Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=[O:8].[CH3:9][Mg]I>>[CH3:9][C:2]1([OH:8])[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2
Reactant: O=C1CC2CCC1C2
Reactant: C[Mg]I
Product: CC1(O)CC2CCC1C2

Procedure:
Norbornanone (I) is reacted with methylmagnesium iodide to give 2-methyl-2-norbornanol (II). The compound (II) is reacted with acetic acid and a 75% solution of sulfuric acid to give 2-acetoxy-1-methylnorbornane (III) which is then converted into 1-methyl- 2-norbornanol (IV) with lithium-aluminum hydride. Then the compound (IV) is enzymatically resolved according to the method reported by Christian Triantaphylides et al., Tetrahedron Letters, 26(15), 1857 (1985) to give (1S)-1-methyl-2-norbornanol (V). This optically active alcohol (V) is then oxidized with pyridine dichromate complex to give (1S)-1-methyl-2-norbornanone (VI). The compound (VI) is reacted with methyltriphenylphosphonium bromide in the presence of n-butyllithium to give (1S)-2-methylenenorbornane (VII) which is then treated with peracetic acid to give an epoxy compound. This epoxy compound is treated with a boron trifluoride etherate complex to give (1S,2S)-1-methyl-2-norbornyl aldehyde (VIII) which is then reduced with lithium aluminum hydride to give (1S,2S)-1-methyl-2-hydroxymethylnorbornane (IX).
Reaction SMILES: [Mg].Cl[CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:17]1(C)[CH:22]=CC(S(OCCC(C)C)(=O)=O)=[CH:19][CH:18]=1.[Cl-].[NH4+].O1CCC[CH2:36]1>>[CH3:16][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:22][CH2:17][CH2:18][CH3:19])[CH3:36]
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)C)cc1
Reactant: CCCCCCCCCC/C=C\CCCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: CCCCCCCCCC/C=C\CCCCC(C)C
Temperature: -20 °C
Reaction time: 2 h
Yield: 30.2 %

Procedure:
In a 1-liter reactor, a Grignard reagent was prepared from 5.0 g (0.206 mole) of magnesium and 46 g (0.2 mole) of 1-chloro-cis-3-tetradecene in exactly the same manner as in Example 4. Next, 100 g of tetrahydrofuran, 45.2 g (0.2 mole) of isoamyl p-toluenesulfonate and 0.5 g of cuprous iodide were placed in another 1-liter reactor and cooled to -20° C. Then, the above-described Grignard reagent was added dropwise thereto. After completion of the reaction, the mixture was stirred at 0° C. for 2 hours and then stirred without cooling until the temperature rose gradually to room temperature. Then, 100 g of a saturated aqueous ammonium chloride solution was added and the resulting mixture was allowed to separate into two layers. The organic layer was recovered and freed of solvent under reduced pressure. The resulting was distilled to obtain 16.1 g of 2-methyl-cis-7-octadecene (purity 96.0%, yield 62%, b.p. 155°-158° C./2 mmHg). MS(m/e): 56(100%), 266 (M+, 27%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:12][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH:1][C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=1)=[O:24]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CN1CCCCC1CCc1ccccc1N
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2ccccc2CCC2CCCCN2C)cc1

Procedure:
Reaction of 2-(o-aminophenethyl)-1-methylpiperidine (80 g., 0.036 mole) with p-toluoyl chloride (6.2 g., 0.04 mole) in 50 ml. of pyridine according to the method of Example 25 provides 2'-[2-(1-methyl-2-piperidyl)ethyl]-p-toluanilide. Crystallization from isopropyl ether and then from isopropyl alcohol provides 3.9 g., (32%) of analytically pure material, m.p. 90.5- 92°C. (corr.).
Reaction SMILES: [Cl-].[OH:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH:30]([C:32]1[N:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1)=O.O1CCCC1.CC(C)([O-])C.[K+]>O>[OH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:30][C:32]2[N:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Reactant: OCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=Cc3ccc(CO)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a mixture of [4-(hydroxymethyl)benzyl](triphenyl)phosphonium chloride (1.283 g, 3.064 mmol), tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (876.3 mg, 3.008 mmol) and anhydrous tetrahydrofuran (10 ml) was added potassium tert-butoxide (383.9 mg, 3.421 mmol), and the mixture was stirred at room temperature for 1 hr. Water (20 ml) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1). The fraction containing the target product was concentrated and the obtained solid was dissolved in ethyl acetate, and extracted twice with 0.2M hydrochloric acid. The aqueous layer was saturated with sodium carbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give tert-butyl 4-(6-{2-[4-(hydroxymethyl)phenyl]vinyl}pyridin-3-yl)piperazine-1-carboxylate (850.2 mg, yield 71.5%, E/Z mixture) as a pale-yellow solid.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:25])=[C:10]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[S:14][C:11]2=[CH:12][N:13]=1)=[O:7])CCC.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO.Cl>[OH:25][C:9]1[C:8]([C:6]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:7])=[N:13][CH:12]=[C:11]2[S:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:16][C:10]=12
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1ncc2sc(-c3ccc(OC)cc3)cc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2cc3c(O)c(C(=O)NCC(=O)O)ncc3s2)cc1

