CN(C=O)C.C(N(CC)CC)C.O>[C:37]([O:36][C:34](=[O:35])[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH:48][C:19](=[O:20])/[CH:18]=[CH:17]/[C:14]1[CH:15]=[CH:16][N:12]([S:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:22])=[CH:8][CH:7]=2)(=[O:11])=[O:10])[CH:13]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)c2)cc1

Procedure:
Starting materials: (E)-3-[1-(4-dimethylamino-benzenesulfonyl)-1H-pyrrol-3-yl)-acrylic acid (compound B3) (0.150 g), HOBt?H2O (0.072 g), triethylamine (259 μl), DMF (10 ml), EDC?HCl (0.269 g), N-BOC-1,2-phenylenediamine (0.049 g). Reaction conditions: room temperature, 1 hour; room temperature, 21 hours.
Reaction SMILES: O[C:2]([C:5]1[S:9][C:8](=[O:10])[S:7][C:6]=1[C:11]1[C:12](=[O:21])[NH:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:4])[CH3:3].C(OC(Cl)=O)C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][C:2]1([CH3:3])[O:21][C:12]2[C:11](=[N:20][C:19]3[C:14]([N:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]2[S:7][C:8](=[O:10])[S:9][C:5]1=2
Reactant: CC(C)(O)c1sc(=O)sc1-c1nc2ccccc2[nH]c1=O
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Oc2nc3ccccc3nc2-c2sc(=O)sc21
Reaction time: 8 h

Procedure:
3-(5-(2-Hydroxypropan-2-yl)-2-oxo-1,3-dithiol-4-yl)quinoxalin-2(1H)-one (6) (130 mg, 0.405 mmol) was partially dissolved in CH2Cl2 (10 mL). Benzylchloroformate (125 μL, 0.81 mmol) and triethylamine (120 μL) were added and the resulting yellow solution was stirred overnight. The volume of the solution was reduced to ca. 3 mL and it was purified by chromatography (silica gel, CH2Cl2) to give pure 4,4-dimethyl-4H-5-oxa-1,3-dithia-6,1,1-diaza-cyclopenta[a]anthracen-2-one (7). Yield: 82 mg (70%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:34])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:32])[C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][O:27]5)[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:33]=1.C[O-].[Na+].C([NH2:40])=O>>[Br:1][C:2]1[C:3]([F:34])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:20]([OH:32])[C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][O:27]5)[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([NH2:40])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:33]=1
Reactant: NC=O
Reactant: COC(=O)c1nc2n(c1C(O)c1ccnn1C1CCCCO1)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: C[O-]
Agent: [Na+]
Product: NC(=O)c1nc2n(c1C(O)c1ccnn1C1CCCCO1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
10-bromo-9-fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-9-fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford the crude title compound which was carried forward without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].B>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][OH:6]
Reactant: O=C(O)c1ccccc1CBr
Agent: B
Solvent: C1CCOC1
Product: OCc1ccccc1CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 3 neck 1-liter round bottomed flask equipped with a stirring bar, argon inlet, and pressure equalizing dropping funnel was added o-bromomethylbenzoic acid (35 g, 163 mmol) and 70 ml of dry tetrahydrofuran (THF). The slurry-solution was cooled in a 0° C. ice-salt bath and the dropping funnel was charged with a solution of borane in THF (212 ml of a 1.0 M solution, 212 mmol). This solution was added to the cold acid mixture, dropwise over 1 hour. When the addition was complete, the cooling bath was removed and the mixture was allowed to warm to room temperature and stir for 1 hour. The reaction was then quenched by careful addition of water (200 ml). The resulting solution was diluted with 600 ml of ether which resulted in a phase separation. The organic layer was separated and washed: H2O (2×500 ml) and brine (1×500 ml). Drying (MgSO4), filtration, and removal of the solvent in vacuo left 25 g of a solid which was recrystallized from boiling ethyl acetate-hexane to give the compound (1a): mp 61°-63° C.; 'H NMR (CDCl3) δ2.05 (s, 1H), 4.60 (s, 2H), 4.80 (s, 2H), 7.20-7.55 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH:45]=[CH:46][CH:47]=1)[CH2:38][NH:39][C:40]([CH:42]1[CH2:44][CH2:43]1)=[O:41].CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:46]2[CH:47]=[CH:35][CH:36]=[C:37]([CH2:38][NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[CH:45]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: O=C(NCc1cccc(Br)c1)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1)C1CC1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), cyclopropanecarboxylic acid 3-bromo-benzylamide (41.7 mg, 0.16 mmol), and Pd[P(Ph)3]4 (15.1 mg, 8.0 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.0 mg. MS: 498.3 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 0.55-0.70 (m, 4H), 1.50-1.60 (m, 1H), 1.73-1.98 (m, 3H), 2.07-2.29 (m, 1H), 3.35-3.56 (m, 2H), 4.24-4.37 (m, 3H), 4.85-5.08 (m, 2H), 6.97-7.54 (m, 12H), 7.63-780 (m, 1H), 8.50-8.59 (m, 1H), 10.06-10.13 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].O.[OH:17][C:18]1[CH:28]=[CH:27][C:21]([CH:22](O)[C:23](O)=[O:24])=[CH:20][CH:19]=1>C(O)(=O)C>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:15][C:23](=[O:24])[CH:22]([C:21]3[CH:27]=[CH:28][C:18]([OH:17])=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)C(O)c1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(O)cc1
Yield: 56.7 %

