Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[C:34]([NH:42][NH2:43])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(OCC)(=O)C>[C:34]([NH:42][NH:43][C:16]([C:12]1[S:11][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:14][C:13]=1[CH3:15])=[O:18])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 13.6 %

Procedure:
To a solution of 2-benzamido-4-methylthiazole-5-carboxylic acid (0.30 g, 1.14 mmol) in tertahydrofuran (28 mL) was added N-methylmorpholine (0.23 mL, 0.21 g, 2.09 mmol) under nitrogen atmosphere, followed by the addition of isobutyl chloroformate (0.2 mL, 0.21 g, 1.54 mmol) dropwise at ambient temperature. The mixture was stirred at ambient temperature for 7 hours. Benzhydrazide (0.23 g, 1.71 mmol) and 4-methylmorpholine (0.15 mL, 0.14 g, 1.36 mmol) were added to the reaction mixture. After being stirred at ambient temperature for 18 hours, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water (3×10 mL). The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The crude product was purified by column chromatography eluted with ethyl acetate/hexanes (20/80 to 30/70) to afford the title compound as a white solid (0.059 g, 14% yield); m.p. 258-260° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.90 (br, 1H), 10.46 (s, 1H), 10.10 (s, 1H), 8.09 (d, J=7.4 Hz, 2H), 7.93 (d, J=6.9 Hz, 2H), 7.65-7.47 (m, 6H), 2.56 (s, 3H); MS (ES+) m/z 381.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]3[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=3[CH:11]=2)=[CH:22][CH:21]=1
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: Cc1ccc(CCl)cc1
Product: CC(=O)c1cc2c(cc1OCc1ccc(C)cc1)C(C)(C)CCC2(C)C
Yield: 131.4 %

Procedure:
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethanone (0.116 g, 0.471 mmol) was alkylated with 4-methylbenzylchloride (0.93 g, 0.659 mmol, 0.087 mL) as described in Example 21. Aqueous workup gave 1-[3(4-Methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl]ethanone 0.217 g (131% crude) as a pale orange solid: 1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 1H, ArH), 7.33 and 7.20 (d, of ABq, J=7.8 Hz, 4H, Ar-H), 6.91 (s, 1H, ArH), 5.08 (s, 2H, OCH2), 2.56 (s, 3H, CH3), 2.35 (s, 3H, ArCH3), 1.66 (br s, 4H, 2CH2), 1.28 (s, 6H, 2CH3), 1.25 (s, 6H, 2CH3).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])=[CH:16][CH:15]=1>>[CH3:11][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])=[CH:18][CH:19]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Reactant: C[C@H](O)Cc1ccc(N)cc1
Product: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(C[C@H](C)O)cc2)n1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 2-chloro-4,6-dimethyl-3-nitropyridine (step 2 of Example 1) and (2S)-1-(4-aminophenyl)-2-propanol (step 2 of Example 248).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[N:31]=[CH:30][C:29]([C:32]([O:34]C3C=CC=CC=3)=O)=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:34])=[CH:30][N:31]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncc(C(=O)Oc3ccccc3)cn2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncc(C(=O)N3CCCCC3)cn2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.3 %

Procedure:
Piperidine (0.02 ml, 0.20 mmol) was added to a dimethylformamide solution (1.0 ml) of 2-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-(phenoxycarbonyl)pyrimidine (40 mg, 0.100 mmol), and stirred at room temperature for 12 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through partitioning thin-layer chromatography (hexane:ethyl acetate=3:7) to obtain the entitled compound (38 mg, 97%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>C(#N)C>[N:35]1([CH2:2][C:3]([NH:5][C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[O:19][CH:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]4)=[CH:10][CH:11]=2)=[O:4])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(CN1CCOCC1)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and morpholine (53 mg). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. 2-Morpholin-4-yl-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide was isolated as its hydrochloride salt. 1H-NMR (400 MHz; d6-DMSO) δ: 11.1 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.32 (m, 5H), 7.01 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 1.9, 10.0 Hz), 4.23 (s, 2H), 4.02-3.76 (m, 4H), 3.55-3.20 (m, 4H), 3.00-2.92 (m, 1H), 2.75-2.69 (m, 1H), 2.19-2.15 (m, 1H), 2.03-1.98 (m, 1H).
Reaction SMILES: O.[C:2]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].O1CCCC1>[C:2]1([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCCCCC=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC(c1ccccc1)c1ccccc1
Yield: 78.4 %

