Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.CCN(C(C)C)C(C)C.[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33])([O-:25])=[O:24]>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][CH2:3][CH2:2][NH:1][S:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])(=[O:33])=[O:34])=[N:6][CH:7]=1)([O-:13])=[O:12]
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(NCCNS(=O)(=O)c2ccccc2[N+](=O)[O-])nc1
Temperature: 23 °C
Reaction time: 6 h

Procedure:
To a suspension of resin-bound (2-aminoethyl)(5-nitro(2-pyridyl))amine (30 g, 21 mmol), CH2Cl2 (250 mL) and iPr2NEt (18.3 mL, 105 mmol) at 23° C. was added 2-nitrobenzenesulfonyl chloride (23.3 g, 105 mmol). The resulting mixture was shaken at 23° C. for 6 h, filtered, washed with NMP, H2O and CH2Cl2 and air dried to yield polymer-bound {2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine.
Reaction SMILES: [C:1]([C:3]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)#[CH:2].[ClH:17].O1CCOCC1>ClCCl>[ClH:17].[C:1]([C:3]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1)#[CH:2]
Reactant: C#CC1(C)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C#CC1(C)CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 3-ethynyl-3-methylpiperidine-1-carboxylate (0.50 g, 2.24 mmol) in dichloromethane (10 mL) was added a solution of hydrogen chloride in 1,4-dioxane (3.0M, 5.0 mL, 15.00 mmol). The resulting solution was allowed to stir at room temperature. After 2 h, the mixture was concentrated to provide 0.34 g (95%) of 3-ethynyl-3-methylpiperidine hydrochloride (340 mg, 95%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]([N-:15]C(C)C)(C)[CH3:13].[Li+].BrCC#N>O1CCCC1>[C:12]([CH2:13][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:15]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccccc1
Agent: N#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine methyl phenylacetate (2.0 g, 13.32 mmol) and tetrahydrofuran (15 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of lithium diisopropylamide (6.66 mL, 2 M in THF, 13.32 mmol). After 1 hour, add α-bromoacetonitrile (1.6 g, 13.32 mmol). After 2 hours, warm the reaction mixture to ambient temperature and partition the reaction mixture between ethyl acetate and water. Separate the aqueous layer and extract three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Distill the residue bulb-to-bulb to give the title compound: bp; 150° C. at 0.5 mm Hg; Rf=0.72 (silica gel, 25% ethyl acetate/hexane).
Reaction SMILES: Cl.Cl.C[Si](C)(C)CCOCN1C2N=CN=C(C3C=NN(C4(CC#N)CNC4)C=3)C=2C=C1.OCC1C=C(C(F)(F)F)N=C(OC2CCC(=O)CC2)C=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:66][CH2:67][C:68]1[CH:73]=[C:72]([C:74]([F:77])([F:76])[F:75])[N:71]=[C:70]([O:78][C@H:79]2[CH2:84][CH2:83][C@H:82]([N:85]3[CH2:88][C:87]([CH2:111][C:112]#[N:113])([N:89]4[CH:93]=[C:92]([C:94]5[C:95]6[CH:102]=[CH:101][N:100]([CH2:103][O:104][CH2:105][CH2:106][Si:107]([CH3:110])([CH3:109])[CH3:108])[C:96]=6[N:97]=[CH:98][N:99]=5)[CH:91]=[N:90]4)[CH2:86]3)[CH2:81][CH2:80]2)[CH:69]=1>ClCCCl>[OH:66][CH2:67][C:68]1[CH:73]=[C:72]([C:74]([F:75])([F:77])[F:76])[N:71]=[C:70]([O:78][C@@H:79]2[CH2:80][CH2:81][C@H:82]([N:85]3[CH2:86][C:87]([CH2:111][C:112]#[N:113])([N:89]4[CH:93]=[C:92]([C:94]5[C:95]6[CH:102]=[CH:101][N:100]([CH2:103][O:104][CH2:105][CH2:106][Si:107]([CH3:108])([CH3:109])[CH3:110])[C:96]=6[N:97]=[CH:98][N:99]=5)[CH:91]=[N:90]4)[CH2:88]3)[CH2:83][CH2:84]2)[CH:69]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@H](Oc6cc(CO)cc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: Cl
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(CO)cc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Reaction time: 0.08 h

