Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:24][C:25]=3[C:26]([F:29])([F:28])[F:27])=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[C:30]1([C:23]2[O:24][C:25]([C:26]([F:27])([F:28])[F:29])=[C:21]([C:19]([NH:18][C:15]3[CH:14]=[CH:13][C:12]([N:9]4[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]4)=[CH:17][CH:16]=3)=[O:20])[N:22]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
A solution of 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid ethyl ester (1.1 g, 2.3 mmol) in 20 mL of MeOH was treated with 2.8 mL (5.6 mmol) of 2 N NaOH, and the reaction mixture was stirred at room temperature overnight. The resulting mixture was then concentrated to remove most of the MeOH solvent. The residue was then neutralized with concentrated HCl. A white precipitate formed. The product was then collected by filtration, washed with water, triturated with ether, and dried to furnish 0.82 g of 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid. This material was used in the next step without further purification.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH2:36][C:37]#[CH:38])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH2:36][C:37]#[CH:38])[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: C#CCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C(O)CO
Product: C#CCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CO
Yield: 26 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(prop-2-yn-1-ylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 26, preparation of starting materials) to give the title compound in 26% yield; NMR spectrum (DMSO-d6) 3.98 (s, 2H), 4.16 (s, 2H), 4.28 (s, 2H), 4.47 (s, 1H), 4.55-4.66 (m, 1H), 5.31 (s, 2H), 7.12-7.21 (m, 1H), 7.25 (d, 1H), 7.32-7.40 (m, 2H), 7.59 (d, 2H), 7.70-7.78 (m, 1H), 7.86-7.92 (m, 1H), 7.97-8.06 (m, 1H), 8.43-8.51 (m, 1H), 8.61 (d, 1H), 9.76 (s, 1H); Mass spectrum MH+ 518.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH2:11]([O:18][CH2:19][C@@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]1[N:31]=[CH:30][C:29]([N:32]([CH3:52])[C:33](=[O:51])[C:34]([C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)([CH3:36])[CH3:35])=[C:28]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=2[CH3:60])[CH:27]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][CH2:19][C@@H:20]1[CH2:25][N:24]([CH:1]=[O:3])[CH2:23][CH2:22][N:21]1[C:26]1[N:31]=[CH:30][C:29]([N:32]([CH3:52])[C:33](=[O:51])[C:34]([C:37]2[CH:42]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)([CH3:35])[CH3:36])=[C:28]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][C:54]=2[CH3:60])[CH:27]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCNC[C@H]2COCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1cc(N2CCN(C=O)C[C@H]2COCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 107.5 %

Procedure:
A mixture of 0.35 ml (3.7 mmol) acetic anhydride and 0.17 ml (4.6 mmol) formic acid was heated at 50° C. for 2 h. After cooling to room temperature a portion of 0.08 ml of this mixture was added to 0.5 ml THF. A solution of 0.10 g (0.14 mmol) (S)-N-[6-(2-benzyloxymethyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide (Example 383a)) in 1 ml THF was added dropwise at 0° C. Conversion was monitored by thin layer chromatography. After complete consumption of the starting material the reaction mixture was diluted with water and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give 0.11 g of crude (S)-N-[6-(2-benzyloxymethyl-4-formyl-piperazin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light yellow solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]([C:27]3([C:30]([O:32][CH3:33])=[O:31])[CH2:29][CH2:28]3)(O)[O:17][N:16]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:33][O:32][C:30]([C:27]1([C:18]2[O:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:28][CH2:29]1)=[O:31]
Reactant: COC(=O)C1(C2(O)ON=C(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a mixture consisting of 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropanecarboxylic acid methyl ester (Example 1, Compound C, 7.16 g) in dioxane (120 mL) is added concentrated aqueous hydrochloric acid (30 mL.) The mixture is brought to 100° C. for three hours. The mixture is cooled and is poured into ice water. The mixture is treated with sodium bicarbonate and is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and is filtered and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with hexanes-ethyl acetate (9:1 v/v) afforded the solid synthetic intermediate 1-[3-(4-hydroxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester (3.23 g, 9.63 mmol.)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[C:8]([N+]([O-])=O)=[CH:9][C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1.[OH-].[Na+]>C(Cl)Cl>[Br:6][C:7]1[C:8]([Cl:3])=[CH:9][C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(Cl)c(Br)c[n+]1[O-]
Temperature: 0 °C

