Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:50][CH2:51][C:52]1[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=1[CH3:58]>ClCCl>[CH:1]1([O:7][CH:8]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:50][CH2:51][C:52]3[C:53]([OH:60])=[N:54][C:55]([CH3:59])=[CH:56][C:57]=3[CH3:58])=[O:16])=[CH:17][CH:18]=2)[CH3:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(OC1CCCCC1)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)OC3CCCCC3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.6 %

Procedure:
To the solution of 4-(1-(cyclohexyloxy)ethyl)benzoic acid (62 mg, 0.25 mmol) in dichloromethane (80 mL) was added o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (143 mg, 0.38 mmol) and triethylamine (76 mg, 0.75 mmol). then the 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (131 mg, 0.86 mmol) was added, the solution was stirred at room temperature for 12 hours, then washed with water (50 mL*3), the organic layer was evaporate ed and purified by column chromatography (silica gel, dichloromethane/meth anol=20:1) to give 4-(1-(cyclohexyloxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (57 mg, 60%). LRMS (M+H+) m/z: calcd: 382.23. found 382; 1H-NMR (300 MHz, CD3OD) δ 7.76 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.11 (s, 1H), 4.69-4.67 (m, 1H), 4.49 (s, 2H), 3.20-3.14 (m, 1H), 2.37 (s, 3H), 2.24 (s, 3H), 1.69 (m. 1H), 1.51-1.49 (m, 3H), 1.38-1.36 (m, 1H), 1.29-1.20 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:7]4[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH:27](O)=[O:28]>>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:8]1[C:7]2[C:22](=[O:26])[NH:23][C:24](=[O:25])[C:6]=2[C:5]2[C:4]3[CH:3]=[C:2]([NH:1][CH:27]=[O:28])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: Nc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Reactant: O=CO
Product: O=CNc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O
Yield: 54 %

Procedure:
Amine (919) prepared as described in example 467 and formic acid were reacted using the procedure described in example 468 with a reaction time of 4 h to give the formamide (921) (54%) as a yellow powder, mp 293–297° C. 1H NMR δ [(CD3)2SO] 12.11 (s, 0.5H), 12.08 (s, 1H), 11.12 (s, 0.5H), 11.08 (s, 1H), 10.34 (s, 1H), 10.30 (s, 0.5H), 9.03 (d, J=1.9 Hz, 1H), 8.69 (m, 0.5H), 8.31 (d, J=1.8 Hz, 1.5H) 7.92 (dd, J=8.8, 1.9 Hz, 1H) 7.42–7.65 (m, 9.5H). Found: C, 64.78; H, 3.53; N, 9.96. C21H12ClN3O3.1/4 THF requires: C, 64.86; H, 3.44; N, 10.32.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([CH3:35])[CH:26]=4)[CH:22]=[C:21]([C:36]([F:39])([F:38])[F:37])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:35][C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([C:36]([F:37])([F:38])[F:39])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)[CH:30]=[CH:29][C:28]=1[C:31]([F:34])([F:33])[F:32]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(N)(=O)=O)s4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.24 g) in dichloromethane (5 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 80:10:1) and crystallization (MeOH/diethyl ether) to yield the title compound as a light yellow solid (0.14 g, 52%). MS (ISN) 532.3 [(M−H)−]; mp 260° C.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].[O:15]=[C:16]([C@@H:34]1[CH2:38][CH2:37][CH2:36][O:35]1)[CH2:17][CH2:18][C@H:19]1[NH:22][C:21](=[O:23])[C@H:20]1[NH:24][C:25](=[O:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>ClCCCl>[OH:3][CH:2]([N:22]1[C@H:19]([CH2:18][CH2:17][C:16](=[O:15])[C@@H:34]2[CH2:38][CH2:37][CH2:36][O:35]2)[C@H:20]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]1=[O:23])[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N[C@@H]1CCC(=O)[C@@H]1CCCO1
Reactant: COc1ccc(COC(=O)C=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2CCC(=O)[C@@H]2CCCO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
p-Methoxybenzyl glyoxylate (3.20 g, 16.5 mmol) in 1,2-dichloroethane (50 ml) was heated at reflux for 1h. using Dean and Stark apparatus. The solution was cooled in ice and treated successively with (3S,4R)-4-[3-oxo-3-[(S)-tetrahydrofuran-2-yl]propyl]-3-phenylacetamidoazetidin-2-one (4.10 g, 12.4 mmol) and triethylamine (170 μl, 1.22 mmol). After stirring at 0° C. for 30 min., the reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 50% ethyl acetate in hexane, then ethyl acetate to yield the title compound as a yellow foam (4.53 g, 70%); νmax (CH2Cl2) 3420, 3226, 1769, 1743, 1681, 1613 and 1516 cm-1 ; m/z (FAB, +ve ion, 3-nitrobenzyl alcohol/sodium acetate) 547 (MNa+).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]1.CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][CH2:28][C@@H:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (300 mg, 0.80 mmol) in DCE (5 mL) was slowly added to a solution of ethyl (3R)-piperidine-3-carboxylate (140 mg, 0.88 mmol) and DIPEA (1.4 mL, 8.0 mmol) in DCE (25 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was purified by MPLC on silica gel using 60-90% EtOAc/Heptane to provide the title compound as white solid. Yield: 265 mg (66%); 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J=7.13 Hz, 3 H), 1.33 (td, J=12.55, 4.00 Hz, 1 H), 1.50-1.57 (m, 3 H), 1.59 (s, 9 H), 1.62-1.71 (m, 2 H), 1.72-1.84 (m, 1 H), 1.90-2.02 (m, 1 H), 2.22-2.38 (m, 2 H), 2.44 (t, J=11.03 Hz, 1 H), 2.57-2.69 (m, 1 H), 3.28-3.41 (m, 2 H), 3.70 (d, J=11.33 Hz, 1 H), 3.91 (dd, J=11.43, 3.81 Hz, 1 H), 4.01 (dd, J=11.23, 2.83 Hz, 2 H), 4.13 (q, J=7.16 Hz, 2 H), 4.25 (d, J=7.42 Hz, 2 H), 7.43 (d, J=8.59 Hz, 1 H), 7.64 (dd, J=8.40, 1.76 Hz, 1 H), 8.18 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=492.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[OH:17])=[O:5])[CH3:2].S(Cl)([Cl:21])(=O)=O.O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:17])[C:8]2[C:13]([C:14](=[O:16])[C:15]=1[Cl:21])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c2ccccc2c1O
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(Cl)C(=O)c2ccccc2C1=O
Reaction time: 1.5 h