Procedure:
{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (400.0 mg, 0.829 mmol) and 4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexanone (300.0 mg, 1.037 mmol) were mixed in dry 1,2-dichloroethane (11.33 mL) and were stirred for 5 minutes. Sodium triacetoxyborohydride (708 mg, 3.34 mmol) was added to this mixture. The reaction mixture was stirred at 25 C for 16 hours, at which time LCMS analysis showed mainly the two diastereomeric products. The reaction was quenched with water, neutralized with NaHCO3 and extracted with ethyl acetate and the solvent was evaporated. The residue was purified by LCMS (pH 10) and the fractions containing the second peak were combined and evaporated to give 1-(cis-4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethyl silyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. MS (ES): 683 (M+1). The first peak contained {1-(trans-4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. MS (ES): 683 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH:17]([OH:28])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:20][CH:19]=1)[N:5]([CH3:16])[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C)CCCN>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH:17]([O:28][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:22][CH:23]=1)[N:5]([CH3:16])[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: COCOc1ccc(C(O)[C@@H](C(=O)OC)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)CCCN
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc(C(OC(=O)c2ccccc2)[C@@H](C(=O)OC)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.6 %

Procedure:
To a solution of O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-hydroxytyrosine methyl ester (erythro isomer) (3.85 g) in dichloromethane (30 ml) were added triethylamine (1.38 g), 4-dimethylaminopyridine (0.45 g) and benzoyl chloride (1.92 g). After stirring for 16 hours at room temperature, 3-dimethylaminopropylamine (3.3 g) was added to the mixture and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (30 ml) and washed with dil. hydrochloric acid, sodium bicarbonate aqueous solution and water. After evaporating, the residue was put on a column of silica gel (MERCK 7734, 150 g) and eluted with n-hexane-ethyl acetate (5:2, V/V) to give O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-benzoyloxytyrosine methyl ester (erythro isomer) (4.49 g).
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:47]([CH:52]1[CH2:56][CH2:55][C:54](=[CH:57][N:58]([CH3:65])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]1=[O:66])[CH2:48][CH2:49][CH2:50][CH3:51].Br[C:68]1[CH:73]=[CH:72][C:71]([C:74]([F:77])([F:76])[F:75])=[CH:70][CH:69]=1.CCCC[O-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:75][C:74]([F:77])([F:76])[C:71]1[CH:72]=[CH:73][C:68]([C:52]2([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:56][CH2:55][C:54](=[CH:57][N:58]([CH3:65])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]2=[O:66])=[CH:69][CH:70]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CCCCCC1CCC(=CN(C)c2ccccc2)C1=O
Agent: [Pd]
Agent: CCCC[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCC1(c2ccc(C(F)(F)F)cc2)CCC(=CN(C)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 71.2 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with tris(dibenzylideneacetone)dipalladium (0) (23 mg, 0.025 mmol, 10 mol % Pd), (S)-BINAP (46 mg, 0.075 mmol, 15 mol %) and 2-pentyl-5-(N-methyl-anilinomethylene)cyclopentanone (136 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. 4-bromobenzotrifluoride (225 mg, 1.0 mmol) and sodium 1-butoxide (96 mg, 1.0 mmol) were added to the tube. The tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 148 mg (71%) of the title compound. The ee was determined to be 90% by chiral HPLC analysis.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[OH:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Reactant: Cc1cccc(B(O)O)c1O
Product: Cc1ccc(-c2cccc(-c3cccc(-c4cccc(C)c4O)n3)n2)c(O)c1
Yield: 84 %

Procedure:
6-(2-Hydroxy-3-methylphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 2-hydroxy-3-methylphenylboronic acid in 84% yield using method F; δH [2H6]-DMSO 13.38,(1H, b), 8.41-8.22,(4H, m), 8.13,(1H, d), 8.09-8.01,(2H, m), 7.96,(1H, d), 7.28,(1H, d), 6.90,(1H, t), 6.80,(2H, m), 2.33,(3H, s), 2.26,(3H s); MS 369 (MH)+; HPLC retention time (system 1) 4.53 minutes.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:6]([N:11]2[CH:15]=[C:14]([CH2:16][OH:17])[C:13]([CH3:18])=[N:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:3]>ClCCl>[CH3:3][N:2]([CH2:4][C:5]1[C:6]([N:11]2[CH:15]=[C:14]([CH:16]=[O:17])[C:13]([CH3:18])=[N:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: Cc1nn(-c2ncccc2CN(C)C)cc1CO
Solvent: ClCCl
Product: Cc1nn(-c2ncccc2CN(C)C)cc1C=O
Yield: 87.4 %