Procedure:
4.2 mL (46 mmol) phosphorus oxychloride in 20 mL DCM were added dropwise at 10° C. to 3.6 g (15 mmol) 5-bromo-2-methyl-4-nitropyridine-1-oxide in 30 mL DCM. The reaction mixture was then refluxed for 5 h, then added to ice water and adjusted to a pH of 10 with 4N aqueous sodium hydroxide solution. The organic phase was separated off and the aqueous phase was extracted twice more with DCM. The combined organic phases were dried on sodium sulphate and evaporated down. The residue was stirred into petroleum ether, the precipitate formed was suction filtered and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Fc1cc(Br)cc(OC2CCCCO2)c1
Yield: 94.8 %

Procedure:
A solution of 3-bromo-5-fluorophenol (1.64 g, 8.59 mmol), 3,4-dihydro-2H-pyran (1.56 mL, 17.2 mmol) and PPTS (0.216 g, 0.859 mmol) in DCM (10 mL) was stirred for 16 h at rt. The reaction was concentrated in vacuo. The residual crude oil was purified by chromatography (SiO2) using a 0% to 20% EtOAc/hexane over 15 min to give the title compound (2.24 g, 8.14 mmol, 95% yield) as a clear oil. 1H NMR (CDCl3) δ: 7.05 (dd, J=2.8, 2.1 Hz, 1H), 6.90 (ddd, J=8.0, 2.2, 1.8 Hz, 1H), 6.77 (dt, J=10.6, 2.2 Hz, 1H), 5.41 (t, J=3.1 Hz, 1H), 3.91-3.81 (m, 1H), 3.72-3.58 (m, 1H), 2.05-1.92 (m, 1H), 1.92-1.82 (m, 2H), 1.81-1.58 (m, 3H); 19F NMR (CDCl3) δ: −110.28 (s); 13C NMR (CDCl3) δ: 164.22 (s), 162.24 (s), 158.78 (d, J=11.8 Hz), 122.41 (d, J=12.5 Hz), 115.88 (d, J=3.3 Hz), 112.33 (s), 112.13 (s), 103.42 (s), 103.22 (s), 96.67 (s), 61.97 (s), 30.05 (s), 25.01 (s), 18.39 (s).
Reaction SMILES: [Cl:1][C:2]1[CH2:3][N:4]=[CH:5][C:6]2([CH3:20])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([N:14]3[CH3:19])[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>O>[Cl:1][C:2]1[CH2:3][NH:4][CH2:5][C:6]2([CH3:20])[CH:17]([CH3:18])[CH:15]3[CH2:16][C:10]4=[C:11]([N:14]3[CH3:19])[CH2:12][CH2:13][C:7]2=[C:8]4[CH:9]=1
Reactant: CC1C2CC3=C(CCC4=C3C=C(Cl)CN=CC41C)N2C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC1C2CC3=C(CCC4=C3C=C(Cl)CNCC41C)N2C
Reaction time: 6.75 h
Yield: 68.9 %

Procedure:
To a stirred solution of 1.50 g of 10-chloro-1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 14 ml of acetic acid, cooled to 15° C. under nitrogen, was added, 1.00 g of sodium cyanoborohydride, with stirring. The reaction mixture was stirred an additional 6.75 hr and water was added. The solution was made basic (pH 12) with 50% aqueous sodium hydroxide solution. The mixture was extracted with ether and the combined organic layers were washed with brine, dried over anhydrous potassium carbonate and filtered. The filtrate was concentrated. The residue was dissolved in 15 ml acetic acid and, as above, treated with 1.63 g of sodium cyanoborohydride for 5 hr. The residue was purified by flash column chromatography (silica gel, 2% triethylamine/0-10% methanol/ether) to afford 1.04 g (69%) of product. Recrystallization from ether-dichloromethane afforded the analytical sample, mp 168°-170° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:66][N:67]([CH3:71])[CH2:68][CH2:69][NH2:70]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:70][CH2:69][CH2:68][N:67]([CH3:71])[CH3:66])=[O:20])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.08 h
Yield: 34.4 %

