Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH2:14][CH3:15])CO)=[O:7])(C)C.CC(OC([NH:23][C@@H:24]([CH2:27][CH2:28][S:29][CH3:30])[CH2:25][OH:26])=O)(C)C>>[CH:9]1([NH:8][C:6](=[O:7])[CH:25]([OH:26])[C@@H:24]([NH2:23])[CH2:27][CH2:28][S:29][CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CSCC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CCCC[C@@H](CO)NC(=O)OC(C)(C)C
Product: CSCC[C@H](N)C(O)C(=O)NC1CCCC1
Yield: 42 %

Procedure:
The same reaction procedure as in Reference Example 12 was repeated except that (S)-2-[N-(2-methyl-2-propyloxycarbonyl)amino]hexanol used in Reference Example 12 was replaced by 7.53 g of (S)-2-[N-(2-methyl-2-propyloxycarbonyl) amino]-4-(methylthio)butanol, whereby 3.22 g of the captioned (2RS,3S)-N-cyclopentyl-3-amino-2-hydroxy-5-(methylthio)pentanamide was obtained in a yield of 42%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][N:4]=1)[CH3:2].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1cc(CO)ccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(COS(C)(=O)=O)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
To a solution of 82 mg of 2-ethyl-4-hydroxymethylpyridine and 79 mg of triethylamine in dichloromethane (2 mL) was added 82 mg of methanesulfonyl chloride, followed by stirring at room temperature for 1 hour. It was purified by PLC (chloroform:methanol=10:1), dissolved in ethyl acetate, washed with an aqueous sodium bicarbonate solution and then with brine and then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation to obtain 47 mg (yield 36%) of a title compound as a yellow oily substance.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[N:3]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:4]2[N:3]=[C:2]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(-c2cc3nccn3c(Cl)n2)cc1OC
Reactant: NCc1ccncc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc3nccn3c(NCc3ccncc3)n2)cc1OC
Temperature: 90 °C
Reaction time: 20 h
Yield: 52.6 %

Procedure:
The mixture of 5-chloro-7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidine (57.94 mg, 0.2 mmol), 4-aminomethylpyridine (23.79 mg, 0.22 mmol), and diisopropylethylamine (38.78, 0.3 mmol) in 2-propanol was stirred at 90° C. for 20 h, and cooled to room temperature. The solvent was evaporated, and 5 ml of ice water was added. Then the resulting product was extracted with 2×10 ml of ethyl acetate. The combined extract was dried over MgSO4. Then the solvent was evaporated and 2 ml of ether was added. The produced solid was collected by filtration and dried to give pure product (38 mg, 52.6%) of [7-(3,4-dimethoxy-phenyl)-imidazo[1,2-c]pyrimidin-5-yl]pyridin-4-ylmethyl-amine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:27]1(=[O:32])[O:31][CH2:30][CH2:29][CH2:28]1>CN(C)C1C=CN=CC=1.CO>[Cl:26][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][N:11]=[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][OH:32])[CH:4]=4)[C:18]=23)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CCCO1
Reactant: NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Agent: CN(C)c1ccncc1
Solvent: CO
Product: O=C(CCCO)NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 95 °C
Reaction time: 10 h

Procedure:
A mixture of 300 mg (0.8054 mmol) of 3-(3-aminomethyl-phenylamino)4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (water content: 1.79%; see Step 90.5), 277 mg (3.22 mmol) of -γ-butyrolactone, 2 mg of 4-dimethylamino-pyridine and 5 ml of methanol is stirred for 10 hours at 95° C. and, after a further addition of 277 mg (3.22 mmol) of γ-butyrolactone and 4 mg of 4-dimethylaminopyridine, for a further 16 hours at 100° C. The reaction mixture is then concentrated by evaporation in vacuo, and the residue is stirred with ethyl acetate and filtered, and the filter residue is recrystallized from methanol, yielding 4-(3-chloro-phenylamino)-3-[3-({4-hydroxy-butyryl-amino}-methyl)-phenylamino]-1H-pyrazolo[3,4-d]pyrimidine having a water content of 0.67%; m.p. 182-184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:29][C:30]1[CH:31]=[C:32]([NH2:40])[C:33](=[CH:38][CH:39]=1)[C:34]([O:36][CH3:37])=[O:35].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[Br:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]([NH:40][C:14](=[O:16])[CH2:13][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][C:7]=2[CH3:12])[CH:31]=1
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Reactant: COC(=O)c1ccc(Br)cc1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)cc1NC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Yield: 66.6 %

