Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:35])=[C:9]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:10]([C:17]2[C:26]3[O:25][CH:24]([F:27])[C:23]([F:29])([F:28])[O:22][C:21]=3[CH:20]=[CH:19][CH:18]=2)[C:11]=1[C:12]([O:14]CC)=O)(=O)C.Cl>>[CH3:35][C:8]1[NH:7][C:6]2[CH2:5][O:4][C:12](=[O:14])[C:11]=2[CH:10]([C:17]2[C:26]3[O:25][CH:24]([F:27])[C:23]([F:28])([F:29])[O:22][C:21]=3[CH:20]=[CH:19][CH:18]=2)[C:9]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1cccc2c1OC(F)C(F)(F)O2
Agent: Cl
Product: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1cccc2c1OC(F)C(F)(F)O2

Procedure:
10 mmol of diethyl 2-acetoxymethyl-1,4-dihydro-6-methyl-4-(2,2,3-trifluoro-1,4-benzodioxan-5-yl)-pyridine-3,5-dicarboxylate are heated in 25 mmol of ethanolic hydrochloric acid for 0.5 hour. The solvent is evaporated off and the residue is crystallized in a little ethanol with the addition of petroleum ether.
Reaction SMILES: [C:1]([O:4][C:5]1[N:6]=[C:7]([CH2:19]Br)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=[O:3])[CH3:2].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C=O)C.CCOCC.O>[C:1]([O:4][C:5]1[N:6]=[C:7]([CH2:19][N:25]2[C:21](=[O:31])[C:22]3[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24]2=[O:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=[O:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc2cc(OC(C)=O)nc(CBr)c2cc1OC
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2cc(OC(C)=O)nc(CN3C(=O)c4ccccc4C3=O)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a stirred solution of 1-(bromomethyl)-6,7-dimethoxyisoquinolin-3-yl acetate SIL 32162 (2.57 g, 7.56 mmol) in dry DMF (60 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added potassium phthalimide (2.43 g, 13.12 mmol) and the mixture was stirred overnight at RT and then diluted with Et2O (150 mL) and H2O (40 mL). A solid appeared and was isolated by filtration. The aqueous phase was isolated and diluted with Et2O (100 mL) before vigorous stirring for 15 min, which gave a new amount of solid that was isolated by filtration (done 3 times). The solids were then combined, further washed with Et2O (100 mL) and dried overnight under vacuum in presence of P2O5, which gave 2.10 g of 1-((1,3-dioxoisoindolin-2-yl)methyl)-6,7-dimethoxyisoquinolin-3-yl acetate SIL 32166 as an off-white solid (68%).
Reaction SMILES: [ClH:1].C[Si]([C:6]#[C:7][CH:8]1[N:17]=[C:16]([NH2:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1)(C)C.[F-].C([NH3+])(C)(C)C>C1COCC1>[ClH:1].[C:7]([CH:8]1[N:17]=[C:16]([NH2:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1)#[CH:6]
Reactant: C[Si](C)(C)C#CC1N=C(N)c2ccccc2N1
Agent: CC(C)(C)[NH3+]
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC1N=C(N)c2ccccc2N1
Reaction time: 2 h

