Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].[ClH:43]>C1COCC1.O1CCOCC1>[ClH:43].[ClH:43].[ClH:43].[NH:11]1[CH2:12][CH2:13][CH:8]([N:6]2[CH2:5][C:4]([CH2:3][C:1]#[N:2])([N:21]3[CH:25]=[C:24]([C:26]4[C:27]5[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[C:28]=5[N:29]=[CH:30][N:31]=4)[CH:23]=[N:22]3)[CH2:7]2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate (3.2 g, 5.4 mmol) in 10 mL of THF was added 10 mL of 4 N HCl in dioxane. The reaction mixture was stirred at room temperature for 2 hours. Removing solvents under reduced pressure yielded 3.25 g (100%) of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride as a white powder solid, which was used directly in the next reaction. LC-MS: [M+H]+=493.3. 1H NMR (400 MHz, DMSO-d6): δ 9.42 (s 1H), 9.21 (s, 1H), 8.89 (s, 1H), 8.69 (s, 1H), 7.97 (s, 1H), 7.39 (d, 1H), 5.68 (s, 2H), 4.96 (d, 2H), 4.56 (m, 2H), 4.02-3.63 (m, 2H), 3.55 (s, 2H), 3.53 (t, 2H), 3.49-3.31 (3, 3H), 2.81 (m, 2H), 2.12 (d, 2H), 1.79 (m, 2H), 0.83 (t, 2H), −0.10 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:16]([NH:23][CH2:24][C:25]#[CH:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH2:16]([NH:23][CH2:24][C:25]#[C:26][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#CCNCc1ccccc1
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)OC)c(C#CCNCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2 g of dimethyl 5-bromodicarboxylate (from Example 3) and 1.25 g of N-benzylpropargylamine are dissolved in methylene chloride in a flask flushed with argon, and 3.4 ml of triethylamine are added dropwise. The mixture is stirred at room temperature for 15 minutes, 25 mg of ((C6H5)3P)2PdCl2 and 4 mg of CuI are added and the mixture is boiled under reflux for 36 hours. After cooling, the mixture is diluted with methylene chloride and washed with water and sodium chloride solution and the combined organic phases are dried over potassium carbonate. After evaporation, 1.25 g of a dark oil which is hydrogenated without purification (Example 18) remain.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].[O:13]([CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26])[Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:26][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([CH2:21][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:23]=1)=[O:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN)c1
Reactant: O=C(Cl)c1cccc(CCCl)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CNC(=O)c2cccc(CCCl)c2)c1
Reaction time: 2 h
Yield: 74.6 %

Procedure:
A solution of 3-(2-chloroethyl)benzoyl chloride (2.43 g, 12.0 mmol) in ethyl acetate (10 mL) was added to a solution of 3-(tert-butyldimethylsiloxymethyl)benzylamine (3.01 g, 12.0 mmol) and triethylamine (3.3 mL, 24 mmol) in ethyl acetate (20 mL) at 0° C., and the resulting mixture was stirred at the same temperature for 2 hours and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed successively with a 5% aqueous potassium hydrogensulfate solution, water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel 200 mL; hexane/ethyl acetate=10/1 to 3/1) to obtain the title compound (3.74 g, 75%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:31]3[CH:32]=[CH:33][C:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])=[CH:29][CH:30]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:22])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Temperature: 105 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see intermediate 100), (39.0 g, 106 mmol), {4-[(ethyloxy)carbonyl]phenyl}boronic acid (22.5 g, 116 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.83 g, 1.58 mmol) were mixed in DME (430 mL) and the resulting mixture was treated with 2N aqueous Na2CO3 (210 mL, 420 mmol). The mixture was degassed under house vacuum with several quenches with nitrogen and then stirred at 105° C. under nitrogen for approximately 6 h before being allowed to cool to room temperature. The mixture was partitioned between AcOEt and water and the layers were separated. The aqueous phase was extracted with AcOEt and the combined organic phases were washed with brine. The organic phase was then filtered through a 70 g silica cartridge, washing the cartridge with AcOEt. The combined filtrate and washings were concentrated in vacuovacuo. The residue was triturated with Et2O then filtered off. The solid obtained was air dried to give ethyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (35.2 g, 80.2 mmol, 76%) as a grey solid. The filtrate was concentrated in vacuo and the residue obtained triturated with Et2O (approximately 30 mL). The solid formed was isolated by filtration and air dried, to give ethyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate as a grey solid (5.96 g, 13.5 mmol, 13%).