Procedure:
5-Methoxy-2-methyl-3-indole acetic acid (5 g, obtainable from Acros), carbonyidiimidazole (4.44 g) and tetrahydrofuran (120 ml) were stirred at room temperature for 30 min after which methyl 4-bromoanthranilate (5.24 g) and pyridinium tosylate (13.69 g) were added and the mixture refluxed for 14 h. After diluting with dichloromethane (200 ml), the residue was washed with 2M hydrochloric acid (200 ml), 2M sodium hydroxide (200 ml), water (200 ml) and brine (200 ml) and dried (MgSO4). After solidifying by treatment with cyclohexane and ethyl acetate, the solid was triturated with ether to afford methyl 4-bromo-2-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}benzoate (6.54 g), MH+ 433, 435; MH− 431, 433; TR 3.67 min.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8]OS(C)(=O)=O)[CH:6]=1.CN(C)C=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:6]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOS(C)(=O)=O)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCN2CCCC2)CC1
Temperature: 50 °C
Yield: 98 %

Procedure:
Combine tert-butyl 4-(4-bromo-1-(2-(methylsulfonyloxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (4.45 g, 9.84 mmol), dimethylformamide (25 mL), and pyrrolidine (2.46 mL, 3.0 eq) under nitrogen. Heat the reaction mixture at 50° C. overnight, then allow to cool to room temperature. Dilute with ethyl acetate. Wash with water followed by saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give the title compound (4.12 g, 98%). MS (ES) m/z=427 [M]+.
Reaction SMILES: C([NH:8][C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.[ClH:16].[NH2:17][N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:21]=2[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]1=2>>[ClH:16].[NH2:8][C@H:9]([C:13]([NH:17][N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:21]=2[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]1=2)=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC1C(=O)N(N)c2ccccc2-c2ccc(F)cc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CC1C(=O)N(NC(=O)[C@@H](N)C(C)C)c2ccccc2-c2ccc(F)cc21

Procedure:
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin6-one (Example 12), the title compound was prepared.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:38]([Si:34]([CH:35]([CH3:37])[CH3:36])([CH:41]([CH3:43])[CH3:42])[O:33][CH2:32][CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1)([CH3:39])[CH3:40]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OCCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 42.6 %

Procedure:
To a solution of Intermediate A (122 mg, 0.75 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 60 mg, 1.5 mmol) and the mixture stirred at RT for 25 min. A solution of Intermediate 66b (315 mg, 0.75 mmol) in DMF (2.5 mL) was added and the mixture stirred at 60° C. for 1.5 h. The cooled mixture was diluted with water and extracted with DCM (5×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (180 mg, 42%). LCMS (Method 3): Rt 3.35 min, m/z 564 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5]=[N+]=[N-])[CH3:2].[Sn](Cl)Cl.[CH3:12][CH:13]([CH3:18])[CH2:14][CH2:15][CH:16]=[O:17]>ClCCl>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:16](=[O:17])[CH2:15][CH2:14][CH:13]([CH3:18])[CH3:12])[CH3:2]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)CCC=O
Agent: Cl[Sn]Cl
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCC(C)C
Temperature: 25 °C
Yield: 55.4 %

Procedure:
A solution of diazo-acetic acid ethyl ester (555 mg, 4.86 mmol) in dichloromethane (8 mL) was treated with tin (II) chloride (88 mg, 0.463 mmol) and stirred vigorously at 25° C. A solution of 4-methyl-pentanal (464 mg, 4.63 mmol) in dichloromethane (2 mL) was added to the mixture dropwise over 10 min resulting in gas evolution. After the nitrogen evolution ceased (approximately 1 h), the reaction was extracted with brine and diethyl ether (2×80 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (ISCO RediSep column, 0 to 7% ethyl acetate in hexanes) to afford the desired product, 6-methyl-3-oxo-heptanoic acid ethyl ester (478 mg, 55%), as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.89 (6H, d, J=6.3 Hz), 1.26-1.29 (4H, m), 1.48-1.57 (2H, m), 2.53 (2H, t, J=7.4 Hz), 3.42 (2H, s), 4.18 (2H, quartet, J=7.6 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:30][CH2:31][CH3:32])[CH:9]2[CH2:18][C:17]3[CH:16]=[C:15]([O:19][S:20]([C:23]4[C:24]([CH3:29])=[N:25][O:26][C:27]=4[CH3:28])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=3[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.C(OC([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>ClCCl>[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:30][CH2:31][CH3:32])[CH:9]3[CH2:18][C:17]4[CH:16]=[C:15]([O:19][S:20]([C:23]5[C:24]([CH3:29])=[N:25][O:26][C:27]=5[CH3:28])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=4[CH2:11][CH2:10]3)[CH2:3][CH2:2]2)=[O:47])[CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CC1CCN(C(=O)C2CCNCC2)CC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.7 %