Procedure:
A suspension of 1,2-dihydro-2-(trimethylsilylethynyl)-4-quinazolinamine hydrochloride (Example 24, 0.6 g, 2.14 mmol) in THF (30 ml) was treated with tert-butyl-ammonium fluoride (1.0M in THF, 2.36 ml) and stirred for 2 h. The mixture was evaporated and purified by flash chromatography on untreated neutral alumina eluting with 20% methanol/dichloromethane to give, after crystallisation with ethanol/ether, the product as a yellow powder (90 mg), m.p. 198°-200° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:17][CH:18](Br)[CH3:19].OP([O-])(O)=O.[K+]>O.C(OCC)(=O)C.CN(C=O)C>[Br:17][CH2:18][CH2:19][N:6]1[C:7]([CH2:9][OH:10])=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: O=[N+]([O-])c1cc(CO)[nH]n1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Temperature: 104 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A 1-L three-necked round-bottomed flask equipped with a mechanical stirrer and thermoregulator was purged with nitrogen and charged with 113a (25.0 g, 175 mmol), DMF (250 mL), and cesium carbonate (70.0 g, 215 mmol) was heated at 104° C. for 5 min. The reaction mixture was then cooled to 0° C. using an ice/acetone bath and dibromoethane (329 g, 1.75 mol) was added portionwise (no exotherm). The reaction was stirred at 0° C. for 1 then at room temperature for 4 h. After this time a solution of KH2PO4 (40 g) in water (400 mL) was added slowly. The reaction mixture stirred at room temperature for 30 min. Ethyl acetate (450 mL) was added and the aqueous layer was separated and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over sodium sulfate, and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to afford an 86% yield (37.5 g) of crude 113b as an orange oil: 1H NMR (300 MHz, CDCl3) δ 6.85 (s, 1H), 4.82 (d, 2H, J=5.4 Hz), 4.66 (t, 2H, J=6.3 Hz), 3.83 (t, 2H, J=6.3 Hz); MS (ESI+) m/z 249.9 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:16]([O:20][C:21](=[O:27])[CH2:22][S:23](Cl)(=[O:25])=[O:24])([CH3:19])([CH3:18])[CH3:17]>CN(C1C=CN=CC=1)C>[C:16]([O:20][C:21](=[O:27])[CH2:22][S:23](=[O:24])(=[O:25])[NH:15][C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[N:11]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)CS(=O)(=O)Cl
Reactant: CC(C)c1ccc(-c2csc(N)n2)cc1
Agent: CN(C)c1ccncc1
Product: CC(C)c1ccc(-c2csc(NS(=O)(=O)CC(=O)OC(C)(C)C)n2)cc1

Procedure:
4-(4-Isopropyl-phenyl)-thiazol-2-ylamine, chlorosulfonyl-acetic acid tert-butyl ester, DMAP (10 mol %) were combined using general procedure C (method 2) to afford [4-(4-Isopropyl-phenyl)-thiazol-2-ylsulfamoyl]-acetic acid tert-butyl ester. LCMS m/z: 398 (M+1)+; 1H NMR (CDCl3, 400 MHz): δ 1.27 (d, 6H); 1.44 (s, 9H); 2.95 (m, 1H); 4.06 (s, 2H); 6.48 (s, 1H); 7.32 (d, 2H); 7.39 (d, 2H); 10.5 (brs, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11](OCC)=[O:12])[O:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.CO.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[CH:11]=[O:12])[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCCC12OCCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=CC1CCCCC12OCCO2
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To the product of Example 74 (10.0 g, 46.7 mmol) in 150 mL of toluene cooled to -78° C. was added dropwise under argon (Ar) 93.5 mL (93.5 mmol) of diisobutylaluminum hydride (DIBAL) in toluene over a 15 min. period. After stirring this reaction for 45 min., MeOH (40 mL) was added dropwise followed by 200 mL of a saturated solution of Rochelle salts (potassium sodium tartrate tetrahydrate). The reaction was warmed to room temperature, stirred for one hour, and the organic layer was separated The aqueous layer was washed with EtOAc and the organic layer was stripped of all toluene. The residue and the EtOAc extract were combined, diluted with EtOAc, washed with water, dried (MgSO4), filtered and stripped of all solvent to yield the crude desired produce. This material was chromatographed through silica gel eluting with a 1:1 mixture of EtOAc and hexane to yield 6.4 g of the title material as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21]3)[CH:17]=[CH:16][C:15]=2[N+:27]([O-])=O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C1COCC1.O.[Fe].CC(O)=O>[OH:26][CH2:25][C:22]1[CH:23]=[CH:24][N:20]([C:18]2[CH:17]=[CH:16][C:15]3[N:27]=[C:9]([C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[C:1]#[N:2])[CH2:10][C:11](=[O:12])[NH:13][C:14]=3[CH:19]=2)[CH:21]=1
Reactant: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3ccc(CO)c3)ccc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc(C2=Nc3ccc(-n4ccc(CO)c4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 3-(3-cyano-phenyl)-N-[5-(3-hydroxymethyl-pyrrol-1-yl)-2-nitro-phenyl]-3-oxo-propionamide (Example M11) by reductive cyclization with Fe/HOAc in THF/H2O at 60° C. according to the general procedure J (method d). Obtained as a brown solid (18 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:19](=[S:20])[N:18]([CH3:22])[CH3:17])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CN(C)C(=S)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)C(=S)Oc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
8.13 g of 5-bromosalicylaldehyde was dissolved in 100 ml of acetone, followed by the addition of 6.7 g of anhydrous potassium carbonate. With stirring at room temperature, 5.0 g of N,N-dimethylthiocarbamoyl chloride was added to the above solution, and the stirring was continued for two hours. The resulting reaction solution was poured into ice water, and crystals thus precipitated were collected by filtration, and dried to obtain 9.2 g of 5-bromo-2-[(N,N-dimethylthiocarbamoyl)oxy]benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:32])[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(c2ccccc2)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(c2ccccc2)C1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(3-phenylpyrrolidin-1-yl)quinolin-7-yl]ethanone (0.0226 g, 0.0644 mmol) and ammonium acetate (0.0496 g, 0.644 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.16 mL, 0.16 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H23ClN3 (M+H)+: m/z=352.2; Found: 352.1.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(=CC=3)C(=O)N([C@@H](C(C)C)C(O)=O)C4)=CC=2)=CC=1.[C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[CH2:55]4)=[CH:48][CH:47]=2)=[CH:39][CH:38]=1)#[N:36]>>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[CH2:55]4)=[CH:50][CH:51]=2)=[CH:39][CH:38]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(C#N)cc4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(C#N)cc4)cc3)ccc2C1=O
Yield: 76 %