Procedure:
23 g of compound (6) prepared above was suspended in 300 ml of chloroform and, while keeping the solution at 5°-10° C., 27.4 g of sulfuryl chloride was slowly dropwise added thereto. After reacting for 1.5 hours, water was added to the reaction solution to conduct separation and extraction. The organic phase was dried with anhydrous sodium sulfate, and chloroform was distilled off under reduced pressure. Rapid purification of the residue through silica gel column chromatography gave compound (7) as crystals. Yield: 8.8 g (33%).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O.[H][H]>[Pt].C(OCC)(=O)C>[CH3:1][CH:2]([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15]
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cccnc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)CNc1c(N)cnc2cccnc12

Procedure:
A catalytic amount of 5% platinum on carbon was added to a solution of N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (1.0 g, 4.1 mmol) in ethyl acetate (50 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen for four hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum to provide N4-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as a crude solid.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.[CH3:24][NH2:25]>C(Cl)(Cl)Cl>[CH3:24][NH:25][C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Reactant: CN
Solvent: ClC(Cl)Cl
Product: CCCOc1ccccc1-c1nc2nc(NC)nnc2c(=O)[nH]1

Procedure:
3-Methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4]triazine (2.0 g) was treated with a solution of methylamine in industrial methylated spirit (33%, 30 ml) at 75° C. in a pressure vessel for 20 hours. The cooled reaction mixture was evaporated under reduced pressure to afford an oily solid which was dissolved in chloroform. The organic solution was washed with water, dried and evaporated under reduced pressure to afford a yellow oily solid which was eluted from a silica column with chloroform/methanol (5%). The fractions containing product were combined and evaporated under reduced pressure to afford a yellow solid (180 mg) which together with another sample (50 mg), similarly prepared, was recrystallised from ethanol to afford the title compound, 140 mg, m.p. 261°-263° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[CH:15][C:16]([C:17](=[O:40])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][C:27]4[C:36]5[C:31](=[C:32]([C:37](=[O:39])[NH2:38])[CH:33]=[CH:34][CH:35]=5)[N:30]=[CH:29][N:28]=4)[CH:20]=3)=[C:10]2[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[N:14]1[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2=[C:16]([C:17]([NH:18][C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH2:25][NH:26][C:27]2[C:36]3[C:31](=[C:32]([C:37]([NH2:38])=[O:39])[CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][N:28]=2)=[O:40])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCn2ncc(C(=O)Nc3cccc(CNc4ncnc5c(C(N)=O)cccc45)c3)c2C1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4cnn5c4CNCC5)c3)ncnc12
Reaction time: 8 h