Procedure:
Under an inert atmosphere 3,5-dimethyl-isoxazole-4-sulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (400 mg, 0.87 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (199 mg, 0.87 mmol, 1 eq.), EDCl (166 mg, 0.87 mmol, 1 eq.), triethylamine (0.25 mL, 1.79 mmol, 2 eq.), and dichloromethane (35 mL) were combined. The mixture was stirred at room temperature for 48 h and then concentrated in vacuo. The residue was taken up in EtOAc (50 mL) and washed with water (30 mL), 1 N NaOH (30 mL), brine (30 mL), and then dried (MgSO4). The solution was filtered and concentrated to afford a yellow oil. The oil was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine as a foam (447 mg), which was deprotected with trifluoroacetic acid, as described herein, to afford 3,5-dimethyl-isoxazole-4-sulfonic acid 7-{[1-(piperidine-4-carbonyl)-piperidin-4-ylmethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester (320 mg), 114M+H]+=609.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:20]3[C:21]([O:26][CH3:27])=[N:22][CH:23]=[CH:24][CH:25]=3)[C:11]=2[OH:28])=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1.CCOC(C)=O>[C:16]([C:14]1[CH:13]=[C:12]([C:20]2[C:21]([O:26][CH3:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[C:11]([OH:28])=[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=2)[CH:15]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1ncccc1-c1cc(C(C)(C)C)cc(CCc2ccc(N)cc2)c1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(CCc2ccc(NS(C)(=O)=O)cc2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
step 5—To a solution of 54 (156 mg, 0.415 mmol) in pyridine (5 mL) at 0° C. was added methanesulfonyl chloride (0.050 mL, 0.643 mmol). The reaction was gradually warmed to RT and stirred for 1.5 h then diluted with EtOAc. The organic layer was washed sequentially with saturated aqueous CuSO4, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 115 mg (61%) of N-(4-{2-[5-tert-butyl-2-hydroxy-3-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-phenyl)-methanesulfonamide (56) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)CC(=O)NC=C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CC(=O)NCC2
Reaction time: 8 h

