Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][N:7]=1)=[O:5].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:12][C:11]1[C:6]([C:4](=[O:5])[CH2:3][NH:2][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[C:15]([F:14])([F:25])[F:26])=[N:7][CH:8]=[C:9]([Cl:13])[CH:10]=1
Reactant: NCC(=O)c1ncc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Yield: 65.8 %

Procedure:
To a suspension of 3.7 g of 2-amino-1-(3,5-dichloropyridin-2-yl)ethanone hydrochloride in 50 ml of ethyl acetate, 30 ml of water and 3.5 g of 2-(trifluoromethyl)benzoyl chloride were added, and 6.1 g of potassium carbonate in 30 ml of water was added dropwise with stirring under cooling with ice, and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction mixture was mixed with 20 ml of ethyl acetate, the resulting organic layer was collected, washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 2:8 to 6:4) as the eluent to obtain 3.8 g of the desired product as pale yellow crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Br:17][C:18]1[CH:24]=[C:23]([F:25])[C:21]([NH2:22])=[C:20]([F:26])[CH:19]=1>C(O)(C)C>[ClH:2].[Br:17][C:18]1[CH:24]=[C:23]([F:25])[C:21]([NH:22][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:20]([F:26])[CH:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1c(F)cc(Br)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3c(F)cc(Br)cc3F)c2cc1OC
Yield: 31.2 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride, (152 mg, 0.6 mmol), (prepared as described for the starting material in Example 1 but without the aqueous work up), and 4-bromo-2,6-difluoroaniline (121 mg, 0.6 mmol) in isopropanol (7 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(4-bromo-2,6-difluoroanilino)-6,7-dimethoxyquinazoline hydrochloride (81 mg, 35%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:5])C.O.[OH-].[K+].Cl>CO>[C:6]1([C:4]([OH:5])=[O:3])[CH:7]=[CH:8][N:9]2[C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: CCOC(=O)c1ccn2c1CCCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccn2c1CCCC2
Yield: 78.9 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid ethyl ester (2b) (3.0 g, 15.5 mmol) in methanol (46 ml) was added water (23 ml) and potassium hydroxide (6.4 g, 97 mmol) and the mixture was stirred at reflux until complete conversion according to LC/MS (ca. 3 h). 160 ml water was added the mixture was acidified with excess hydrochloric acid. The forming precipitate was filtered off, washed once with water and dried in vacuo to give 2.02 g (79%) of 5,6,7,8-tetrahydro-indolizine-1-carboxylic acid as white solid. LC/MS (method 5; MS ionization method ES−): Rt=3.08 min; m/z=164.06 (M−H−).
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8](Cl)[C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[NH2:15][CH2:16][CH2:17][OH:18]>O>[S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:15][CH2:16][CH2:17][OH:18])[C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NCCO
Reactant: NS(=O)(=O)c1cc2c(Cl)nccc2o1
Solvent: O
Product: NS(=O)(=O)c1cc2c(NCCO)nccc2o1
Temperature: 110 °C
Yield: 76.7 %

Procedure:
A mixture of 2-sulfamoyl-4-chloro-furo[3,2-c]pyridine (1.75 g, 7.5 mmol) in 2-aminoethanol (5.5 ml, 91 mmol) was heated at 110° C. for 5 hours. This solution was diluted with water and the product was extracted into ethyl acetate. The ethyl acetate extract was evaporated and the residue was triturated with diethyl ether to give solid product (1.48 g). This material was recrystallized from ethyl acetate to give pure product (1.38 g, 71% yield), m.p. 192°-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH3:10][C:11](=[O:14])[C:12]#[CH:13].C(NC(C)C)(C)C>C1COCC1.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]#[C:12][C:11](=[O:14])[CH3:10])[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: C#CC(C)=O