Procedure:
37 mg (0.56 mmol) 3-{3-[(8-Carbamoyl-quinazolin-4-ylamino)-methyl]-phenylcarbamoyl}-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester were dissolved in 1.5 ml dioxane and 280 μl 4 N HCl in dioxane were added. The mixture was stirred overnight and evaporated to dryness.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[CH:4][C:5]([Cl:20])=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]([CH2:16][C:17]#[CH:18])[C:9]2=[O:19])[CH:7]=1.[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2[CH2:28][CH2:29][CH2:30][CH2:31][C:23]1=2.C(OCC)(=O)C>C(O)(=O)C>[Cl:20][C:5]1[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]([CH2:16][C:17]#[CH:18])[C:9]2=[O:19])=[CH:7][C:2]([N:1]2[C:22](=[O:27])[C:23]3[CH2:31][CH2:30][CH2:29][CH2:28][C:24]=3[C:25]2=[O:26])=[C:3]([F:21])[CH:4]=1
Reactant: C#CCn1c(=O)[nH]c(=O)n(-c2cc(N)c(F)cc2Cl)c1=O
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCn1c(=O)[nH]c(=O)n(-c2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)c1=O
Yield: 55.9 %

Procedure:
A solution of 1-(5-amino-2-chloro-4-fluorophenyl)-3-(2-propynyl)-s-triazine-2,4,6-(1H, 3H,5H)-trione (1.50 g, 4.83 mmol), and 3,4,5,6-tetrahydrophthalic anhydride (0.73 g, 4.83 mmol) in acetic acid (3 mL) is heated at 100° C. for 5 hours, cooled, and poured into ethyl acetate. The organic mixture is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow semi-solid. Flash column chromatography of the semi-solid using silica gel and an ethyl acetate/hexanes (1:2) solution gives the title product as a white solid (1.20 g, mp 127°-135° C.).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:21]=[CH:20][C:19]4[C:15](=[CH:16][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]=4)[CH:14]=3)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]([C:13]4[CH:21]=[CH:20][C:19]5[C:15](=[CH:16][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27])[N:18]=5)[CH:14]=4)[OH:12])=[CH:9][N:10]=3)[N:7]=2)[CH:33]=[N:32]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(C(O)c4ccc5nn(COCC[Si](C)(C)C)cc5c4)n3n2)cn1

Procedure:
(rac)-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazol-5-yl]-methanol (Stage 150.3, 134 mg, 0.296 mmol) was charged into a microwave vial together with DME (2 mL), 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H -pyrazole (173 mg, 0.815 mmol), followed by 2 M Na2CO3 (0.300 mL) and PdCl2(PPh3)2 (20 mg). The RM was submitted to microwave irradiation at 150° C. for 30 min. After filtration and evaporation of the solvent, the residue was taken into EtOAc and washed with saturated aqueous sodium carbonate. The aqueous phase was again extracted 3 times with EtOAc. Combined organic layers were washed with brine and dried on Na2SO4. After evaporation of the solvent the crude was purified by flash chromatography (CombiFlash® Companion System®, with 12 g RediSep® silica gel column, DCM/MeOH=100:0->92:8) to afford the title compound (tR 1.17 min (conditions 2), MH+=476)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([CH:17]3[C:18]([CH3:20])([CH3:19])[C:16]3([CH3:24])[CH3:15])=[O:22])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: Cc1ccc2cc[nH]c2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1ccc2c(C(=O)C3C(C)(C)C3(C)C)c[nH]c2c1
Yield: 65.8 %

Procedure:
A mixture of 6-methylindole (1.0 g, 7.6 mmol), ethylmagnesium bromide (1.0 M solution in THF, 9.1 mL, 9.1 mmol), zinc chloride (1.0 M solution in Et2O, 9.1 mL, 9.1 mmol) and the product of Example 1A (11 mmol) in 25 mL of dichloromethane was processed as described in Example 1B to provide the title compound (1.3 g, 5.0 mmol, 65% yield). MS (DCI/NH3) m/z 256 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH3:6])[C:3](O)=[O:4].[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][CH2:34][CH2:35][NH:36][CH3:37])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][CH2:34][CH2:35][N:36]([CH3:37])[C:3](=[O:4])[CH:2]([OH:1])[CH3:6])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC(O)C(=O)O
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CC(O)C(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 56 %