Procedure:
To a solution of 8-methoxy-1,3-dihydro-benzo[d]azepin-2-one (10.33 g, 0.055 mol) in acetic acid (200 mL) was added palladium 10% wt on Carbon (50% wet; 2 g). The mixture was shaken in a Parr apparatus under an atmosphere of hydrogen (50 PSI) overnight. Filtration through Celite and evaporation of solvent provided the crude product, which was triturated with a mixture of ether and DCM, filtered, and dried overnight in high vacuum to afford 8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one. 1H-NMR (CDCl3) δ 7.03 (d, J=8.3 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H), 6.69 (s, 1H), 6.17 (br s, 1H), 3.81 (s, 2H), 3.79 (s, 3H), 3.55 (q, J=5.1 Hz, 2H), 3.06 (t, J=5.8 Hz, 2H); LC/MS (ESI+): 192.07 (M+H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[C:11]([N:13]([CH3:26])[C:14](=[O:25])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12].[Cl-].[Na+]>CN(C=O)C>[Br:9][C:10]1[C:11]([N:13]([CH3:26])[C:14](=[O:25])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:1])[CH:17]=1)=[O:12]
Reactant: CN1C(=O)C(Br)=C(c2c[nH]c3ccccc23)C1=O
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(Br)=C(c2cn(C)c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Potassium carbonate (140 mg, 0.98 mmol) and methyl iodide (0.06 mL, 0.98 mmol) were added under ice cooling to 2-bromo-3-(1H-indol-3-yl)-N-methylmaleimide (100 mg, 0.33 mmol) synthesized according to a known method (Tetrahedron, Vol. 44, p. 2887, 1988) and dissolved in DMF (5 mL), and the whole was stirred for 2 hours. The reaction mixture was warmed to room temperature, added with saturated aqueous sodium chloride solution, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=1:1) to obtain 2-bromo-3-(1-methyl-1H-indol-3-yl)-N-methylmaleimide (99 mg, 95.1%) as red solids.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=2)[N:20]=[CH:19][N:18]=1.C(NC(C)C)(C)C>C1COCC1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[Cl:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ncnc2ccc(I)cc12
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccc3ncnc(Cl)c3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A mixture of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (1.12 g, 5.35 mmol), 4-chloro-6-iodoquinazoline (1.35 g, 4.65 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.16 g, 0.23 mmol), copper(I) iodide (0.044 g, 0.23 mmol), and diisopropylamine (0.47 g, 4.65 mmol) in anhydrous THF (20 mL) was stirred at room temperature under nitrogen for 2 hours. After concentration, the residue was dissolved in CH2Cl2 (100 mL), washed with aqueous NH4Cl and brine, dried over sodium sulfate, and concentrated to give the crude product as brown oil. Purification by silica gel column using 20% EtOAc in hexane afforded 1.63 g (94%) of the title compound as a sticky, yellow oil: 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.67-1.75 (m, 2H), 1.87-1.92 (m, 2H), 2.84 (m, 1H), 3.20-3.26 (m, 2H), 3.78 (br d, 2H), 7.88 (dd, 1H), 7.97 (d, 1H), 8.26 (d, 1H), 9.00 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15])[CH3:14]
Reactant: CCOC(=O)CBr
Reactant: CCOP([O-])CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CP(=O)(CCCCc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (10 ml) was added triethylamine (0.34 ml, 0.0024 mole) and the solution was cooled in an ice bath to 0° C. Trimethyl silyl chloride (0.31 ml, 0.0024 mole) was added to the above solution dropwise, followed by ethyl bromoacetate (0.27 ml, 0.0024 mole). The ice bath was removed and the mixture stirred at room temperature for 6 hours and poured into 50% aqueous HCl (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting yellow oil (0.6 g) was vacuum dried to get 0.58 (84%) of title compound. TLC, silica gel, acetone:hexane (1:1), Rf =0.28.
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[C:11]([CH:25]=[O:26])=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[K].OO.[O-:30][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[C:11]([C:25]([OH:30])=[O:26])=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCCCCCn1cc(C=O)c2cc(-c3cccc(C)c3)ccc21
Agent: OO
Agent: [K+]
Agent: [K]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCn1cc(C(=O)O)c2cc(-c3cccc(C)c3)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
The method of Andreani, A.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.; Roda, A.; Guardigli, M.; Traniello, S.; Spisani, S. N-Benzyl-2-chloroindole-3-carboxylic acids as potential anti-inflammatory agents. Synthesis and screening for effects on human neutrophil functions and on COX1/COX2 activity. Eur J Med. Chem. 2004, 39, 785-91, was followed. Compound 9 (0.573 mmol, 1 equiv) was dissolved in 10 mL of acetone and treated with a solution of potassium permanaganate (KMnO4, 1.5 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 5 h, treated with 10% H2O2 until the pink color of KMnO4 was not observed and then filtered. The solvent was removed under reduced pressure and the resulting residue was filtered again (if necessary), acidified with 2M HCl and extracted with Et2O. The organic solvent was removed in vacuo and the residue was purified by column chromatography with hexane/EtOAc as eluting solvents. Yield: 62%; 1H NMR (300 MHz, CDCl3): δ 8.84 (s, 1 H), 7.92 (s, 1 H), 7.54-7.48 (m, 2 H), 7.41-7.29 (m, 3 H), 7.14 (d, J=6.6 Hz, 1 H), 4.12 (t, J=6.6 Hz, 2 H), 2.44 (s, 3 H), 1.87 (t, J=6.6 Hz, 3 H), 1.37-1.25 (m, 10 H), 0.86 (t, J=6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ 170.3, 142.3, 141.9, 138.4, 138.2, 136.1, 136.0, 135.8, 128.5, 128.3, 127.4, 124.6, 120.3, 110.3, 106.3, 47.2, 31.7, 31.1, 29.8, 29.1, 22.6, 21.5, 21.5, 14.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([B-](F)(F)F)=[CH2:10].[K+].C(N(CC)CC)C>C(O)CC>[Cl:1][C:2]1[N:7]=[C:6]([CH:9]=[CH2:10])[CH:5]=[CH:4][N:3]=1
Reactant: C=C[B-](F)(F)F
Reactant: Clc1ccnc(Cl)n1
Agent: [K+]
Solvent: CCCO
Solvent: CCN(CC)CC
Product: C=Cc1ccnc(Cl)n1
Temperature: 100 °C

Procedure:
A mixture of 2,4-dichloropyrimidine (4.4 g, 29.5 mmol), potassium vinyltrifluoroborate (4.58 g, 32.5 mmol), PdCl2 (dppf)-CH2Cl2 (1.21 g, 1.48 mmol) and triethylamine (4.12 mL, 29.5 mmol) in nPrOH (148 mL) was purged with nitrogen for 15 min, heated to 100° C. for 5 h, and cooled to room temperature. The mixture was treated with water and extracted with EtOAc (×3). The combined organics were washed with brine, dried (sodium sulfate), concentrated, and purified by flash chromotography to afford 2-chloro-4-ethenylpyrimidine as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.56 (d, J=5.1, 1H), 7.21 (d, J=5.1, 1H), 6.70 (dd, J=10.6, 17.4, 1H), 6.57-6.51 (m, 1H), 5.79 (dd, J=0.8, 10.6, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[C@@H:19]1([NH:29][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:18])([F:17])[F:1])=[CH:10][CH:11]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: FC(F)(F)c1ccccc1-c1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
2′-(Trifluoromethyl)[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.