Procedure:
3,3,3-Triacetoxy-3-iodophthalide (0.553 g, 1.3 mmol) is added to a solution of [1-[3-(dimethylaminomethyl)-2-pyridyl]-3-methyl-pyrazol-4-yl]methanol (0.146 g, 0.59 mmol) in dichloromethane (4 mL) at room temperature. After one hour the reaction is quenched by addition of 2N sodium carbonate solution and the compound is extracted in dichloromethane. The organic layer is separated, dried over magnesium sulfate and the solvent evaporated in vacuo to afford 126 mg of 1-[3-(dimethylaminomethyl)-2-pyridyl]-3-methyl-pyrazole-4-carbaldehyde that is used with no further purification. MS (m/z): 245 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[S:22][C:23]=3[CH3:24])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:24][C:23]1[S:22][C:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][CH:26]=2)=[N:20][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:35])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], {6-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester was treated with LiOH to obtain {6-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethoxy]-indol-1-yl}-acetic acid as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:18]([O-])=O)=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>CO.[Pd]>[NH2:18][C:3]1[C:2]([NH2:1])=[CH:11][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Temperature: 25 °C
Yield: 96 %

Procedure:
To a mixture of intermediate methyl 3-amino-5-(4-morpholinyl)-2-nitrobenzoate, prepared as described in Example 26, step c (98 g, 0.35 mol) in MeOH (2.2 L) was added Pd/C (9.8 g, 10%) and the resulting mixture was then stirred at room temperature under H2 (4 atm) atmosphere. After stirring for 16 h, it was filtered and concentrated in vacuum to give the crude product (84.4 g, 96%) as a dark solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.85 (t, 4H, J=4.8 Hz), 3.70 (t, 4H, J=4.8 Hz), 3.76 (s, 3H), 4.77 (br. S, 2H), 5.86 (br. S, 2H), 6.54 (d, 1H, J=2.7 Hz), 6.61 (d, 1H, J=2.7 Hz); LC-MS: m/e=252 [M+1]+
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Cl)[N:30]=1>CN(C)C=O>[Cl:28][C:29]1[N:30]=[C:31]([CH2:35][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: ClCc1cccc(Cl)n1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3cccc(Cl)n3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Tetrahydrofuran (3 mL) and a 5 N aqueous sodium hydroxide solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylfornamide (1 mL) solution of 2-chloro-6-chloromethyl-pyridine (36.3 mg, 0.22 mmol) described in Manufacturing Example 52-1-2 was added to a suspension of this solid and N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (39.5 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[C:14]2[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nccc2c1[nH]c1cc(O)ccc12
Product: Cc1nccc2c3ccc(OCc4ccccc4)cc3n(Cc3ccccc3)c12
Yield: 66 %

Procedure:
The title compound was synthesized from 1-methyl-7-hydroxy-β-carboline (1 g, 3.173 mmol) in presence of 1-bromomethylbenzene (1.085 g, 6.346 mmol) as described here above.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.Br[CH2:36][C:37]([OH:39])=[O:38]>C1COCC1.O>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:8][CH2:9][CH2:10][O:11][CH2:36][C:37]([OH:39])=[O:38])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CBr
Reactant: OCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)COCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59 %

Procedure:
2-(Triphenylmethoxy)ethanol (3.98 g, 0.013 mol) was dissolved in dry THF (50 ml) and a 2.5 M solution of butyllithium in hexane (5.5 ml, 0.0137 mol) was added at 0° C. A solution of bromoacetic acid (1.81 g, 13.0 mmol) was separately treated with a 2.5 M solution of butyllithium in hexane (5.5 ml, 13.7 mmol) at 0° C. before the two solutions were mixed. This reaction mixture was heated at reflux for 68 h, cooled, and water (200 ml) was added. Washing with ethyl acetate was followed by acidification of the aqueous phase with 0.5 M citric acid solution (50 ml). Extraction with ethyl acetate (2 × 100 ml) and drying (MgSO4) provided crude [2-(triphenylmethoxy)ethoxy]acetic acid (2.78 g, 58%). This acid was dissolved in dichloromethane (30 ml) and dicyclohexylcarbodiimide (1.72 g, 0.0083 mol) was added, followed by 4-pyrrolidinopyridine (0.11 g, 0.00074 mol) and ethanol (0.89 ml, 2 equiv.) (A. Hassner et al., Tetrahedron Lett. (1978) 4475). The reaction mixture was stirred for 16 h at room temperature and filtered to remove dicyclohexyl urea. The filtrate was evaporated, and the residue was purified by flash chromatography on silica gel (3 × 20 cm). Elution with cyclohexane containing 1-3% ethyl acetate provided the desired [2-(triphenylmethoxy)ethoxy]acetic acid ethyl ester (1.5 g, 50%) as an oil.
Reaction SMILES: I[C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>C1(C)C=CC=CC=1.O.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>[CH3:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][N:10]=[CH:11][C:2]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH3:27]
Reactant: CNC(=O)c1ccncc1I
Reactant: Cc1ccccc1B(O)O
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: O
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccncc1-c1ccccc1C
Temperature: 80 °C
Yield: 88.6 %

