Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH:12]1([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])[CH2:14][CH2:13]1>C1COCC1>[CH:12]1([C:15]2([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:8][O:16]2)[CH2:13][CH2:14]1
Reactant: O=C(c1ccc(F)cc1)C1CC1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(C2(C3CC3)CO2)cc1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of cyclopropyl(4-fluorophenyl) methanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH:5]1[CH:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][C:23]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[F:1][C:2]([F:13])([F:14])[CH2:3][O:4][CH:5]1[CH:7]([C:8]([O:10][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[C:23]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:24]=2)=[O:9])[C:6]1([CH3:11])[CH3:12]
Reactant: CC1(C)C(OCC(F)(F)F)C1C(=O)O
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(OCC(F)(F)F)C1C(=O)OCc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 15 h

Procedure:
To 10 ml DMF is added 0.88 g 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylic acid (4.14 mmol) and 1.146 g potassium carbonate (8.29 mmol), after which is added 1.2 g 4-fluoro-3-phenoxybenzyl bromide. This mixture is stirred under nitrogen for 15 hours. The reaction mixture is extracted with ether and the ether phase is washed with water (3×) and brine, and dried over sodium sulfate. The solvent is then removed to yield 4-fluoro-3-phenoxybenzyl 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: O1CCCC1.P(Br)(Br)[Br:7].CC1C=CC(S(O[C:21]2[CH2:25][CH:24]([C:26](=[O:43])[NH:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[C:35](=[O:42])[NH:36][CH:37]([CH:39]3[CH2:41][CH2:40]3)[CH3:38])[N:23]([C:44]3[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=3)[N:22]=2)(=O)=O)=CC=1>O>[Br:7][C:21]1[CH2:25][CH:24]([C:26]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[C:35](=[O:42])[NH:36][CH:37]([CH:39]2[CH2:41][CH2:40]2)[CH3:38])=[O:43])[N:23]([C:44]2[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[N:22]=1
Reactant: Cc1ccc(S(=O)(=O)OC2=NN(c3ncccc3Cl)C(C(=O)Nc3ccc(Cl)cc3C(=O)NC(C)C3CC3)C2)cc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: C1CCOC1
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 235.1 %

Procedure:
A tetrahydrofuran (1 ml) solution comprising 0.16 g of phosphorus tribromide was dropwise added to a mixed liquid comprising 1.0 g of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl 4-methylbenzenesulfonate and 9 ml of tetrahydrofuran under cooling with ice. After stirring for 5 minutes, the reaction liquid was heated to 45° C. 5 hours later, the reaction liquid was poured to 50 ml of water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/1) to obtain 0.73 g of the desired product in the form of a paste.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[C:11]([CH2:18][N:19]2[C:23](=[O:24])[N:22]([CH2:25][C@H:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[C:21]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)=[N:20]2)[CH:10]=1.C1C=CC2N(O)N=[N:45]C=2C=1.C(Cl)CCl.N>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([NH2:45])=[O:16])=[C:11]([CH2:18][N:19]2[C:23](=[O:24])[N:22]([CH2:25][C@H:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[C:21]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)=[N:20]2)[CH:10]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Agent: N
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2cccc(Cl)c2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
45 mg (0.07 mmol) of the compound from Example 134 were initially charged in 1 ml of DMF, and 13 mg (0.09 mmol) of HOBt and 18 mg (0.09 mmol) of EDC were added. After 10 min of stirring at RT, 80 μl (1.44 mmol) of ammonia solution (35% strength in water) were added, and the mixture was stirred at RT for 16 h. Under reduced pressure, the reaction solution was then freed of excess ammonia, about 3 ml of water were added and the mixture was extracted three times with in each case 5 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 20 mg (46% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Sn](C)(C)C)=[CH:5][N:4]=1.FC(F)(F)S(O[C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:29][CH3:30])=[C:24]([O:31][CH3:32])[CH:23]=2)(=O)=O.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([O:29][CH3:30])=[C:24]([O:31][CH3:32])[CH:23]=3)=[CH:5][N:4]=1
Reactant: COc1ccc([Sn](C)(C)C)cn1
Reactant: COc1cc2cc(OS(=O)(=O)C(F)(F)F)cnc2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc3cc(OC)c(OC)cc3c2)cn1

