Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C@H:19]([CH3:28])[CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[NH3:29].C(OCC)(=O)C.O>CN1CCCC1=O.[Cu-]=O>[NH2:29][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C@H:19]([CH3:28])[CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: N
Reactant: C[C@H](COC1CCCCO1)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21
Agent: O=[Cu-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](COC1CCCCO1)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Temperature: 80 °C
Yield: 70 %

Procedure:
Copper (I) oxide (9.2 mg, 0.06 mmol) was added to (5-bromopyridin-3-yl){7-[(1R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (285 mg, 0.64 mmol) (see Preparation 26) and concentrated ammonia solution (2 mL) in 1-methyl-2-pyrrolidinone (0.5 mL). The mixture was heated in a sealed vessel at 80° C. for 17 hours. Ethyl acetate (5 mL) and water (5 mL) were added to the reaction mixture and then filtered through a glass fibre filter. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The crude solid was purified by column chromatography on silica gel (gradient of EtOAc:MeOH:cNH3 100:0:0 to 95:5:0.5) to afford the title compound as a colourless oil in 70% yield, 171 mg.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:24]=[C:23]([NH:25][CH3:26])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20].N1C=CC=CC=1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36]>O1CCCC1>[Cl:3][C:4]1[CH:24]=[C:23]([N:25]([C:33]([O:34][CH2:35][CH3:36])=[O:37])[CH3:26])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20]
Reactant: CNc1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)N(C)c1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of methyl 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate dihydrochloride (418 mg), pyridine (396 mg) and tetrahydrofuran (4.2 ml) was added dropwise ethyl chlorocarbonate (0.115 ml) under ice-cooling and the mixture was stirred at room temperature for 6 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was pulverized in diethyl ether to give methyl 3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (340 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[C:11]([F:31])=[CH:12][C:13]([O:19][C@H:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[C:14]([CH:18]=1)[C:15]([NH2:17])=O)(=[O:9])=[O:8].C(N(CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:15]([C:14]1[C:13]([O:19][C@H:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]([F:31])=[C:10]([S:7]([N:6]([CH2:5][C:4]2[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=2[O:2][CH3:1])[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][N:33]=2)(=[O:8])=[O:9])[CH:18]=1)#[N:17]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C(N)=O)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C#N)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of the 5-{[(2,4-dimethoxybenzyl)(pyrimidin-4-yl)amino]sulfonyl}-4-fluoro-2-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzamide (64.3 mg, 0.107 mmol) prepared in Example 62c in dichloromethane (2.0 mL), triethylamine (41.0 μL, 0.300 mmol) and trifluoroacetic acid (21.0 μL, 0.150 mmol) were added with cooling on ice, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution, triethylamine (41.0 μL, 0.300 mmol) and trifluoroacetic acid (21.0 μL, 0.150 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified with silica gel chromatography (ethyl acetate) to yield the title compound (32.3 mg, 53%) as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.O1CCOCC1.[C:26](=[S:28])=O.[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>O>[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][C:26]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[S:28])=[CH:32][CH:31]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C=S
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(CC(=S)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
16.5 G (0.1 mol) of L-phenylalanine and 27.8 ml (0.2 mol) of triethylamine were dissolved in 100 ml of water. To this solution was added dropwise 150 ml of dioxane containing 6.0 g (0.1 mol) of carbonyl sulfide at a temperature of from 5°to 10° C in 15 minutes while cooling with ice. After stirring at a temperature of 10° C for 15 minutes, 14.1 g (0.1 mol) of 4-methylbenzylchloride was added dropwise to the solution in 10 minutes and the solution was then stirred at room temperature for 1 hour. After completion of the reaction, a syrup-like substance was formed in a similar manner to that described in Example 1, which was then crystallized from 60 ml of ethylacetate and 300 ml of petroleum ether to obtain 25.7 g of white crystals.
Reaction SMILES: [Br-:1].[K+].[N+]([O-])(O)=O.[Br:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC(Cl)C>[Br:1][C:13]1[CH:14]=[C:9]([CH2:8][Br:7])[CH:10]=[CH:11][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(CBr)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: O=[N+]([O-])O
Product: COc1ccc(CBr)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.6 %