Reaction SMILES: C(N(CC)CC)C.[C:8](O)(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(=O)OCC.[NH2:38][C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][C:49]=1[NH:50][CH2:51][CH2:52][N:53]([CH3:55])[CH3:54])[C:42]([N:44]([CH3:46])[CH3:45])=[O:43]>C(Cl)(Cl)Cl>[CH3:54][N:53]([CH3:55])[CH2:52][CH2:51][N:50]1[C:49]2[CH:48]=[CH:47][C:41]([C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[CH:40][C:39]=2[N:38]=[C:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CN(C)CCNc1ccc(C(=O)N(C)C)cc1N
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCCCCc1nc2cc(C(=O)N(C)C)ccc2n1CCN(C)C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
Triethylamine (1.52 ml) was added to a suspension containing n-docosanoic acid (3.339 g) in chloroform (34 ml), and then ethyl chlorocarbonate (1.04 ml) was added thereto while being cooled with ice. The reaction mixture was stirred for 1.5 hours, and then a solution containing 3-amino-4-{[2-(dimethylarnino)ethyl]amino}-N,N-dimethylbenzamide (2.454 g) in chloroform (12 ml) was added thereto. After being stirred for 3 hours while being cooled with ice, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (8.2 ml) was added to a suspension containing the residue (6.094 g) in ethanol (61 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (5.119 g) was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=50:1-30:1), thereby yielding the entitled compound (3.320 g) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].N1C=CC=CC=1.[Cl:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([CH2:20][Cl:19])[CH:22]=1
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Amino-5-chloro-benzoic acid methyl ester (1.5 g) was dissolved in anhydrous methylene chloride (25 ml). Pyridine (1.4 ml) and 3-(chloromethyl)benzoyl chloride (1.4 ml) were added dropwise to the solution at 0° C., and the mixture was then stirred at room temperature for 30 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was then washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure to precipitate crystals. The precipitated crystals were collected by filtration through Kiriyama Rohto and were washed with ether to give 5-chloro-2-(3-chloromethyl-benzoylamino)-benzoic acid methyl ester as a useful intermediate (2.4 g, yield 90%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:4]=1[NH2:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O1CCCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([NH:5][C:13](=[O:15])[CH3:14])=[C:3]([C:2]([F:1])([F:11])[F:12])[CH:9]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
A solution of 2-(trifluoromethyl)-4-bromoaniline (4.8 g, 20 mmol) in dry tetrahydrofuran (20 mL) was cooled to 0° C. and then treated with acetic anhydride (8.2 g, 80 mmol). The reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The crude residue precipitated from diethyl ether (50 mL) and hexanes (50 mL). The solid was collected by filtrated and washed with hexanes to afford N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (5.07 g, 90%) as an amorphous white solid: EI-HRMS m/e calcd for C9H7BrF3NO (M+) 281.8352, found 281.8348.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][CH2:9][C:10](Br)=[O:11].C(N(CC)CC)C>ClCCl>[Br:8][CH2:9][C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: Nc1ccccc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)Nc1ccccc1
Temperature: 25 °C

Procedure:
A solution of aniline (0.016 mol) in 40 mL of dichloromethane is cooled on ice, and 1.0 equivalent of bromoacetyl bromide in 3 mL of dichloromethane is added dropwise, followed by 0.019 mol of triethylamine (TEA). The solution turns dark and a precipate forms, as the reaction mixture is warmed to RT over 3 h. The mixture is concentrated and taken up in ethyl acetate (EtOAc) and washed three times with water. The organic phase is dried over anhydrous sodium sulphate (Na2SO4), filtered and concentrated. The residue is purified by crystallization from EtOAc to afford 2-bromo-N-phenylacetamide: m.p. 131-135° C.; 1H-NMR (CDCl3) δ 4.01 (s, 2H), 7.18 (m, 1H), 7.36 (m, 2H), 7.54 (2H), 8.09 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:18][C:13]4([CH2:17][CH2:16][NH:15][CH2:14]4)[CH2:12][CH2:11][N:10]3[C:19](=[O:21])[CH:20]=2)=[N:3][CH:2]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34].[Cl-].[NH4+]>O1CCCC1>[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([N:15]1[CH2:16][CH2:17][C:13]2([CH2:12][CH2:11][N:10]3[C:19](=[O:21])[CH:20]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[N:8]=[C:9]3[NH:18]2)[CH2:14]1)=[O:34]