Procedure:
To a suspension of 450 mg (1.7 mmol) 3-iodo-N-methyl-isonicotinamide in 10 ml toluene were added successively 60 mg (0.05 mmol) tetrakis(triphenylphosphine)palladium(0), 2.5 ml 2 M sodium carbonate solution in water and 342 mg (2.5 mmol) o-tolylboronic acid. The mixture was heated under argon at 80° C. for 20 h. The aqueous layer was separated and washed twice with toluene. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 341 mg (87%) of the title compound as a light yellow solid. M.p. 90-92° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:57]([C:59]1[CH:64]=[CH:63][C:62]([N:65]2[CH2:69][CH2:68][CH:67]([C:70](O)=[O:71])[C:66]2=[O:73])=[CH:61][CH:60]=1)#[N:58]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:70]([CH:67]1[CH2:68][CH2:69][N:65]([C:62]2[CH:63]=[CH:64][C:59]([C:57]#[N:58])=[CH:60][CH:61]=2)[C:66]1=[O:73])=[O:71]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: N#Cc1ccc(N2CCC(C(=O)O)C2=O)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 3.4 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.434 mmol), PyBOP (0.340 g; 0.651 mmol), N,N-diisopropylethylamine (0.224 mL; 1.30 mmol) and 1-(4-cyanophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.434 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified preparative HPLC (method 1) to yield 0.006 g (3%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([CH3:8])=[CH:6][CH:7]=1.O.Cl.[CH3:15][N:16](C)C=O>>[C:15]([C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([CH3:8])=[CH:6][CH:7]=1)#[N:16]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Br)ccc1C
Agent: Cl
Solvent: O
Product: COC(=O)c1cc(C#N)ccc1C
Reaction time: 0.5 h

Procedure:
0.5 g of cuprous cyanide was added to 1 g of methyl 4-bromo-o-toluate obtained in Reference example 18 dissolved in 0.7 ml of dimethylformamide and the mixture was refluxed under heating for 6 hours. Then, to the reaction mixture were added 2.6 ml of water, 0.5 ml of conc. hydrochloric acid and 1.75 g of ferric chloride and the mixture was stirred at 60° to 70° C. for 30 minutes. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed from the solution to obtain 0.76 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][C:16]1[NH:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:4]([C:18]2[NH:17][C:16]([CH3:15])=[CH:20][C:19]=2[CH3:21])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Cc1c[nH]c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C(=O)c2cccnc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
2-Chloronicotinoyl chloride (3.4 g, 20 mmol) (Aldrich, Milwaukee, Wis.) was added to a solution of aluminum chloride (2.7 g, 20 mmol) (Aldrich, Milwaukee, Wis.) in dichloromethane (100 mL) at 0° C., followed by a solution of 2,4-dimethylpyrrole (2.9 g, 30 mmol) in dichloromethane (20 mL). The mixture was then stirred at room temperature for one hour. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 2.9 g (62%) of (2-chloro-pyridin-3-yl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH3:14].O>C(O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
In 200 g of ethanol were dissolved 86.5 g (0.5 mol) of 4-bromophenol and 22 g (0.55 mol) of sodium hydroxide. To the solution at 70° C., 75.4 g (0.55 mol) of n-butyl bromide was added dropwise. The solution was allowed to ripen for 4 hours and cooled to room temperature, after which 120 g of water was added. The oily matter was separated therefrom and concentrated by a rotary evaporator, yielding 90 g of 4-n-butoxyphenyl bromide. This was used in the subsequent reaction without further purification.