Procedure:
To solution of potassium bromide (29.6 g, 248 mmol) in nitric acid (21% by volume, 149 g, 497 mmol), was added dichloroethane (188 mL) and tetrabutylammonium chloride (1.04 g, 3.73 mmol) followed by 4-(bromomethyl)anisol (25.0 g, 124 mmol) in dichloroethane (62 mL), and the reaction was stirred at room temperature for 5 h. The organic layer was separated, washed with water (2×100 mL, 2×150 mL), 2% aqueous potassium carbonate (150 mL), dried over sodium sulfate, and the solvent removed under vacuum. The residue was purified by being run through a flash silica gel plug (10% ethyl acetate in hexanes) to give the title compound (I-42) (9.22 g, 26% yield). 1H NMR (400 MHz, CDCl3) δ: 7.59 (d, 1H), 7.30 (dd, J=8.2, 2.2 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 4.44 (s, 2H), 4.44 (s, 3H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[F:31][C:32]([F:42])([F:41])[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>>[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:38]([C:37]3[CH:39]=[CH:40][C:34]([O:33][C:32]([F:31])([F:41])[F:42])=[CH:35][CH:36]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:27])=[O:26]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1OC(F)(F)F)CC2

Procedure:
Off-white solid. MS (ESI): 539.10 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-(trifluoromethoxy)-aniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:49][C:50]1[CH:58]=[CH:57][C:53]([CH:54]([OH:56])[CH3:55])=[CH:52][CH:51]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][C:50]([CH3:49])=[CH:51][CH:52]=2)[CH3:55])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(C(C)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 88 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (72 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (109 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently 4-methyl-α-methylbenzyl alcohol (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (98 mg, yield 81%)
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][CH:7]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[C:23]([CH3:30])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:31])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:39][O:40][C:41](=[O:44])[CH2:42][NH2:43].CCN(CC)CC>ClCCl>[CH3:39][O:40][C:41](=[O:44])[CH3:42].[C:1]([Si:5]([CH3:37])([CH3:36])[O:6][CH:7]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([S:26]([NH2:43])(=[O:28])=[O:27])=[C:23]([CH3:30])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Product: COC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
An aliquot of 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonyl chloride (step D) (4 ml, 1.5 mmol) is added to a suspension of glycine methyl ester hydrochloride (565 mg, 4.5 mmol) and Et3N (0.94 ml, 6.75 mmol) in dichloromethane (10 ml) at 0° C. It is stirred at RT overnight, concentrated, and partitioned between EtOAc and 1N HCl. The organic layer is concentrated and chromatographed (Hex to 20% EtOAc/Hex) to give the title product (380 mg, 40%).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([O:8]CC2C=CC=CC=2)[CH:6]([O:16]CC2C=CC=CC=2)[CH:5]([CH2:24][O:25]CC2C=CC=CC=2)[CH2:4][CH:3]1[OH:33].[CH2:34]([N:38]=[C:39]=S)[CH2:35][CH2:36][CH3:37].CI.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:34]([NH:38][C:39]1[O:33][CH:3]2[CH2:4][CH:5]([CH2:24][OH:25])[CH:6]([OH:16])[CH:7]([OH:8])[CH:2]2[N:1]=1)[CH2:35][CH2:36][CH3:37]
Reactant: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: CCCCN=C=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCNC1=NC2C(CC(CO)C(O)C2O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.2 %