Procedure:
The compound of example 253 was prepared analogous to compound of example 225 by hydrolysis of compound of example 252.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[NH2:16])(=O)[CH3:2].C([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[C:23]([Cl:29])[CH:22]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(OCC)(=O)C>[Cl:29][C:23]1[CH:22]=[C:21]([OH:20])[CH:28]=[CH:27][C:24]=1[CH2:25][N:16]1[C:6]2[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:14]=[CH:15][C:5]=2[N:4]=[C:1]1[CH3:2]
Reactant: CC(=O)Oc1ccc(CBr)c(Cl)c1
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(N)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(O)cc3Cl)c2c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 15.6 %

Procedure:
Ethyl 4-(acetylamino)-3-aminobenzoate (6.34 g), 4-acetoxy-2-chlorobenzyl bromide (14.0 g), potassium carbonate (5.12 g), and sodium iodide (1.28 g) were added to ethyl acetate (35 ml) and uo (13 ml) and the whole was stirred for 15 hours at 70° C. The organic layer was separated, washed with water, and concentrated under reduced pressure. Ethanol (30 ml) and 35% hydrochloric acid (3.2 g) were added to the oily residue and the mixture was stirred for 3 hours at 70° C. After extraction of the reaction solution with ethyl acetate and water, the organic layer was separated and concentrated. The residue was crystallized by addition of ethanol. Crystals obtained by filtration was dried to obtain 1-(2-chloro-4-hydroxybenzyl)-6-(ethoxycarbonyl)-2-methylbenzimidazole (1.53 g).
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[F:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (S)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 201.1) and pyrimidin-5-ylboronic acid to afford a white powder. HPLC (Condition 4) tR=4.98 min, UPLC-MS (Condition 3) tR=0.97 min, m/z=478.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.65 (m, 1H) 1.84 (m, J=6.60 Hz, 1H) 2.15-2.29 (m, 1H) 2.96 (dd, J=10.75, 6.84 Hz, 1H) 3.06-3.42 (m, 5H) 4.60 (t, J=5.28 Hz, 1H) 7.47-7.64 (m, 2H) 7.96 (dd, J=13.10, 2.15 Hz, 1H) 8.06 (d, J=2.35 Hz, 1H) 8.77 (d, J=2.74 Hz, 1H) 8.84-8.94 (m, 2H) 9.17 (s, 1H) 10.29 (s, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=1.[CH2:20]([O:27][C:28]1[C:29]([O:36][CH3:37])=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>COCCOC.O>[CH2:20]([O:27][C:28]1[C:29]([O:36][CH3:37])=[C:30]([CH2:31][C:16]#[N:17])[CH:33]=[CH:34][CH:35]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1c(C=O)cccc1OCc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: COc1c(CC#N)cccc1OCc1ccccc1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
9.3 g (83 mmol) Potassium tert-butoxide in 30 mL 1,2-dimethoxyethane are cooled to −30° C. 9.1 g (45 mmol) toluene-4-sulfonylmethylisocyanide in 30 mL 1,2-dimethoxyethan are added slowly and the resulting mixture is cooled to −50° C. A mixture of 10.0 g (41.3 mmol) 3-benzyloxy-2-methoxy-benzaldehyde (see CN 102451178) in 80 mL 1,2-dimethoxyethane are added within 30 min and stirred for 2 h at −50° C. After that time 60 mL MeOH are added and stirred for 2 h under reflux. The mixture is cooled to r.t., diluted with water and extracted with DCM. The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel; cyclohexane/EtOAc 4:1) to yield the desired product.