Reactant: Clc1cc(Cl)cc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,3-dichloro-5-iodo-benzene (3.44 g, 12.6 mmol) in THF (220 mL) was added PdCl2(PPh3)2 (904 mg, 1.29 mmol), 3-butyn-2-one (2.18 g, 32.0 mmol), copper(I)iodide (380 mg, 2 mmol) and diisopropylamine (44 mL). The reaction mixture was stirred at room temperature for 48 hours, filtered and evaporated. The residue was purified by column chromatography using methylene chloride:hexanes (1:1) as eluent. The desired 4-(3,5-dichloro-phenyl)-3-butyn-2-one product was isolated in 977 mg yield.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22][C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1>C1COCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH:28][C:25]2[S:26][CH:27]=[C:23]([S:22][CH3:21])[N:24]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CSc1csc(N)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1csc(NC(=O)c2ccc(OC(C)=O)cc2)n1
Temperature: 25 °C
Yield: 109 %

Procedure:
Into a solution of 510 (0.815 g, 4.10 mmol) and dry THF (20.0 mL) was added a solution of triethylamine (0.572 mL, 4.10 mmol) and dry THF (5.00 mL), followed by a solution of 508 (0.500 g, 3.42 mmol) dissolved in dry THF (15.0 mL). The reaction was stirred at room temperature. After stirring overnight, the reaction was concentrated in vacuo. The residue was partitioned between a saturated aqueous sodium bicarbonate and dichloromethane. The dichloromethane layer was washed a second time with the saturated sodium bicarbonate solution and than twice with aq. 1 M HCl. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give crude 512 (1.15 g, >100%) as a brown solid. The crude product was suspended in diethyl ether, stirred and filtered. The filter pad was washed with ether several times, and dried in vacuo to give 512 (0.692 g, 63%) as a light brown solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([OH:13])=[O:12]>C(OC(=O)C)(=O)C>[CH3:5][N:6]1[CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[CH:8]=[C:7]1[C:11]([OH:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cn1cccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])cc1C(=O)O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (20 mL) was treated with nitric acid (4.0 mL, 70%) and the mixture heated to 50° C. for 15 min then cooled to room temperature, and slowly added to a suspension of 1-methyl-2-pyrrolecarboxylic acid (4 g, 15.98 mmol) in of Ac2O (12 mL) cooled to −25° C. The mixture was stirred at −15° C. for 0.5 hr, then the temperature was allowed to rise to ambient, and stirring was continued for 20 min. The mixture was again cooled to −25° C. and the precipitate collected in a funnel cooled with dry ice, the solid was washed with a small quantity of cold Ac2O (−25° C.). The crystalline solid was taken up in water containing NaOH (1 g). Acidification with the HCl precipitated the pure compound. NMR as previously reported.
Reaction SMILES: O.[NH2:2]N.C[N:5](/[CH:7]=[N:8]/[C:9]([C:11]1[C:19]2[N:18]=[C:17]([CH3:20])[N:16]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:15]=2[CH:14]=[C:13]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:12]=1)=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH3:20][C:17]1[N:16]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:15]2[CH:14]=[C:13]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[CH:12]=[C:11]([C:9]3[N:8]=[CH:7][NH:5][N:2]=3)[C:19]=2[N:18]=1
Reactant: NN
Reactant: Cc1nc2c(C(=O)/N=C/N(C)C)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2c(-c3nc[nH]n3)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Hydrazine hydrate (3 mL) was added to a solution of N-[(1E)-(dimethylamino)methylidene]-2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxamide (130 mg, 0.29 mmol) in acetic acid (10 mL) and stirred at 130° C. for 30 min. The reaction mixture was cooled to rt and poured into saturated Na2CO3 solution (20 mL). A filtration was performed, and the filter cake was purified by silica gel chromatography eluted with EtOAc to give the product (88 mg, 72%), as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.50 (s, 3H), 3.09 (s, 4H), 3.71 (s, 4H), 6.06 (s, 2H), 6.37 (d, 1H, J=7.8 Hz), 7.20 (s, 1H), 7.34 (t, 1H, J=7.8 Hz), 7.54 (s, 1H), 7.61-7.72 (m, 2H,), 7.86 (d, 1H, J=8.4 Hz), 8.02 (d, 1H, J=7.8 Hz), 8.09 (s, 1H), 8.25 (d, 1H, J=8.4 Hz), 13.85 (s, 1H); LC-MS: m/e=425 [M+1]+