Procedure:
A mixture of 103.2 g (0.50 mol) of 2,4-di-tert-butylphenol and 102.4 g (0.55 mol) of 4-hydroxymandelic acid monohydrate in 100 ml of acetic acid is refluxed for 24 hours under a nitrogen atmosphere. The reaction mixture is then diluted with 140 ml of 50% aqueous acetic acid, cooled, and the precipitate formed is filtered off. The residue is washed with another 200 ml of 50% aqueous acetic acid and then dried, giving 95.9 g (57%) of 5,7-di-tert-butyl-3-(4-hydroxyphenyl)benzofuran-2-one, melting point 187°-190° C. (compound (101), Table 1).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[CH:11]=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:6])=[O:5].I[CH3:23]>CN(C=O)C>[CH3:23][N:7]([C:8]1[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[CH:11]=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])[S:4]([CH3:3])(=[O:6])=[O:5]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)cc(C(=O)OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)c1
Reaction time: 5 h

Procedure:
To a stirred suspension of NaH (0.24 g, 10 mmol, 60% in oil dispersion) in 10 mL of DMF was added dimethyl 5-(methylsulfonamido)isophthalate (1.435 g, 5 mmol) followed by iodomethane (0.62 mL, 10 mmol) at room temperature. After 5 h, the reaction was quenched by H2O (25 mL). Then the reaction mixture was extracted with EtOAc, further washed with H2O to remove excess of DMF, dried over anhydrous Na2SO4 and concentrated. The crude product thus obtained was washed with hexanes to give dimethyl 5-(N-methylmethylsulfonamido)isophthalate as a white solid in 91% (1.37 g) yield.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19](O)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:34]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O>O1CCCC1>[C:1]1([CH:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:42][CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: NCCN1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C

Procedure:
To a suspension of 6-[(2,2-diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl) 9H-purine-2-carboxylic acid (249 g, 0.561 moles) (Preparation 21) in anhydrous tetrahydrofuran (2500 ml) was added N,N′-carbonyldiimidazole (109 g, 0.672 moles) in two portions over 10 minutes. The resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen whereupon the solid gradually dissolved to give a cloudy pale orange solution. After stirring for 2.5 h, the reaction mixture was cooled in an ice-bath, and a solution of 2-(1-piperidinyl)ethylamine (86.4 g, 0.674 moles) in anhydrous tetrahydrofuran (100 ml) was added over a period of 55 minutes during which time a clear orange solution formed. The reaction mixture was stirred at room temperature for a further 17.5 hours. Deionised water (10 ml) was then added and the reaction mixture was then distilled at atmospheric pressure until approximately 2400 ml of distillate had collected. To the resultant amber oil was added isopropanol (2000 ml) and distillation at atmospheric pressure was continued until approximately 50 ml of distillate had collected. The resultant dark orange solution was allowed to cool to ambient temperature and further isopropanol (600 ml) was added to give a solution of the title compound in isopropanol that may be used directly without further purification.
Reaction SMILES: [C:1](C1C=C2C(=CC=1)N(C1CCCCO1)N=C2)#C.[C:18]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[N:26]=[CH:25]2)#[C:19][CH2:20][CH3:21]>>[C:18]([C:22]1[C:23]([CH3:1])=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[N:26]=[CH:25]2)#[C:19][CH2:20][CH3:21]
Reactant: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: C#Cc1ccc2c(cnn2C2CCCCO2)c1
Product: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1C