Procedure:
In a 100-milliliter three-necked flask equipped with a stirring device and a nitrogen substituting device, 1.2 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and a solution of 12.4 g of 1,1-diphenyl-1-heptene in 50 milliliters of tetrahydrofuran were introduced, and contacted with hydrogen gas at a normal pressure with stirring. After hydrogen absorption was stopped, the catalyst was filtered off and the solution was concentrated. Thereafter, by carrying out a distillation under a decreased pressure, 9.8 g of 1,1-diphenyl heptane was obtained as colorless liquid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH2:15])[CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH3:3].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28](O)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28]([NH:15][C:10]3[CH:9]=[CH:8][C:7]4[CH2:6][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:14][CH2:13][C:12]=4[CH:11]=3)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: CN(C)CC1CCc2cc(N)ccc2C1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Product: CN(C)CC1CCc2cc(NC(=O)c3cc(-c4ccc(Cl)cc4)c[nH]3)ccc2C1

Procedure:
Following preparation as described in WO03087046, 6-((dimethylamino)methyl)-5,6,7,8-tetrahydronaphthalen-2-amine was converted to the title compound (8 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (25 mg) following the procedure described in step C of Example 1. MS (ESI) 408 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C@@H:25]2[CH2:27][O:26]2)[CH:22]=[CH:23][CH:24]=1>C(O)C>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=1)[CH2:27][C@@H:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=1)[OH:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc(CCNCc2ccccc2)cc1
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: CCO
Product: O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A solution of N-benzyl-2-(4-bromophenyl)ethanamine (13.5 g) in ethanol (270 ml) was added (2R)-2-(3-chlorophenyl)oxirane (8.63 g) and the solution was refluxed for 48 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was chromatographed on silica gel (eluent: hexane/ethyl acetate=9/1) to give (1R)-2-[benzyl[2-(4-bromophenyl)ethyl]amino]-1-(3-chlorophenyl)ethanol (18.6 g) as a colorless oil.
Reaction SMILES: [OH:1][C@H:2]([CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][Si](C(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:39][CH:38]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:34]=[CH:33][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1>C(Cl)(Cl)Cl.CO>[OH:1][C@H:2]([CH2:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)=[O:19])[CH2:16][CH2:17]2)=[CH:33][CH:34]=1
Reactant: COC(=O)COc1ccc(NC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)C)cc4)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(O)COc1ccc(NC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 56.3 %

Procedure:
Methyl 2-{4-[({4-[4-(2-{[(2S)-2-hydroxy-3-(4-{[isopropyl(diphenyl)silyl]oxy}phenoxy)propyl]amino}ethyl)anilino]piperidinyl}carbonyl)amino]phenoxy}acetate (0.16 g, 0.192 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.64 g, 0.108 mmol)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[OH:18][CH2:17][CH2:16][N:15]([CH2:14][CH2:13][OH:12])[CH2:19][CH2:20][CH2:21][NH:22][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: NCCCN(CCO)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: OCCN(CCO)CCCNc1ccc2ccccc2n1

Procedure:
A mixture of 5.05 g. of 2-chloroquinoline, 5.5 g. of bis(2-hydroxyethyl)aminopropylamine and 3.0 g. of sodium carbonate is heated in 20 ml. of refluxing isopropanol for 24 hours. The reaction mixture is then filtered, solvent removed in vacuo and the residue chromatographed over silica gel to obtain an oil of 2-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[CH2:35]([S:37]([NH2:40])(=[O:39])=[O:38])[CH3:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: O=C(O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 46.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chlorophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.25 g, 0.53 mmol) obtained in step 2 and ethanesulfonamide (0.32 g, 2.63 mmol), the title compound (0.14 g, 47%) was obtained.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][C@@H:31]([C:39]([OH:41])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C[O-].[Na+]>COCCO.C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][C@H:31]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]([OH:41])=[O:40])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.16 mmol), D-phenylalanine (514 mg, 3.1 mmol), and NaOMe (126 mg, 2.3 mmol) in 2-methoxyethanol (10 mL) was refluxed for 2 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (0-60% 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 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 36 mg of the title compound as a dull yellow solid. MS: (+) m/z 520.27 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=O>ClCCCl.P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:17]=1
Reactant: O=C(NCc1cnccn1)c1cc(Cl)ccc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Oc1ccc(Cl)cc1-c1ncc2cnccn12
Temperature: 25 °C
Yield: 18 %