Reactant: O=c1cc(-c2ccncn2)nc2n1CCC1(CCNC1)N2
Reactant: O=C(Cl)c1cccc(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1cccc(F)c1)N1CCC2(CCn3c(nc(-c4ccncn4)cc3=O)N2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 0.3 g (1.055 mmol) of 8-pyrimidin-4-yl-3,4-dihydrospiro [pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-one dissolved in 5 ml of tetrahydrofuran at room temperature were added 0.18 ml (1.27 mmol) of triethylamine and 0.152 ml (1.27 mmol) of 3-fluoro-benzoyl chloride. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2h. The reaction mixture was added to a saturated aqueous solution of ammonium chloride, extracted with a mixture of dichloromethane/menthanol in the proportions of 100/0 to 80/20, dried and evaporated. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane/menthanol in the proportions of 100/0 to 70/30 to give 0.310 g (72%) of pure product as grey solid. Mp: 296-298° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24].O>O1CCCC1>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:9][C:10]1[N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1
Reactant: ClCCCCBr
Reactant: Cc1cccc2nccn12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: ClCCCCCc1cccc2nccn12
Reaction time: 0.25 h

Procedure:
In an argon atmosphere, 51.5 ml (103 mmol) of a 2M lithium diisopropylamide solution (produced by Aldrich Company) was added to a solution of 13.6 g (103 mmol) of 5-metylimidazo[1,2-a]pyridine in 100 ml of tetrahydrofuran at -78° C. After stirring at constant temperature for 15 minutes, 17.64 g (103 mmol) of 1-bromo-4-chlorobutane was added, followed by stirring for 1 more hour. After stirring at 0° C. for 1 hour, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent; ethyl acetate) to yield 18.74 g (81.7%, light yellow oily substance) of the desired product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.Br.[Br:13][C:14]1[S:18][C:17]([NH2:19])=[N:16][CH:15]=1.C(N(C(C)C)C(C)C)C>C(O)C>[Br:13][C:14]1[S:18][C:17]2=[N:19][C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)=[CH:2][N:16]2[CH:15]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Nc1ncc(Br)s1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Fc1ccc(-c2cn3cc(Br)sc3n2)cc1
Yield: 19.4 %

Procedure:
To a solution of 2-bromo-1-(4-fluoro-phenyl)-ethanone (2 g, 9.215 mmol) in 100 ml ethanol were added 5-bromo-thiazol-2-ylamine hydrobromide (2.396 g, 9.215 mmol) and ethyl-diisopropyl-amine (1.19 g, 9.215 mmol). The mixture was stirred under reflux for 8 h and evaporated. Water was added to the residue and extracted with ethyl acetate. The organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 532 mg (20%) of the desired product. MS: M+H+=296.96.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>O>[C:16]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)(=[O:18])[CH3:17]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of (−) tyrosine xxvii (2.50 g, 13.8 mmol) in NaOH (aq) (2 N, 7.59 mL, 15.2 mmol) was added H2O (6 mL). This vigorously stirred solution was cooled to 0° C., and acetic anhydride (3.25 mL, 3.52 g, 34.5 mmol) was added via syringe pump over 30 min. During this addition, excess NaOH (aq) (2 N, 34.5 mL, 69.0 mmol) was added in 10 portions. After the addition was complete, the reaction was warmed to room temperature and stirred for 45 min. The colorless solution was then carefully acidified to pH 2 with 6 N HCl (aq). After concentrating under reduced pressure, the resulting solid was extracted with 15% H2O in acetone (4×). The filtrate was concentrated under reduced pressure to afford a slightly yellow oil. The addition of H2O (1.5 mL) afforded N-acetyl tyrosine as a white precipitate (670 mg, 3.00 mmol, 22%) that was