Procedure:
The title compound was prepared from 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilypethynyl)-1H-indazole following the procedures outlined for Intermediate 2 (step 2) and Intermediate 3. 1H NMR (300 MHz, DMSO-d6): δ 7.97 (s, 1H), 7.27 (d, 1H), 7.11 (d, 1H), 5.59 (dd, 1H), 3.58 (m, 1H), 3.50 (m, 1H), 2.38 (s, 3H), 2.17 (q, 2H), 2.13 (m, 1H), 1.77 (m, 2H), 1.50 (m, 1H), 1.36 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: COC1C(C(N2CCSC2=S)=O)=CC(C(NC)=O)=CC=1C(NC)=O.[CH2:25]([O:32][C:33](=[O:65])[NH:34][CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:64])[C:40]1[CH:45]=[C:44]([C:46]([N:48]2[CH2:52][CH2:51][S:50][C:49]2=[S:53])=[O:47])[C:43]([O:54][CH3:55])=[C:42]([C:56]([N:58]2CCS[C:59]2=S)=[O:57])[CH:41]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33](=[O:65])[NH:34][CH2:35][CH2:36][CH2:37][NH:38][C:39](=[O:64])[C:40]1[CH:45]=[C:44]([C:46]([N:48]2[CH2:52][CH2:51][S:50][C:49]2=[S:53])=[O:47])[C:43]([O:54][CH3:55])=[C:42]([C:56](=[O:57])[NH:58][CH3:59])[CH:41]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1c(C(=O)N2CCSC2=S)cc(C(=O)NCCCNC(=O)OCc2ccccc2)cc1C(=O)N1CCSC1=S
Agent: CNC(=O)c1cc(C(=O)NC)c(OC)c(C(=O)N2CCSC2=S)c1
Product: CNC(=O)c1cc(C(=O)NCCCNC(=O)OCc2ccccc2)cc(C(=O)N2CCSC2=S)c1OC
Yield: 71 %

Procedure:
Compound 7C was prepared by the same procedure as compound 7A except compound 6C was used instead of compound 6A. Separation and purification were performed as described for compound 7A, pure material was obtained as a thick, bright yellow oil, yield: 71%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)[CH:21]=[CH:20][N:19]=1>Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(-c3c[nH]c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Agent: Cl
Product: Fc1cccc(F)c1-c1ccc2[nH]cc(-c3nccc(N[C@@H]4CCCNC4)n3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-tert-butyl 3-(2-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)pyrimidin-4-ylamino)piperidine-1-carboxylate (500 mg, 0.757 mmol) in dioxane (10 mL) was treated with aqueous 1N NaOH (5 mL) and heated at 100° C. for 2 h. The resulting mixture was cooled to RT, and quenched with ice cold water. The resulting precipitate was collected by filtration, washed with ice cold water and dried to obtain the pure (R)-tert-butyl 3-(2-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrimidin-4-ylamino)piperidine-1-carboxylate (350 mg, 92%). (R)-tert-butyl 3-(2-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrimidin-4-ylamino)piperidine-1-carboxylate (350 mg, 0.69 mmol) was treated with ethanolic HCl (10 mL). The reaction mixture was stirred at RT for 16 h and then extracted with DCM. The combined organic layers were dried; filtered and concentrated to give the crude product, which was purified by recrystallization using 10% MeOH in CHCl3 to yield (R)-2-(5-(2,6-difluorophenyl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-4-amine MS (ESI, pos. ion) m/z: 406 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C1([O:24][C:25](=O)[NH:26][C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[C:30]([C:35]#[N:36])=[CH:29][N:28]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:35]([C:30]1[C:31]([CH2:33][CH3:34])=[CH:32][C:27]([NH:26][C:25]([N:7]2[C:6]3[C:11](=[CH:12][C:13]([CH:14]=[O:15])=[C:4]([CH:3]([O:2][CH3:1])[O:16][CH3:17])[N:5]=3)[CH2:10][CH2:9][CH2:8]2)=[O:24])=[N:28][CH:29]=1)#[N:36]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCc1cc(NC(=O)N2CCCc3cc(C=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 90 °C