Procedure:
A suspension of 5-chloro-2-hydroxy-N-(pyrazin-2-ylmethyl)benzamide (0.38 g, 1.4 mmol) in a mixture of 1,2-dichloroethane (6 mL) and phosphoryl chloride (6 mL) was heated at reflux for 2 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was suspended in water (10 mL), and the pH was adjusted to 6-7 with 1 N aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate (3×30 mL) followed by dichloromethane (3×40 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-10% gradient of methanol in dichloromethane to afford 4-chloro-2-(imidazo[1,5-a]pyrazin-3-yl)phenol as a pale yellow solid in 18% yield (0.064 g): MS (ES+) m/z 245.9 (M+1), 247.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:6][N:5]2[C:24]=1[C:25]1[S:26][C:27]([C:36]2[N:40]=[CH:39][N:38](C3CCCCO3)[N:37]=2)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:29]=1.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[CH:6][N:5]2[C:24]=1[C:25]1[S:26][C:27]([C:36]2[N:40]=[CH:39][NH:38][N:37]=2)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:29]=1
Reactant: Cc1nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2ccc(CN3CCNCC3)cn2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Yield: 47.7 %

Procedure:
tert-Butyl 4-[(2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridin-6-yl)methyl]piperazine-1-carboxylate (0.025 g, 0.039 mmol) was treated with Trifluoroacetic Acid (2.0 mL, 26 mmol) in Methylene chloride (2.0 mL, 31 mmol) at r.t, for 18 hours. The mixture was rotavaped. The residue was triturated with hexane (3×5 mL). The solid residue was suspended in water and neutralized with saturated aqueous NaHCO3 to pH ˜9, extracted with 10% MeOH in DCM (3×10 mL). The combined organic layer was dried over Na2SO4, filtered, rotavaped and dried in hi-vac to give a solid product (0.0085 g, 45% yield). LCMS: (FA) ES+ 457, ES− 455. 1H NMR (400 MHz, d-chroloform & d4-methanol) δ 9.82 (σ, 1H), 8.14 (σ, 1H), 7.80-7.82 (m, 2H), 7.55-7.58 (m, 1H), 7.37-7.46 (m, 4H), 3.54 (s, 2H), 2.84 (m, 2H), 2.76 (s, 3H), 2.47 (s, br, 2H), 2.32 (m, 4H).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6].[NH2-].[Na+].[CH3:10][O:11][CH2:12][C:13](OC)=[O:14].Cl>CCOCC>[CH3:10][O:11][CH2:12][C:13](=[O:14])[CH2:1][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COCC(=O)OC
Reactant: CCCCC(C)=O
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCC(=O)CC(=O)COC
Reaction time: 0.2 h
Yield: 122.6 %

Procedure:
2-Hexanone (96.8 g) was added dropwise over 15 min under nitrogen to a stirred suspension of sodium amide (37.7 g) in dry ether (1 liter) at room temperature. The mixture was stirred for 12 min, a solution of methyl methoxyacetate (50.3 g) in dry ether (150 ml) was added dropwise over 20 min, and the mixture was heated under reflux for 2 h. The mixture was cooled, poured into ice and 2N hydrochloric acid (600 ml) and the aqueous layer extracted with ether (4×300 ml). The organic layers were washed with 8% sodium bicarbonate solution and brine, dried and evaporated to give an orange liquid (102 g). Purification by DFC, eluting with System A (5:95) gave a yellow liquid (36 g).
Reaction SMILES: [OH:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CS(C)=O>[CH2:18]([O:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[F:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C