Procedure:
A mixture of 800 mg (2.94 mmol) of 2-methoxy-5-trimethylstannyl-pyridine, 994 mg (2.94 mmol) of 6,7-dimethoxyquinolin-3-yl trifluoromethane sulfonate, 374 mg (8.82 mmol) of anhydrous lithium chloride and 170 mg (0.147 mmol) of Pd(PPh3)4 in 15 mL of anhydrous dioxane is flushed thoroughly with nitrogen and refluxed for 6 hours. The mixture is diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 (75 mL), dried (Na2SO4) and evaporated. The resulting residue is chromatographed on silica gel (eluting with chloroform) to give a solid material which is recrystallized from ethyl acetate to give 3-(2-methoxypyrid-5-yl)-6,7-dimethoxyquinoline m.p. 170.5°-171.5° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.Cl.[S:9]1[CH:13]=[C:12]([NH2:14])[N:11]=[CH:10]1.C(N(CC)CC)C>C(Cl)Cl.O>[S:9]1[CH:13]=[C:12]([NH:14][C:5](=[O:7])[CH3:6])[N:11]=[CH:10]1
Reactant: Nc1cscn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cscn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (153 mg, 1.50 mmol) was added to the solution of thiazol-4-amine hydrochloride from example 2.2 (100 mg, 1.0 mmol) and triethylamine (152 mg, 1.50 mmol) in DCM (5 mL). The solution was stirred for overnight at room temperature. The reaction mixture was diluted with water, washed with 0.1 M HCl (10 mL), NaHCO3 solution and brine. The combined organic layers were dried with Na2SO4, filtered and concentrated. The resulting mixture was deposited onto silica gel and loaded onto a silica gel column and eluted with EA/PE (1:2) to aim product (55 mg, 0.39 mmol, 38.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:12]([OH:25])[CH2:13][O:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:6]=[C:5]2[CH3:32].[CH3:33]OS(C(F)(F)F)(=O)=O.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:12]([O:25][CH3:33])[CH2:13][O:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:6]=[C:5]2[CH3:32]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2cc(C)c3cc(Cl)ccc32)cc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: CO[C@H](COS(=O)(=O)c1ccc(C)cc1)[C@H](c1ccccc1)n1cc(C)c2cc(Cl)ccc21

Procedure:
A mixture of (2S,3S)-toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (Intermediate in EXAMPLE 119, step 6, 0.52 g, 1.1 mmol), trifluoro-methanesulfonic acid methyl ester (0.6 mL, 5.5 mmol), and 2,6-di-tert-butyl-4-methyl-pyridine (1.1 g, 5.5 mmol) was heated at reflux in dichloromethane (20 mL) for 2 hours. The reaction was partitioned between ethyl acetate (25 mL) and a 1N aqueous solution of hydrochloric acid (25 mL). The organics were separated and washed with a saturated aqueous solution of sodium bicarbonate (25 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified via flash column chromatography (silica, 20% ethyl acetate in hexane) to give (2S,3S)-toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indol-1-yl)-2-methoxy-3-phenyl-propyl ester. To a solution of toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indol-1-yl)-2-methoxy-3-phenyl-propyl ester (0.13 g, 0.27 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (1.4 mL, 2.7 mmol) and the reaction heated in a sealed tube for 12 hours. Upon completion, the reaction was partitioned between a saturated aqueous solution sodium bicarbonate (25 mL) and dichloromethane (25 mL). The organics were separated and removed in vacuo. The residue was taken up in diethyl ether (25 mL) and washed with a 1 N aqueous solution of hydrochloric acid (25 mL). The aqueous layer was basified to pH 8 with a saturated aqueous solution of sodium bicarbonate (50 mL). The product was extracted with diethyl ether (25 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The free base was dissolved in a minimum amount of ethanol and treated with a 4N solution of hydrochloric acid in dioxane and stirred for 1 hour s. The ethanol was removed in vacuo to give [(2R,3S)-3-(5-chloro-3-methyl-1H-indol-1-yl)-2-methoxy-3-phenylpropyl]methylamine as a yellow oil. MS (ESI) m/z 343
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)#[N:34].N1C=CC=CC=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[C:38]2[CH:39]=[CH:40][C:35]([C:33]#[N:34])=[CH:36][CH:37]=2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(c2ccc(C#N)cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 20.5 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol), 4-cyanophenylboronic acid (127.7 mg, 869 μmol; 4 eq.), copper(II) acetate (158 mg, 869 μmol; 4 eq.) and 4 Å molecular sieve (500 mg) were initially charged in dichloromethane (5 ml), pyridine (281 μl; 16 eq.) and triethylamine (121 μl; 4 eq.) were added and the mixture was subsequently stirred at RT for 4 days. The reaction mixture was then filtered through kieselguhr which was then repeatedly washed with methanol, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil, C-18 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). This gave the title compound as a colorless solid (25 mg, 19.5% of theory).
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:35][CH:34]=3)[S:30][C:29]=2[CH:47]=1.[Br-].[Al+3].[Br-].[Br-]>S(Cl)(Cl)=O.CN(C=O)C>[N:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([C:32]3[C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:47][C:29]=4[S:30][C:31]=3[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:35][CH:34]=3)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reactant: O=C(O)c1ccc(O[C@@H]2CCCC[C@H]2N2CCCCC2)cc1
Agent: [Al+3]
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(C(=O)c3ccc(O[C@@H]4CCCC[C@H]4N4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.698 g (5.60 mmol) of 4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]benzoic acid (Part C) was dissolved in 30 mL of thionyl chloride at room temperature. To this was added 434 μL (5.60 mmol) of DMF as a catalyst. The mixture was stirred for 3 days at room temperature. The thionyl chloride was removed under reduced pressure and the residue was treated with dry benzene to remove azeotropically the residual thionyl chloride and then placed under high vacuum. The crude acid chloride was suspended in 50 mL of anhydrous dichloroethane, and to this was added 1.799 g (5.09 mmol) of 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B). After cooling the slurry to 0° C., aluminum bromide (6.79 g, 25.4 mmol) was added, producing a dark red mixture. The ice bath was removed and the reaction mixture was stirred at room temperature for 6 h. The mixture was poured into 100 mL of cooled (0° C.) 2.0 N NaOH. The aqueous layer was extracted with EtOAc (3×400 mL). The combined organic layers were washed with 300 mL of brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified using PrepLC (8% of (10% concd NH4OH in MeOH) in CH2Cl2).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].O1CCOCC1>O>[C:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: C=C(C)C(=O)Cl
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)C(=O)NCCCCCCCCCCCC(=O)O
Yield: 73 %