Procedure:
To a solution of Intermediate B (142 mg, 0.318 mmol) in dry THF (3 mL) was added a solution of butyl isothiocyanate (45.7 mg, 0.397 mmol) in dry THF (1 mL). The mixture was stirred at room temperature for 16 h. Solvents were evaporated under reduced pressure. The residue was dissolved in acetone (3 mL). MeI (90 mg, 0.64 mmol) was added. The mixture was stirred at room temperature for 5 h. Satd. aqueous NaHCO3 (2 mL) was added and stirred at room temperature for 10 min. The mixture was further diluted with satd. aqueous NaHCO3 (20 mL), extracted with EtOAc (2×15 mL). The combined extracts were washed with brine and dried over Na2SO4. Solvents were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with 96:3:1 EtOAc-MeOH—NH4OH (28% aqueous) to give the aminooxazoline (87.2 mg, 52%) as a syrup. 1H NMR (400 MHz, CDCl3) δ 7.38-7.26 (m, 15H), 4.83 (d, J=11.5 Hz, 1H), 4.80-4.76 (m, 1H), 4.77 (d, J=11.3 Hz, 1H), 4.69 (d, J=11.5 Hz, 1H), 4.46 (d, J=11.2 Hz, 1H), 4.45 (s, 2H), 4.05 (dd, J=7.9, 4.4 Hz, 1H), 3.64 (t, J=5.9 Hz, 1H), 3.56 (dd, J=9.0, 4.2 Hz, 1H), 3.52-3.46 (m, 2H), 3.25-3.11 (m, 2H), 2.18 (dt, J=14.8, 3.4 Hz, 1H), 2.05-1.98 (m, 1H), 1.88 (ddd, J=15.1, 12.1, 3.7 Hz, 1H), 1.53-1.46 (m, 2H), 1.38-1.28 (m, 2H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClC=CCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([O:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClC=CCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
A mixture of p-nitrobenzenesulfonic acid (20 g), phosphorous pentoxide (50 g) and 1,2-dichloroethylene (100 ml) is heated at reflux for 4 days. The hot supernatant is decanted from the gummy residue and allowed to cool to room temperature. The resulting crystalline precipitate of p-nitrobenzenesulfonic anhydride (1.5 g) is collected, washed with anhydrous diethylether, and dried under vacuum. The gummy residue is twice more refluxed overnight with 100 ml portions of dichloroethylene and worked up as above to provide additional p-nitrobenzenesulfonic anhydride (4.0 g); mp 171°-172°.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:5][CH:6]=1.[CH3:20][Si:21]([CH3:34])([CH3:33])[C:22]#[C:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)(C)C>[CH3:12][C@@H:10]1[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:7]([C:4]2[NH:5][CH:6]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([C:23]#[C:22][Si:21]([CH3:20])([CH3:34])[CH3:33])=[CH:25][CH:26]=3)[N:3]=2)[CH2:11]1
Reactant: C[C@H]1C[C@@H](c2nc(I)c[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: C[Si](C)(C)C#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2nc(-c3ccc(C#C[Si](C)(C)C)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Yield: 99.7 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(4-iodo-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (150 mg, 0.3976 mmol) and ([4-(2-trimethylsilylethynyl)phenyl]boronic acid (130 mg, 0.6 mmol) in isopropanol (3 mL) are added sequentially Pd(DPPF)(Cl)2.CH2Cl2 (16 mg, 0.02 mmol), and 2 M NaHCO3 (600 uL, 1.2 mmol). The mixture is heated to 85° C. in a sealed tube overnight. After reaction, the solvent is removed under reduced pressure and the residue is purified by flash column chromatography on silica gel using methanol/CH2Cl2 0-5% to provide tert-butyl (2S,4S)-4-methyl-2-[4-[4-(2-trimethylsilylethynyl)phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (168 mg, 95%).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH:3]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[O:25])=[CH:22][CH:21]=1)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:9][CH:10]=1.C1COCC1.[OH-].[Na+]>CO>[CH3:1][C:2]([CH3:36])([CH3:35])[CH:3]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:22][CH:21]=1)[NH:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A 20 drams vial was charged with methyl (±)-3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)amino)propyl)benzamido)propanoate (92 mg, 0.18 mmol), THF (1.8 mL) and MeOH (1.8 mL). NaOH 1M aq. (0.9 mL) was then added in one portion and the resulting mixture stirred for 30 minutes at room temperature. Organic solvents removed under reduced pressure and 5 mL of water added to the vial. Under magnetic stirring, citric acid solution (10%, aq.) added dropwise to reach ca. pH 3. The solid formed was recovered with a büchner funnel, washed with water and dried under high vacuum to provide (±)-3-(4-(2,2-dimethyl-1-((6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)amino)propyl)benzamido)propanoic acid as a white solid (76.9 mg, 86.0%). 1H NMR (400 MHz, DMSO-d6) δ 0.98 (s, 9H) 2.44-2.48 (m, 2H) 3.38-3.47 (m, 2H) 4.33 (d, J=8.22 Hz, 1H) 6.54 (d, J=8.41 Hz, 1H) 7.17 (dd, J=8.90, 2.84 Hz, 1H) 7.44 (d, J=8.22 Hz, 2H) 7.55 (d, J=9.00 Hz, 1H) 7.74 (d, J=8.41 Hz, 2H) 7.84 (d, J=2.54 Hz, 1H) 8.08 (s, 1H) 8.44 (t, J=5.28 Hz, 1H) 8.84 (s, 1H) 12.18 (br. s., 1H); MS (M+1): 490.4.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]([CH3:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](=[S:23])=[S:22].[OH-].[Na+].[CH3:26]I>O1CCCC1>[CH3:26][S:22][C:21](=[S:23])[N:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)[CH:15]([CH3:20])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CC(C)Nc1ccc(Nc2ccccc2)cc1
Reactant: S=C=S
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSC(=S)N(c1ccc(Nc2ccccc2)cc1)C(C)CC(C)C