Procedure:
20 g of 4-hydroxy-3,5-difluorobenzaldehyde are dissolved in dimethylsulfoxide, and potassium carbonate and benzyl chloride are added thereto. After the mixture is stirred at room temperature, water is added thereto. The mixture is extracted with ethyl acetate and evaporated to remove the solvent. The residue is purified by silica gel column chromatography to give 17.4 g of 4-benzyloxy-3,5-difluorobenzaldehyde.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3](Cl)=[O:4].[CH3:9][C:10]1([CH3:37])[CH2:15][O:14][CH:13](/[CH:16]=[CH:17]/[C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH:26]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[OH:27])[O:12][CH2:11]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:9][C:10]1([CH3:37])[CH2:11][O:12][CH:13](/[CH:16]=[CH:17]/[C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH:26]([O:27][C:3](=[O:4])[C:2]([CH3:8])([CH3:1])[CH2:6][CH3:7])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:14][CH2:15]1
Reactant: CCC(C)(C)C(=O)Cl
Reactant: CCCCCCCCCC(O)c1cc(C)cc(C)c1/C=C/C1OCC(C)(C)CO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC(OC(=O)C(C)(C)CC)c1cc(C)cc(C)c1/C=C/C1OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
2,2-Dimethylbutyryl chloride (1.2 mL, 8.66 mmol) and 4-dimethylaminopyridine (1.17 g, 9.58 mmol) were added under a nitrogen atmosphere at room temperature to a solution of the alcohol prepared in the preceding paragraph (880 mg, 2.18 mmol) in 50 mL of methylene chloride. After the addition, the solution was stirred at room temperature for 5 hours. The solution was washed with 10% HCl, 10% NaHCO3, dried (anh. K2CO3) and the solvent removed under reduced pressure. Purification of the residual oil on silica gel (230-400 mesh) using 4:1 methylene chloride:hexane as an eluent gave 2,2-dimethylbutanoic acid (E)-1-[2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)-ethenyl]-3,5-dimethylphenyl]decyl ester as an oil (960 mg, 88%): IR (film) 2910, 2840 and 1720 cm-1 ; NMR (DMSO-d6) δ 0.66-0.78 (6H, m), 0.86 (3H, t, J=9 Hz), 1.02-1.20 (9H, m), 1.20-1.40 (14H, m), 1.50-1.70 (2H, m), 2.20 (3H, s), 2.24 (3H, s), 3.56 (2H, d, J=10 Hz), 3.64 (2H, d, J=10 Hz), 5.10 (1H, d, J=4 Hz), 5.68 (1H, dd, J=4, 15 Hz), 5.74-5.84 (1H, m), 6.78 (1H, d, J=15 Hz), 6.98 (2H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][CH3:11])[CH:4]=1.[C-:12]#[N:13].[Na+]>C(O)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:12]#[N:13])=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: COc1cc(CBr)ccc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CC#N)ccc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.290 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). The mixture was stirred at 60° C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8 Hz, 1 H), 6.88-6.84 (m, 2 H), 3.92 (s, 3 H), 3.74 (s, 2 H). 13C NMR (100 MHz, CDCl3) δ 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[NH2:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:6][O:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[O:15][CH2:2][C:3](=[O:4])[NH:16][C:10]=12)=[O:17]
Reactant: COC(=O)c1cccc(O)c1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1NC(=O)CO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At RT chloro-acetyl chloride (8.06 mmol) is added dropwise to a solution of 2-amino-3-hydroxy-benzoic acid methyl ester (7.33 mmol) in DMF (50 mL). After 20 min K2CO3 (34.9 mmol) is added portionwise, the mixture is stirred for 16 h at RT and the solvents are removed in vacuo. Water and DCM are added, the layers are separated and the organic layer is washed with brine and dried over Na2SO4. The solvents are removed in vacuo to give a crude product which is purified by FC (heptane to heptane/EtOAc 6/4). LC-MS: tR=0.82 min; [M+CH3CN+H]+=249.0.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[N:7]1)C.O.[NH2:13][NH2:14]>C(O)C>[N:6]1([CH2:5][C:4]([NH:13][NH2:14])=[O:11])[CH:10]=[CH:9][N:8]=[N:7]1
Reactant: CCOC(=O)Cn1ccnn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)Cn1ccnn1
Temperature: 4 °C
Yield: 73 %

Procedure:
As described for example 112a, [1,2,3]triazol-1-yl-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture heated under reflux for 3 h. The mixture was cooled to 4° C. and the precipitated product was filtered off and dried to afford the title compound as a white solid (yield: 73%). MS: m/e=141.2[M]+.