Procedure:
0.3 Mole of methacrylic acid chloride and 0.3 mole of 12-aminododecanoic acid were reacted in a mixed solvent of dioxane and water under Schotten Baumann reaction conditions to obtain N-methacryloyl-12-aminododecanoic acid in a yield of 73%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CN(C)[CH:23]=[O:24].P(Cl)(Cl)([Cl:28])=O>C(Cl)(Cl)Cl>[Cl:28][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH:23]=[O:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(C=O)=C(Cl)c2ccc(F)cc2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A 54 g quantity (0.18 mole) of 1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone was suspended in a mixture of 500 ml of chloroform and 57 ml (0.74 mole) of N,N-dimethylformamide. To the suspension was added dropwise with stirring 60 ml (0.64 mole) of phosphorus oxychloride over a period of 30 minutes with cooling in an ice-saline solution bath. After the addition, the resulting mixture was further stirred at 20° C. for 2 hours and refluxed with heating for 18 hours. After being cooled to room temperature, the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was washed sequentially with water and a saturated saline solution, dried over magnesium sulfate and concentrated. The resulting crystals were washed with a 1:2 mixture of diethyl ether and n-hexane, giving 54 g (86%) of the desired product in the form of a mixture of E- and Z-isomers as light brown solids.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:11])=[O:7].C1CCNCC1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(N=C=O)C=CC=CC=1>CC#N>[CH2:29]([N:15]1[CH2:16][CH2:17][C@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)[CH2:14]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CCNC1
Solvent: C1CCNCC1
Solvent: O=C=Nc1ccccc1
Solvent: CC#N
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CCN(Cc2ccccc2)C1
Temperature: 45 °C
Reaction time: 5 h
Yield: 44.4 %

Procedure:
A solution of (S)-3-[N-{3-(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine (0.060 mmol) in CH3CN (1.1 mL) and (piperidinomethyl)polystyrene (2.6-2.8 mmol/g, 30 mg) were added to a solution of benzyl bromide (0.050 mmol) in CH3CN (0.4 mL). The reaction mixture was stirred at 45° C. for 5 h. After the mixture was cooled to room temperature, the resin was removed by filtration and the filtrate was concentrated. The residue was resolved in CH3CN (1.0 mL) and phenyl isocyanate (0.008 mL, 0.05 mmol) was added. The mixture was stirred at room temperature for 1 h, loaded onto Varian™ SCX column, and washed with CH3OH (15 mL). Product was eluted off using 2 N NH3 in CH3OH (6 mL) and concentrated to afford (S)-1-benzyl-3-[N{3-(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine (compound No.239) (9.0 mg, 44%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 406.0 (M++H, C21H22F3N3O2).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:9]1[CH:10]=[C:11]2[N:15]([N:16]=1)[C:14]([C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([N+:25]([O-:27])=[O:26])[C:18]=1[CH3:28])=[N:13][NH:12]2)([CH3:8])([CH3:7])[CH3:6].CO>C1COCC1.N1C=CC=CC=1>[C:1]([N:12]1[C:11]2=[CH:10][C:9]([C:5]([CH3:8])([CH3:7])[CH3:6])=[N:16][N:15]2[C:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([N+:25]([O-:27])=[O:26])[C:18]=2[CH3:28])=[N:13]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1-c1n[nH]c2cc(C(C)(C)C)nn12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)n1nc(-c2c(C)cc(C)c([N+](=O)[O-])c2C)n2nc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Acetyl chloride (12 g, 154 mmole) in THF (80 ml) was added dropwise to a stirred solution of Coupler 1 (22.5 g, 65.2 mmole) in pyridine (110 ml) keeping the temperature below 15° C. The reaction mixture was stirred for a further 2 hours and then added slowly to ice cold water (2000 ml) and methanol (200 ml). After 30 minutes the solid was collected, washed with water, and dried to give the product 24.1 g (100%) m.p. 169°-171° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[N:11]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>C(#N)CCC.C(OCC)(=O)C>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[N:11]=2)[CH2:5][CH2:4]1
Reactant: NCC1CCNCC1
Reactant: CCN(CC)c1nc(Cl)c2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Solvent: CCOC(C)=O
Product: CCN(CC)c1nc(N2CCC(CN)CC2)c2ccccc2n1