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C:5]1([NH:8][C:9]([C:11]2[C:12]([OH:41])=[C:13]3[C:18](=[C:19]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[N:20]=2)[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16](=[O:34])[C:15]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:14]3)=[O:10])[CH2:7][CH2:6]1.[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:27]([N:17]1[C:18]2[C:13](=[C:12]([OH:41])[C:11]([C:9]([NH:8][C:5]3([CH2:4][C:3]([OH:42])=[O:2])[CH2:6][CH2:7]3)=[O:10])=[N:20][C:19]=2[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:14]=[C:15]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:16]1=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)CC1(NC(=O)c2nc(-c3cccnc3)c3c(cc(-c4ccccc4)c(=O)n3Cc3ccccc3)c2O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1(NC(=O)c2nc(-c3cccnc3)c3c(cc(-c4ccccc4)c(=O)n3Cc3ccccc3)c2O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.3 %

Procedure:
A mixture of {1-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-cyclopropyl}-acetic acid methyl ester (5 mg, 0.0089 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 2 days, then concentrated to approximately one-third of its original volume. 1 M HCl was added until pH was about 3, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated to give 2.3 mg of the title compound as a yellow solid. MS: (+) m/z 547.35 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[OH:16])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:20][C:21]([OH:23])=[O:22]>O1CCCC1>[CH3:14][CH:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:16][CH2:20][C:21]([OH:23])=[O:22])[CH3:15]
Reactant: O=C(O)CBr
Reactant: CC(C)c1cc(C(C)C)c(O)c(C(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(OCC(=O)O)c(C(C)C)c1
Reaction time: 16 h
Yield: 61.9 %

Procedure:
A solution of 2,4,6-triisopropylphenol (4.0 g, 18 mmol) in 50 mL tetrahydrofuran was added dropwise to a suspension of sodium hydride (1.52 g, 38 mmol) in 25 mL tetrahydrofuran. The resulting pale green suspension was stirred for 30 minutes before a solution of bromoacetic acid (2.52 g, 18 mmol) in 50 mL tetrahydrofuran was added dropwise. The resulting thick suspension was stirred for 16 hours and then concentrated in vacuo. The residue was partitioned between 1N HCl and dichloromethane, the organic extract was dried over MgSO4, filtered, and concentrated to give a yellow solid. Recrystallized from hexanes to give 3.1 g of [2,4,6-tris(1-methylethyl)phenoxy]acetic acid, mp 105°-108° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2].[H-].[Na+].[Cl:19][Ti:20](Cl)([Cl:31])[C:21]1([CH3:30])[C:25]([CH3:26])=[C:24]([CH3:27])[C:23]([CH3:28])=[C:22]1[CH3:29]>C1(C)C=CC=CC=1>[Cl:19][Ti:20]([Cl:31])([C:21]1([CH3:30])[C:22]([CH3:29])=[C:23]([CH3:28])[C:24]([CH3:27])=[C:25]1[CH3:26])[O:16][C:5]1[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(-c2ccccc2)c1O
Reactant: CC1=C(C)C(C)([Ti](Cl)(Cl)Cl)C(C)=C1C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1=C(C)C(C)([Ti](Cl)(Cl)Oc2c(-c3ccccc3)cccc2C(C)C)C(C)=C1C
Temperature: 25 °C
Yield: 67 %