Procedure:
N-phenyl-N'-(1,3-dimethylbutyl)-p-phenylenediamine (26.8g, 0.10 mol) is dissolved in 100 mL tetrahydrofuran in a 250 mL, 3-neck round bottom flask. Carbon disulfide (7.6g, 0.10 mol) is added over 0.5 hours with the concurrent addition of an aqueous solution of sodium hydroxide (4.0g, 0.10 mol). When addition is complete, methyl iodide (14.2g, 0.10 mol) is added and the mixture refluxed for 1 hour. The solvent is then stripped off on a rotary evaporator and the residue extracted with methylene chloride. The extract is dried with MgSO4 and the solvent is again removed on the rotary evaporator to yield the product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:26](=[O:27])[N:25]([CH3:29])[CH3:24])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CN(C)C(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)N(C)C)nc3cc21

Procedure:
3-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-1,1-dimethyl-urea was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and N,N-dimethylcarbamoyl chloride (81 μl, 0.88 mmol). The title compound was obtained as brown powder (39 mg, 12%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]2[C:3]([CH3:15])=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(SCCCCCl)cc1
Reactant: Cc1cc2c(cc1O)C(C)(C)OC(=O)N2
Product: Cc1ccc(SCCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 4 from 6-hydroxy-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and 4-tert-Butyl-benzenesulfonyl chloride and purified by HPLC.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[CH3:9][CH:10]1[CH2:15][CH2:14][C:13](=O)[CH:12]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)[CH2:11]1.O.[ClH:27]>C(O)(=O)C.CCOCC>[ClH:27].[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][N:6]1[C:13]2[CH2:14][CH2:15][CH:10]([CH3:9])[CH2:11][C:12]=2[CH:17]=[C:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Reactant: CCN(CC)CCN
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCN(CC)CCn1c(-c2ccccc2)cc2c1CCC(C)C2

Procedure:
A solution of 5.94 g (0.05 mole) of 2-diethylaminoethylamine and 11.52 g (0.05 mole) of 4-methyl-2-phenacyl-cyclohexanone in glacial acetic acid is refluxed under nitrogen for 8 hours. Water is added to the mixture, and the mixture is acidified with dilute hydrochloric acid and washed with ether. The aqueous solution is basified with 10% sodium carbonate and extracted with ether to give a light brown oil. The oil is dissolved in ether and ethereal hydrogen chloride is added to give a granular off-white salt. The salt is recrystallized from an isopropanol-ether mixture and then from a methanol-ether pair to give 1-(2-diethylaminoethyl)-2-phenyl-5-methyl-4,5,6,7-tetrahydroindole hydrochloride as light tan crystals, m.p. 171°-177° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:18]2[C:19]([F:30])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[C:25]([O:28][CH3:29])[CH:24]=[CH:23]3)[CH2:16][OH:17])[CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:18]2[C:19]([F:30])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[C:25]([O:28][CH3:29])[CH:24]=[CH:23]3)[CH2:16][OH:17])[CH2:10][CH2:9]1
Reactant: COc1ccc2ccc(F)c(C(CO)CN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ccc(F)c(C(CO)CN3CCC(N)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
A solution of rac-{1-[2-(7-fluoro-2-methoxy-quinolin-8-yl) -3-hydroxy-propyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (WO 2007/081597, 1.42 g, 3.28 mmol) in a mixture of TFA (15 mL) and DCM (9 mL) was stirred at rt for 20 min. The solvent was removed in vacuo and the residue was diluted in sat. NaHCO3 (20 mL). The pH was adjusted to 12 adding 6M NaOH. The aq. layer was extracted 3 times with DCM-MeOH (9-1, 3×25 mL). The combined org. layers were washed once with brine (20 mL), dried over Na2SO4, filtered and concentrated to dryness to afford the title amine as a yellowish gum (1.1 g, 100% yield).