Procedure:
To a flask charged with 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 7)(90 mg, 0.211 mmol) and HATU (96 mg, 0.253 mmol) was added DMF (3 mL) and the resulting mixture was treated with DIPEA (0.110 mL, 0.632 mmol). After stirring for 5 min, the mixture was treated with N1,N1-dimethylethane-1,2-diamine (37.1 mg, 0.421 mmol). After stirring for 3 min, the solution was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 (×3), then dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was subsequently dissolved in MeOH and dried (hydrophobic frit). The solvent was removed and the residue triturated in Et2O to give 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)nicotinamide (36 mg, 0.072 mmol, 34.4% yield) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:14])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C=Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 4-formylcinnamic acid (7.04 g, 40 mmole), anhydrous potassium carbonate (16.5 g, 120 mmole) and methyl iodide (8.5 g, 60 mmole) in dry N,N-dimethylformamide (50 ml) was stirred overnight at room temperature and the solvent evaporated in vacuo. The product was partitioned between ether and water and the organic phase washed with brine and dried (MgSO4). Evaporation gave 7.32 g (97%) of the title ester of mp (aqueous methanol) 83°-85° C., νmax (mull) 1723, 1683, 1635 cm-1, δ(CDCl3) 3.83 (3H, s, CH3), 6.52 (1H, d, J15 Hz, C=CHCO2), 7.75 (1H, d, J 15 Hz, ArCH=C), 7.79 (4H, ABq, J 6 Hz, Δν16.5 Hz, arom), 10.08 (1H, s, CHO).
Reaction SMILES: C([C@H:3]([S:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH2:38])[CH3:34]>CO>[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH:38][C:4](=[O:6])[CH2:3][S@:7](=[O:8])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:15]=[N:14][CH:13]=1)[CH3:34]
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Reactant: CCN(CC)CCN
Solvent: CO
Product: CCN(CC)CCNC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Temperature: 30 °C
Yield: 60.3 %

Procedure:
(S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (73 mg, 0.16 mmol) in anhydrous MeOH (1.5 mL) was added N,N-diethylethylenediamine (0.12 mL, 0.84 mmol) dropwise. The reaction mixture was heated at 30° C. for 4 hours. The reaction mixture was evaporated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed once with brine, dried (anhydrous Na2SO4), concentrated. The residue was purified by chromatography (silica gel, 50:1 CHCl3:MeOH to 10:1 CHCl3:MeOH). The product containing fractions were concentrated to give the title compound as a foamy solid (50 mg, 59%).
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].C([O-])(=O)C.[Na+].[Br:44]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:44][C:22]1[CH:21]=[N:20][C:7]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:19])[CH3:17])[C:9]3[CH:10]=[N:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[C:6]=2[C:23]=1[N:24]1[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:25]1
Reactant: BrBr
Reactant: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(Br)cnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A mixture of (S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)pyrrolidin-3-yl(ethyl)carbamate (125 mg, 0.23 mmol), sodium acetate (38 mg, 0.46 mmol), and bromine (36 μL, 0.7 mmol) in acetic acid (1 mL) was stirred at ambient temperature for 1 minute. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow oil, which was used in the next step without any further purification (65 mg).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH2:17][CH3:18])([CH3:16])[NH:13][C:12]([CH2:20][CH3:21])([CH3:19])[CH:11]1[CH3:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](Br)[CH:24]=[CH2:25]>CN(C)C=O>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH2:17][CH3:18])([CH3:16])[N:13]([CH2:25][CH:24]=[CH2:23])[C:12]([CH2:20][CH3:21])([CH3:19])[CH:11]1[CH3:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: CCC1(C)CC(OC(=O)c2ccccc2)C(C)C(C)(CC)N1
Solvent: CN(C)C=O
Product: C=CCN1C(C)(CC)CC(OC(=O)c2ccccc2)C(C)C1(C)CC
Yield: 23.6 %

Procedure:
To a solution of 6.0 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidyl benzoate (Compound 10 - prepared using the same procedure as is described in Preparation 2) in 20 ml of dimethylformamide were added 6.0 g of allyl bromide, and the mixture was heated at 110°-115° C. for 9 hours. The mixture was then concentrated by evaporation under reduced pressure and 50 ml of benzene were added. The resulting mixture was then washed, in turn, with an aqueous solution of sodium carbonate and with water and was then dried over anhydrous sodium sulphate. After removing the solvent, the residue was distilled under reduced pressure, giving 1.6 g of Compound 36 as a colourless, viscous liquid (bp 163° C./0.004 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[C:4]([O:6]C)=[O:5].[I-].[Li+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(Cl)cc(I)cc1Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1c(Cl)cc(I)cc1Cl
Temperature: 130 °C
Yield: 87.9 %