Procedure:
700 mg (3.28 mmol) of 2-isopropyl-6-phenylphenol and 236 mg (9.84 mmol) of sodium hydride were dissolved in 10 ml of toluene, and then refluxed for 4 hours. The refluxed solution was cooled to room temperature, and then a solution of 930 mg (3.21 mmol) of trichloro(pentamethylcyclopentadienyl)titanium (IV) was slowly added dropwise thereto, and the mixture was refluxed for 24 hours. After completion of the reflux reaction, volatile components were removed from the reaction solution, and the residue was washed with purified hexane, recrytallized from a mixed solvent of toluene/hexane −35° C., filtered, and then dried in a vacuum, thus obtaining 1.0 g of a red solid.
Reaction SMILES: C(O)=O.[CH2:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=3)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]=2)=[CH:8][CH:7]=1)[CH3:5].C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][NH:29][CH2:58][C@H:56]([OH:57])[CH2:55][O:54][C:51]4[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=4)=[CH:25][CH:26]=3)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]=2)=[CH:10][CH:11]=1)[CH3:5]
Reactant: CCc1ccc(-c2nc3cccnc3n2-c2ccc(CCN)cc2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=CO
Product: CCc1ccc(-c2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)cc1
Yield: 34.8 %

Procedure:
2-{4-[2-(4-Ethylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}-1-ethanamine formate (0.27 g, 0.746 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.2 g, 0.5 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol) to give the title compound (0.13 g, 0.174 mmol).
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([NH2:18])[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH2:19]([C@H:27]1[CH2:32]N[CH2:30][CH2:29][NH:28]1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:30][CH2:29][NH:28][C@@H:27]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:32]3)[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Yield: 42.3 %

Procedure:
By using a similar method of Example 460, using 2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.47 g, 5.69 mmol) and (S)-2-phenethyl-piperazine (1.08 g, 5.69 mmol) to give 1.04 g of the title compound as a yellow solid: mass spectrum (ion spray): m/z=432 (M+1); Analysis for C25H29N5S: calcd: C, 69.57; H, 6.77; N, 16.22; found: C, 69.40; H, 6.90; N, 15.98.
Reaction SMILES: N#N.[Cl-].[NH4+].C(O)C.[I:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[O:18][CH3:19]>[Fe].O>[I:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:18][CH3:19]
Reactant: COc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1I
Temperature: 85 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
In a 3-neck 250 mL round-bottomed flask equipped with a stir bar, condenser and N2 lines was placed iron powder (3.50 g, 62.7 mmol), ammonium chloride (4.88 g, 91.3 mmol), ethanol (72 mL) and water (23 mL). The mixture was heated to 85° C. and then 2-iodo-1-methoxy-4-nitro-benzene (5.0 g, 17.9 mmol) was added portion wise over a period of about 2 minutes. The mixture was allowed to stir at 85° C. for 2 hours and then filtered through celite. The celite was washed with EtOH (100 mL) and the filtrate was concentrated. To the concentrated material was added water (100 mL) and ethyl acetate (150 mL). The organic portion was removed and the aqueous portion was re-extracted with ethyl acetate (150 mL). The organic portions were combined, washed with brine (150 mL), dried (MgSO4) and concentrated. The crude material was purified by column chromatography utilizing 50% EtOAc/hexanes as the eluent to produce 3.92 g of 3-iodo-4-methoxy-phenylamine (I-45, X═I, Y═H, Z═NH2, R1═CH3) as a brown semi-solid in 88% yield. MS (ESI+): 250.1 (M+1)