Procedure:
The procedure described in Example 1 was repeated using 2-hydroxypropanoic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 56% yield; NMR spectrum (DMSO-d6) 1.08 (d, 3H), 3.11 (s, 3H), 3.82-4.12 (m, 2H), 4.36-4.47 (m, 3H), 4.52-4.72 (m, 1H), 5.31 (s, 2H), 7.18 (d, 1H), 7.25 (d, 1H), 7.34 (d, 1H), 7.35-7.40 (m, 1H), 7.52-7.62 (m, 2H), 7.70-7.76 (m, 1H), 7.86-7.91 (m, 1H), 7.94-7.97 (m, 1H), 8.44 (s, 1H), 8.61 (d, 1H), 9.75 (s, 1H); Mass spectrum MH+ 508.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].Cl>O1CCCC1>[C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(COCCCCCO)=NOC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(COCCCCCOS(C)(=O)=O)=NOC(C)(C)C

Procedure:
First, 0.23 g of 5-hydroxypentyloxyacetone O-tert-butyloxime, 0.12 g of triethylamine, and 10 ml of tetrahydrofuran are placed in a reaction vessel, to which 0.14 g of methanesulfonyl chloride is slowly added with stirring under ice cooling. After completion of the addition, the reaction mixture is further stirred at room temperature for 30 minutes, poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which affords 5-(methanesulfonyloxy)pentyloxyacetone O-tert-butyloxime.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36]N)=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:33](=[CH:34][CH:35]=1)[NH:36][CH:2]=[C:6]2[CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:24])[CH3:25])[CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:14]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC3OCCO3)CC2)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]cc(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[3-(1,3-dioxolan-2-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(4-methoxyphenyl)hydrazine hydrochloride: ESMS m/e: 420.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[CH3:26]I>CC#N>[OH:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([C:24]=2[O:25][CH3:26])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: CI
Reactant: CC(C)(C)c1ccc(NC(=O)c2c[nH]c3ccccc3c2=O)cc1O
Solvent: CC#N
Product: COc1c(C(=O)Nc2ccc(C(C)(C)C)c(O)c2)cnc2ccccc12

Procedure:
N-(3-Hydroxy-4-tert-butyl-phenyl)-4-methoxy-quinoline-3-carboxamide (415) was synthesized following the general scheme above reacting N-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (428) with methyl iodide. 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.46 (s, 1H), 8.99 (s, 1H), 8.42 (t, J=4.2 Hz, 1H), 7.95-7.88 (m, 2H), 7.61-7.69 (m, 1H), 7.38 (d, J=2.1 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.96 (dd, J=8.4, 2.1 Hz, 1H), 4.08 (s, 3H), 1.35 (s, 9H); HPLC ret. time 3.46 min, 10-99% CH3CN, 5 min run; ESI-MS 351.5 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:20][CH2:19][C:18](O)([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[CH3:28])[CH2:19][CH2:20]2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(C2CCC(O)(c3ccc(C)cc3C)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1N1CCN([C@H]2CC[C@H](c3ccc(C)cc3C)CC2)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-(2-methoxyphenyl)-4-[1-hydroxy-1-(2,4-dimethylphenyl)cyclohex-4-yl]piperazine in dichloromethane (anhydrous) at room temperature was added trifluoroacetic acid (8 equivalents). The solution was stirred overnight. Excess trifluoroacetic acid was removed under vacuo and the residue poured into sodium bicarbonate solution. The neutralised aqueous layer was extracted with dichloromethane, washed with salt solution, dried (MgSO4) and filtered. The solvent was removed and the residue purified by silica gel pressure column chromatography using hexane/ether (2/1) as eluant. The solid residue was recrystallised from ether to give the title compound which was converted to its dihydrochloride, m.p. 219° C. (dec.).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(O)=[O:2].C(Cl)(=O)C>CC(C)=O>[CH3:15][O:14][C:11]1[CH:10]=[C:6]2[C:5]([CH2:4][C:1](=[O:2])[O:8][C:7]2=[O:9])=[CH:13][CH:12]=1
Reactant: COc1ccc(CC(=O)O)c(C(=O)O)c1
Solvent: CC(=O)Cl
Solvent: CC(C)=O
Product: COc1ccc2c(c1)C(=O)OC(=O)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a suspension of 2-(carboxymethyl)-5-methoxybenzoic acid (5.22 g) (synthesised using the procedure in Tetrahedron 1975, 31, 2607-19) in acetone (50 ml) was added acetyl chloride (7.06 ml) and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and azeotroped with toluene (×3). The resultant solid was triturated with diethyl ether to yield 7-methoxy-1H-isochromene-1,3(4H)-dione as a brown solid (4.36 g); NMR Spectrum: (DMSOd6) 3.84 (s, 3H), 4.20 (s, 2H), 7.36 (m, 2H), 7.50 (s, 1H).