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].O.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[Br:13][C:9]1[CH:8]=[C:7]([CH2:6][CH:2]([NH:1][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: NC(Cc1cccc(Br)c1)C(=O)O
Reactant: CCOC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)NC(Cc1cccc(Br)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a suspension of 2-amino-3-(3-bromophenyl)propanoic acid (11.0 g, 45.5 mmol) and NaHCO3 (11.5 g, 136.5 mmol) in THF (100 mL)/H2O (100 mL), ethyl 2-chloro-2-oxoacetate (18.4 g, 135.2 mmol) was added dropwise at 0° C. The mixture was stirred at RT overnight, acidified with aqueous critic acid (10%), and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (100 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by Combiflash reverse phase chromatography (50%˜60% MeCN/H2O containing 0.01% TFA) to afford 3-(3-bromophenyl)-2-(2-ethoxy-2-oxoacetamido)propanoic acid as a colorless oil (5.2 g, 33%). MS (ES+) C13H14BrNO5 requires: 343, 345 found: 344 [M+H]+, 346 [M+2+H]+(1:1).
Reaction SMILES: [CH3:1]N(C=O)C.[Br:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1.[H-].[Na+].CI>O>[Br:6][C:7]1[C:12]([O:13][CH3:1])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1
Reactant: CN(C)C=O
Reactant: Oc1cc(Cl)cnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc(Cl)cnc1Br

Procedure:
To a DMF (60 mL) solution containing 2-bromo-5-chloro-3-hydroxypyridine (19.95 g, 95.7 mmol) at 0° C. was added NaH (2.53 g, 105.3 mmol) portion wise. After the cessation of H2 evolution, CH3I (14.26 g, 100.5 mmol) was added dropwise and the reaction stirred ~16 h. Water (1.9 mL) was added and the solvent removed under reduced pressure. The concentrate was triturated with 5 portions of CH2Cl2. The combined organic phases were washed with sat. NaCl solution, dried with K2CO3, filtered, and concentrated in vacuo. Silica gel chromatography (95:5 Hexane:EtOAc) of the concentrate afforded the title compound.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:1]([N:4]([CH:5]1[CH2:6][CH2:7][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:13][CH2:14]1)[C:23](=[O:24])[O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH3:3]
Reactant: CCCNC1CCC2(CC1)OCCO2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: CCCN(C(=O)OCc1ccccc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-propyl-1,4-dioxaspiro[4.5]decan-8-amine (2.97 g, 14.9 mmol) from above step A in THF is treated with TEA (2.1, 14.9 mmol) and benzyloxycarbonyl chloride (2.1 mL, 14.9 mmol). The mixture was stirred for 18 h at room temperature. THF was removed under vacuum and the residue was taken EtOAc and washed with 10% citric acid, saturated NaHCO3, and saturated NaCl. The solution was dried over Na2SO4 and evaporated under vacuum. The residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: C1C=CN=CC=1.F.[Si]([O:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[N:25][C:26]=1[CH:27]([O:30][CH3:31])[O:28][CH3:29])[N:23]([C:32]([NH:34][C:35]1[CH:40]=[C:39]([NH:41][CH2:42][CH2:43][O:44][CH3:45])[C:38]([C:46]#[N:47])=[CH:37][N:36]=1)=[O:33])[CH2:22][CH2:21][CH2:20]2)(C(C)(C)C)(C)C>C1COCC1>[C:46]([C:38]1[C:39]([NH:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:40][C:35]([NH:34][C:32]([N:23]2[C:24]3[C:19](=[CH:18][C:17]([CH2:16][OH:15])=[C:26]([CH:27]([O:30][CH3:31])[O:28][CH3:29])[N:25]=3)[CH2:20][CH2:21][CH2:22]2)=[O:33])=[N:36][CH:37]=1)#[N:47]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CO[Si](C)(C)C(C)(C)C)c(C(OC)OC)nc32)ncc1C#N
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CO)c(C(OC)OC)nc32)ncc1C#N
Reaction time: 2 h

Procedure:
HF-Pyridine (426 μL, 3.31 mmol) was added to a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 74, 900 mg, 1.577 mmol) in THF (7 ml) at room temperature. The reaction mixture was stirred for approximately 2 h, quenched with saturated aqueous NaHCO3 and partitioned with ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried using Na2SO4, filtered and concentrated to give the title compound as a white solid. (UPLC-MS 3) tR 0.85 min; ESI-MS 457.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 13.71 (s, 1H), 8.21 (s, 1H), 7.57 (s, 1H), 7.54 (s, 1H), 5.49 (s, 1H), 5.28 (s, 1H), 4.71 (d, 2H), 4.07-3.99 (m, 2H), 3.67-3.59 (m, 2H), 3.55 (s, 6H), 3.51-3.45 (m, 2H), 3.41 (s, 3H), 2.85 (t, 2H), 2.05-1.96 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>C1COCC1>[N:4]1([CH2:3][CH2:2][NH:1][S:16]([C:14]2[S:15][C:11]([Cl:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: NCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCN1CCOCC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a stirred solution of 4-(2-aminoethyl)-morpholine (1.80 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (1.34 g, 93%) as a colorless oil. MS (ISN) 309.0 [(M−H)−].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:8])[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-methoxy-4-nitrobenzoic acid (6.81 g, 34.54 mmol) in sulfurous dichloride (50 mL) was stirred at reflux for 8 hours. After cooling to ambient temperature, the mixture was concentrated under vacuum and the residue was dissolved in dichloromethane (60 mL). 1-Methylpiperazine (3.6 g, 36.27 mmol) was added at 0° C. and the mixture was stirred at ambient temperature for 4 hours. The mixture was poured into water (100 mL) and extracted with dichloromethane (2×200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide the crude title compound. MS: 280.2 (M+H+).
Reaction SMILES: [CH2:1]([O:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][N:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[O:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:12]=[N:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:15][CH:14]=2)=[CH:21][CH:20]=1)=[O:29]
Reactant: O=C(O)[C@H]1CCCO1
Reactant: CCCCCCCCOc1ncc(-c2ccc(O)cc2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ncc(-c2ccc(OC(=O)[C@H]3CCCO3)cc2)cn1

Procedure:
901 mg (3 mmol) of 4-(2-n-octyloxy-5-pyrimidinyl)phenol, 464.5 mg (4 mmol) of (R)tetrahydrofuran-2-carboxylic acid and also 49 mg (0.4 mmol) of 4-dimethylaminopyridine are added at room temperature to a solution of 825 mg (4 mmol) of dicyclohexylcarbodiimide in 20 ml of dry dichloromethane while stirring. After stirring for 10 hours at room temperature, the reaction solution is evaporated down in vacuo. Chromatographic purification and recrystallization from n-hexane yield 710 mg (59%) of colorless crystals with [α]D25 =-8.8° (c=2, CHCl3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[O:30][C:31]1[O:35][C:34]([C:36](Cl)=[O:37])=[CH:33][CH:32]=1>C1COCC1>[Cl:26][C:27]1[CH:28]=[C:29]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[O:30][C:31]1[O:35][C:34]([C:36]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:15]=3)[CH2:10][CH2:9]2)=[O:37])=[CH:33][CH:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Reactant: O=C(Cl)c1ccc(Oc2cc(Cl)cc(Cl)c2)o1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)o3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-(3,5-dichlorophenoxy)-2-furoyl chloride: ESMS m/e: 600.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](Cl)=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCOCC1.[H][H].[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][CH:16]=[C:11]2[C:10]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Clc1ncnc2c1c(-c1ccco1)nn2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: c1ccc(Cn2nc(-c3ccco3)c3cncnc32)cc1

Procedure:
5.81g of 1-benzyl-4-chloro-3-(2-furyl)pyrazolo[3,4-d]pyrimidine are dissolved in 450 ml of dioxane and hydrogenated in the Parr apparatus at a hydrogen pressure of 3 bar for 5 h using 4 g of 20% Pd(OH)2 on carbon after addition of 2.61 ml of triethylamine. After filtration through kieselguhr, evaporation and chromatography, 2.26 g of yellowish crystals are obtained (m.p.=106° C., Rf=0.2 toluene/ethyl acetate=4:1).