washed with H2O (3×). The washings were saved for later precipitations. To a solution of N-acetyl tyrosine (72 mg, 0.32 mmol) in 1:1 THF:H2O (1 mL) was added NaOH (aq) (1 N, 0.32 mL, 0.32 mmol). Benzyl chloroformate (49 μL, 58 mg, 0.34 mmol) was added followed by the dropwise addition of K2CO3 (aq) (2 N, 0.16 mL, 0.32 mmol). After stirring for 7 h at rt, the reaction was poured over H2O (10 mL) and carefully acidified to pH 2 with 6 N HCl (aq). The product was extracted from the water layer with EtOAc (3×), and the combined organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product xxix as a white solid (81 mg, 0.24 mmol, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:19])[N:3]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[Br:27]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1.CCOC(C)=O>[Br:27][C:9]1[N:8]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]2)[C:7]2[C:2]([Cl:1])=[N:3][C:4]([Cl:19])=[CH:5][C:6]=2[N:10]=1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(Cl)nc(Cl)c32)CC1
Temperature: 35 °C
Reaction time: 0.75 h

Procedure:
4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (1 g, 3.35 mmol) was dissolved in THF (10 mL). Disodium hydrogen phosphate (1.43 g, 10.1 mmol) was added, and the reaction was warmed to 35° C. with stirring. 1,3-dibromo-5,5-dimethylhydantoin (1.15 g, 4.02 mmol) was added in 1 portion, and the reaction was continued with stirring at 35° C. After 45 minutes, the reaction was diluted with EtOAc (100 mL) and washed with aqueous NaHSO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column with 0 to 50% EtOAc/hexanes provided 2-bromo-4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine.
Reaction SMILES: ClC1C(Cl)=CC=CC=1C1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH2:11][CH2:10]1.[Na+].[I-].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1CCNCC1.CCN(C(C)C)C(C)C>CC#N>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH2:13][CH2:14]1
Reactant: Clc1cccc(C2CCN(CCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Reactant: COc1ccccc1N1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCOc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A mixture of intermediate 44 (42.2 mg, 0.17 mmol) and NaI (49.5 mg, 0.33 mmol) in CH3CN (3 mL) was heated to reflux for 30 min and then cooled to rt. To this mixture was added intermediate 65 (35.0 mg, 0.18 mmol), followed then by DIEA (0.063 mL, 0.36 mmol). The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by ISCO to give 6-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-1H-indazole (compound 50) (36.6 mg, 60%). HPLC: 99%, RT 3.907 min. MS (ESI) m/z 367.20 [M+H]+.
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[Se:16][CH:17]=[CH:18][CH:19]=2)=[C:11]([F:20])[C:10]=1[F:21])[CH3:7].[CH:22](N1CCOCC1)=[O:23]>C1COCC1.ClCCl.Cl>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[Se:16][C:17]([CH:22]=[O:23])=[CH:18][CH:19]=2)=[C:11]([F:20])[C:10]=1[F:21])[CH3:7]
Reactant: O=CN1CCOCC1
Reactant: CCOc1ccc(-c2ccc[se]2)c(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1ccc(-c2ccc(C=O)[se]2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
7.6 ml (44.4 mmol) of TMP are initially introduced at −20° C. in THF, and 26.7 ml (42.4 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 25 min at this temperature, a solution of 11.7 g (38.6 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)selenophene in 80 ml of THF is added. When the addition is complete, the batch is warmed to RT over the course of 45 min and left at this temperature for 20 min. The solution is cooled to −40° C., and N-formylmorpholine is added. The reaction mixture is warmed to RT and stirred for 4.5 h. The solution is diluted with a lot of dichloromethane, and 2 N hydrochloric acid is added. The mixture is briefly stirred vigorously, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with water. The solution is dried using sodium sulfate and concentrated to dryness. The residue is digested in cold ethanol, and the solid is filtered off with suction. Drying in vacuo gives 5-(4-ethoxy-2,3-difluorophenyl)selenophene-2-carbaldehyde as a violet solid.