Procedure:
A mixture of 4-(aminomethyl)-piperidine (1.2 g, 11 mmol), 4-chloro-2-diethylaminoquinazoline (1.2 g, 5.1 mmol) and Hunig's base (2.8 ml, 16 mmol) in 10 ml of butyronitrile was reacted for 12 hours at 100° C. After cooling, ethyl acetate (50 ml) and 50 ml of sodium hydroxide (10%) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×25 ml). The combined organic phases were dried (Na2SO4), concentrated on a rotary evaporator and purified by chromatography on silica gel (eluent: methylene chloride/ethanol/ammonia, 50/10/1) to give the free base as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]=[C:8]([C:13]3[CH:14]=[C:15]([S:23]([N:26]4[CH2:30][CH2:29][C@@H:28]([N:31]([CH3:33])[CH3:32])[CH2:27]4)(=[O:25])=[O:24])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:7][C:6]=2[C:5]2=[CH:34][N:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[N:36]=[C:4]2[N:3]=1.[Cl:46][C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][C:54]=1[O:55][CH3:56])[CH2:50][NH2:51].Cl.CCN(C(C)C)C(C)C>CCCCO>[CH3:32][N:31]([CH3:33])[C@@H:28]1[CH2:29][CH2:30][N:26]([S:23]([C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH3:22])=[C:13]([C:8]3[NH:7][C:6]4[C:5]5[C:4](=[N:36][N:35]([CH2:37][C:38]6[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=6)[CH:34]=5)[N:3]=[C:2]([NH:51][CH2:50][C:49]5[CH:52]=[CH:53][C:54]([O:55][CH3:56])=[C:47]([Cl:46])[CH:48]=5)[C:11]=4[C:10](=[O:12])[N:9]=3)[CH:14]=2)(=[O:25])=[O:24])[CH2:27]1
Reactant: CCCOc1ccc(S(=O)(=O)N2CC[C@@H](N(C)C)C2)cc1-c1nc(=O)c2c(Cl)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1
Reactant: COc1ccc(CN)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCCOc1ccc(S(=O)(=O)N2CC[C@@H](N(C)C)C2)cc1-c1nc(=O)c2c(NCc3ccc(OC)c(Cl)c3)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1

Procedure:
A mixture of (3R)-1-[[3-(5-Chloro-4,8-dihydro-8-[(4-methoxyphenyl)methyl]-4-oxo-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-yl)-4-propoxyphenyl]sulfonyl]-3-(dimethylamino)pyrrolidine (39 mg, 0.06 mmol), 3-chloro-4-methoxybenzylamine.HCl (25 mg, 0.12 mmol) and DIEA (78 mg, 0.6 mmol) in n-BuOH was heated at 125° C. under nitrogen for 4 h. The reaction mixture was concentrated and the residue was chromatographed (silica gel, 5% MeOH in DCM) to give the desired product (42.6 mg) as a yellow solid. LC: 4.36′ (Gradient 1); MH+: 787.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][N:27]([CH3:37])[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C[Al](C)C>ClCCCl>[NH3:13].[CH3:37][N:27]([CH3:26])[CH2:28][CH2:29][CH2:30][N:31]1[CH2:32][CH2:33][N:34]([C:21]([C:19]2[O:20][C:16]([CH2:15][N:13]([CH3:14])[S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:25])(=[O:12])=[O:11])=[N:17][N:18]=2)=[O:23])[CH2:35][CH2:36]1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: CN(C)CCCN1CCNCC1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CCCN(C)C)CC3)o2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), N,N-dimethyl-3-(piperazin-1-yl)propan-1-amine (27 mg, 0.16 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.