Procedure:
Methyl 2,6-dichloro-4-iodobenzoate (46 g, 0.14 mol) was dissolved in pyridine (1380 mL) and water (230 mL). Lithium iodide (37.2 g, 0.28 mol) was added in one portion. The resulting mixture was heated at 130° C. for 30 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in 2N HCl (500 mL) and extracted with ethyl acetate (3×1 L). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in N-methyl morpholine (5 mL) and concentrated again. The residue was diluted with 2N HCl (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give 2,6-dichloro-4-iodobenzoic acid (39 g, yield: 88%). 1H NMR (DMSO-d6, 400 MHz) δ 14.26 (brs, 1H), 7.99 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[O:9][C:10]2=[O:11])=[CH:6][CH:5]=1)([O-])=O.CCCCC[C@H](O)C=C[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]1O>[Fe]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[O:9][C:10]2=[O:11])=[CH:6][CH:5]=1
Reactant: O=C1OC(=Cc2ccc([N+](=O)[O-])cc2)c2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: CCCCC[C@H](O)C=C[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Product: Nc1ccc(C=C2OC(=O)c3cc(N)ccc32)cc1

Procedure:
6-Nitro-3-(p-nitrophenylmethylene)phthalide prepared by the process mentioned in "Nihon Kagaku Kaishi (Journal of Japan Chemical Society)", page 110 (1973) was reduced with iron powder by conventional method and the resulting crude product was crystallized from isopropanol to obtain 6-amino-3-(p-aminophenylmethylene)phthalide.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:20]([NH2:23])[CH:21]=[CH2:22].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:20]([NH:23][S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH:21]=[CH2:22]
Reactant: C=CCN
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of Example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in DCM (10 ml). Allylamine (0.034 ml; 0.46 mmol; 1.40 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After one hour, the solvents are evaporated. The crude product is purified by preparative HPLC, affording Compound (12) is obtained as white-off solid (75 mg; 50%). 1H NMR (DMSO-d6) δ 2.22 (s, 3H), 2.51 (s, 3H), 3.61 (m, 2H), 5.14 (m, 1H), 5.26 (m, 1H), 5.80 (m, 1H), 7.28 (d, J=3.8 Hz, 1H), 7.62 (d, J=3.8 Hz, 1H), 8.17 (t, J=6 Hz, 1H), 12.39 (s, 1H). M−(ESI): 356.12; M+(ESI): 358.12. HPLC, Rt: 3.06 min (purity: 100%).
Reaction SMILES: [C:1]1([C:6]2[N:10]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:9]3=[C:8]([C:16]([NH:18][C@@H:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([NH:22][CH3:23])=[O:21])=[O:17])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1>[Pd].CO>[CH:1]1([C:6]2[N:10]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:9]3=[C:8]([C:16]([NH:18][C@@H:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([NH:22][CH3:23])=[O:21])=[O:17])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(C2=CCCC2)n2c1CN(C)CC2)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)c1nc(C2CCCC2)n2c1CN(C)CC2)C(C)(C)C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Palladium on carbon (wet) (0.014 mg, 0.013 mmol) was suspended in methanol (1 mL) and transferred under nitrogen into a hydrogenation reaction vessel followed by methanol (1 mL). (S)-3-cyclopentenyl-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide (0.062 g, 0.17 mmol) in methanol (3 mL) was added and the mixture was hydrogenated at 60 psi for 2 h. The mixture was filtered through a celite plug and concentrated. The residue was purified ion exchange chromatography, eluting the product with 2N methanolic ammonia to provide Compound 303 (0.05 mg, 78%) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 1.01 (s, 9H), 1.55 (m, 2H), 1.76 (m, 2H), 1.87 (m, 2H), 2.39 (s, 3H), 2.69 (m, 5H), 2.90 (s, 1H), 3.84 (m, 4H), 4.28 (s, 1H), 6.40 (m, 1H), 7.59 (d, 1H). LCMS (+ESI) m/z 376.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)O1>>[NH:28]1[C:27]2[C:26](=[C:4]([C:2]3[N:3]=[C:4]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:5]4[S:10][C:9]([C:26]5[CH:30]=[N:29][NH:28][CH:27]=5)=[CH:8][C:6]=4[N:7]=3)[CH:5]=[CH:6][CH:8]=2)[CH:30]=[N:29]1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: c1cc(-c2nc(N3CCOCC3)c3sc(-c4cn[nH]c4)cc3n2)c2cn[nH]c2c1

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (50 mg) was coupled to 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane via General Procedure I. The product was purified by reverse phase HPLC to yield 18.1 mg of 203. MS (Q1) 404 (M)+.