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 400 mg, 1.69 mmol), phenyl(5-cyano-4-ethylpyridin-2-yl)carbamate (intermediate 111, 773 mg, 2.89 mmol) and DMAP (293 mg, 2.40 mmol) in DMF (3 ml) was heated for 1 h at 90° C. The cooled reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution, extracted 2× with EtOAc, the organic layers dried over Na2SO4 and evaporated. The residue was applied to a 40 g RediSep® column and purified by normal phase chromatography, eluting with hetane and then a gradient from heptane to EtOAc. Product containing fractions were combined and evaporated to give the title compound. (UPLC-MS 6) tR 1.23; ESI-MS 410.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[C:29]([O:33][C:34](=[O:38])[C@H:35]([CH3:37])[NH2:36])([CH3:32])([CH3:31])[CH3:30]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][NH:36][C@@H:35]([CH3:37])[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:38]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: C[C@H](NCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (105.5 mg, 0.282 mmol) and L-alanine tert-butyl ester hydrochloride (51.2 mg, 0.282 mmol) according to Reference R and the general procedure for reductive amination to give (S)-tert-butyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzylamino)propanoate as a yellow-orange solid. MS (ESI) m/z: Calculated: 503.2; Observed: 503.8 (M++1).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(N(CC)CC)C.[CH3:15][C:16]1[CH:52]=[CH:51][CH:50]=[CH:49][C:17]=1[CH2:18][NH:19][C:20]([C@@H:22]1[C:26]([CH3:28])([CH3:27])[S:25][CH2:24][N:23]1[C:29](=[O:48])[C@@H:30]([OH:47])[C@@H:31]([NH:39][C:40](=[O:46])[C@H:41]([CH:43]([CH3:45])[CH3:44])[NH2:42])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:21]>C(OCC)(=O)C>[CH3:15][C:16]1[CH:52]=[CH:51][CH:50]=[CH:49][C:17]=1[CH2:18][NH:19][C:20]([C@@H:22]1[C:26]([CH3:28])([CH3:27])[S:25][CH2:24][N:23]1[C:29](=[O:48])[C@@H:30]([OH:47])[C@@H:31]([NH:39][C:40](=[O:46])[C@@H:41]([NH:42][C:5](=[O:7])[CH3:6])[CH:43]([CH3:45])[CH3:44])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:21]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C)C(C)C
Reaction time: 8 h

Procedure:
Acetic anhydride (31 μl) and triethylamine (46 μl) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) (162 mg) obtained in the step 2 of Example 8 in ethyl acetate (5 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was reprecipitated from ethyl acetate/n-hexane to obtain the title compound (143 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[CH:24](=O)[C:25]1[O:29][CH:28]=[CH:27][CH:26]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:24]([C:25]3[O:29][CH:28]=[CH:27][CH:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=Cc1ccco1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: c1coc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (200 mg, 0.646 mmol) in dimethylformamide (2 mL) was added furfural (80.7 mg, 0.840 mmol) and oxone (258 mg, 0.420 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (121 mg, 49% yield) as pale yellow crystals.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17]C)[CH:13]=2)[CH:8]=1)[CH2:2][CH2:3][CH3:4].Br>C(O)(=O)C>[CH2:1]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccc2cc(OC)ccc2c1
Agent: Br
Solvent: CC(=O)O
Product: CCCCNCc1ccc2cc(O)ccc2c1
Yield: 80 %

Procedure:
A mixture of butyl-(6-methoxy-naphthalen-2-ylmethyl)-amine (10.0 g, 41.09 mmol), prepared in the previous step, 300 mL of 48% HBr and 200 mL of glacial acetic acid was refluxed under nitrogen for 19 h (overnight). The solvent was removed under reduced pressure. The resulting residue was partitioned between ethyl acetate and 5% sodium bicarbonate. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give 6-butylaminomethyl-naphthalen-2-ol (7.54 g, 80%) as a brown solid, mp 108-112° C.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]=[C:9]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:6][C:5]([CH3:24])=[CH:4][N:3]=1.C1N2CCN(CC2)C1.O>CN(C)C=O.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>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:2]3=[N:3][CH:4]=[C:5]([CH3:24])[CH:6]=[C:7]3[NH:8][C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][CH:13]=1
Reactant: Cc1cnc(Cl)c(N=C(Cc2ccc(F)cc2)c2ccncc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc2c(-c3ccc(F)cc3)c(-c3ccncc3)[nH]c2c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
6.15 g (18.1 mmoles) of (2-Chloro-5-methyl-pyridin-3-yl)-[2-(4-fluoro-phenyl)-1-pyridin-4-yl-ethylidene]-amine are dissolved in 100 mL of dimethylformamide under nitrogen. 6.4 g of DABCO (56 mmoles) and 610 mg of bis(triphenylphosphine)palladium dichloride are subsequently added to the reaction mixture which is stirred for 5 hours at 120° C. The cooled reaction mixture is then poured into water and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is recrystallized into ethyl acetate to afford 5.3 g of 3-(4-Fluoro-phenyl)-6-methyl-2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine as a yellowish solid.