Reaction SMILES: Cl[CH:2]([C:7]1[N:11]([CH3:12])[C:10]([S:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[N:9][N:8]=1)[CH2:3][CH:4]1[CH2:6][CH2:5]1.[N-:18]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.O>[CH:4]1([CH2:3][CH:2]([C:7]2[N:11]([CH3:12])[C:10]([S:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[N:9][N:8]=2)[NH2:18])[CH2:6][CH2:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1c(SCC2CC2)nnc1C(Cl)CC1CC1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(SCC2CC2)nnc1C(N)CC1CC1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
To a crude solution of the 3-(1-chloro-2-cyclopropylethyl)-5-[(cyclopropylmethyl)thio]-4-methyl-4H-1,2,4-triazole from step d in DMF (3 mL) under nitrogen was added sodium azide (1.0 g, 15 mmol). The mixture was stirred at 65° C. for 20 h, then cooled to room temperature, diluted with water and extracted into ethyl acetate. The organic extract was washed with water and then brine before being dried (MgSO4) and concentrated. The residue was taken up in THF (10 mL), and water (2 mL) was added followed by triphenylphosphine (1.6 g, 6.1 mmol). The reaction mixture was stirred under nitrogen for 5 h, then concentrated in vacuo. The residue was dissolved in methanol and applied to an SCX cartridge. Elution with methanol afforded organophosphorus residues and subsequent elution with 2M ammonia in methanol provided the title amine.
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][C:14]([S:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[C:14]([S:17]([N:19]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)=[O:18])([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC(C)(C)S(N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=NS(=O)C(C)(C)C)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A mixture of tert-butyl 3-oxoazetidine-1-carboxylate (4 g, 23.37 mmol), 2-methylpropane-2-sulfinamide (3.12 g, 25.7 mmol) and tetraethoxytitanium (10.66 g, 46.7 mmol) in THF (40 ml) in a 20 ml sealed tube was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature, quenched with water and filtered through a bed of Celite. The solid material was washed with ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered and concentrated to obtain a crude mixture. The crude product was then purified by column chromatography (20% EtOAc in Hexane) to afford tert-butyl 3-(tert-butylsulfinylimino)azetidine-1-carboxylate Yield: 1.5 g (24%). 1H NMR (400 MHz, CDCl3): δ 5.15-4.94 (m, 1H), 4.75 (m, 1H), 4.68 (s, 2H), 1.45 (s, 9H), 1.27 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([OH:14])=O)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:46][O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([N:57]3[CH2:58][CH2:59][CH:54]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=4[O:47][CH3:46])[CH2:55][CH2:56]3)=[O:14])=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1C(=O)O
Reactant: COc1ccccc1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C1CCN(C(=O)c2c(C)[nH]c3cc(Cl)ccc23)CC1
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of 0.040 g (0.19 mmol) 6-chloro-2-methyl-1H-indole-3-carboxylic acid, 0.069 ml (0.40 mmol) N,N-diisopropylethylamine and 0.061 g (0.19 mmol) 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 1 ml dry N,N-dimethylformamide were added 0.038 g (0.20 mmol) 4-(2-methoxy-phenyl)-piperidine at room temperature. After stirring for 1 h the reaction mixture was quenched with 0.5 M aqueous sodium hydroxide solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (0.050 g; 69%) as a white solid.