Procedure:
4-Hydroxy-2-(4-methoxy-phenyl)-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester, example 3-d, (23 mg, 0.064 mmol) and glycine (63 mg, 0.64 mmol) were suspended in 1.3 mL of 0.5 N NaOMe in methanol. The reaction mixture was heated at reflux temperature for 16 hours, cooled, and diluted with 1 N HCl to precipitate out a white solid. The precipitate was collected on a fine glass fritted filter, washed twice with water, and dried under hi-vacuum to isolate 20 mg of the title compound. MS: (+) m/z 359.04 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31])([O-:22])=[O:21]>C(N(CC)CC)C>[OH2:16].[OH2:21].[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:31])[NH:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1)([O-:22])=[O:21]
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Product: O
Product: O=C(Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12)Nc1ccccc1[N+](=O)[O-]
Reaction time: 6 h
Yield: 58.5 %

Procedure:
The preparation is carried out in the same way as in Example 20, from 1.5 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 1.53 ml of triethylamine and 1.79 g of 2-nitrophenyl isocyanate. After reacting for 6 hours at a temperature in the region of 20° C., the insoluble material is filtered and washed with water and then with isopropyl ether. 0.7 g of 8-[3-(2-nitrophenyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one dihydrate are thus obtained in the form of an orangey solid, the melting point of which is greater than 260° C. (Analysis C20H18 N6O6.0.83H2O, % calculated C: 54.79, H: 4.14, N: 19.17, % found C: 54.5, H: 3.8, N: 19.1).
Reaction SMILES: O=[C:2]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.[BH4-].[Na+].[NH3:20]>>[NH2:20][CH:2]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC(=O)C2(CCCC2)C1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CC(N)C2(CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of tert-butyl 4-oxo-2-azaspiro[4.4]nonane-2-carboxylate (8.56 g, 35.77 mmol) in ammonia (7M in methanol, 100 mL) was added Ti(Oi-Pr)4 (22.37 g, 78.6 mmol) and the reaction mixture was stirred at rt overnight. Then NaBH4 (2.71 g, 71.54 mmol) was added portion-wise and the resulting mixture was stirred at rt for another 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as yellow oil (5 g, 58%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:14][C:13]2=[O:25])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:27]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:58][C@@H:59]([CH2:89]O)[CH2:60][N:61]1[CH:65]=[CH:64][C:63]([NH:66]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:62]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:14][C:13]2=[O:25])[C:9]([NH:66][C:63]2[CH:64]=[CH:65][N:61]([CH2:60][C:59]([OH:58])([CH3:89])[CH3:27])[N:62]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2)=CC1=O
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3cccc(F)c3)=CC2=O)n1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 51.6 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(3-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (200 mg, 0.6 mmol) in dichloromethane (10 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143 mg, 0.7 mmol) and N,N-diisopropylethylamine (223 mg, 1.7 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (117 mg, 0.8 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 110 mg, 0.7 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-2-[4-(3-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (150 mg, 54%) as a brown sticky solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.83-1.08 (m, 2H), 1.16 (br. s., 6H), 1.18-1.33 (m, 4H), 1.67-1.81 (m, 5H), 1.81-2.00 (m, 2H), 3.67 (br. s., 1H), 3.94 (s, 2H), 4.09 (d, J=18.1 Hz, 1H), 4.30 (d, J=18.1 Hz, 1H), 4.91 (dd, J=8.8, 6.4 Hz, 1H), 5.05 (s, 1H), 6.69 (br. s., 1H), 6.93 (d, J=8.8 Hz, 1H), 6.99 (d, J=7.8 Hz, 2H), 7.30 (br. s., 1H), 7.34-7.45 (m, 1H), 8.64 (br. s., 1H).
Reaction SMILES: NCC(C1NC2C(C=1)=CC=CN=2)OC1CCCCO1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][N:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([CH:31]([O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1)[CH2:32][N:33]1C(=O)C3=CC=CC=C3C1=O)[NH:26]2.NN.O>CCO>[NH2:33][CH2:32][CH:31]([C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[C:22]([O:21][CH3:20])[CH:30]=[CH:29][N:28]=2)[O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1
Reactant: COc1ccnc2[nH]c(C(CN3C(=O)c4ccccc4C3=O)OC3CCCCO3)cc12
Agent: NCC(OC1CCCCO1)c1cc2cccnc2[nH]1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccnc2[nH]c(C(CN)OC3CCCCO3)cc12
Yield: 65.2 %

Procedure:
Following the same procedure as for 9a. From 4-Methoxy-2-[2-phthalimido-1-(2,3,5,6-tetrahydropyran-2-yl)oxyethyl]-7-azaindole (2.9 g, 10 mmol) in EtOH (100 ml) and NH2NH2.H2O (420 μl, 15 mmol). After a reaction time of 3 h. a diastereomeric mixture (1:1) of 9b (1.9 g, 95%) was obtained.
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[CH3:10][C:11]1[S:20][C:19]2[NH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[NH:15][C:14](=S)[C:13]=2[CH:12]=1.[S:26]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C@H:33]2[CH2:38][NH:37][CH2:36][CH2:35][NH:34]2)=[CH:27]1.S1C=CC=C1CC[C@H]1CNCCN1>ClCCl.CO.ClCCl.N1C=CC=CC=1>[CH3:10][C:11]1[S:20][C:19]2[NH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[N:15]=[C:14]([N:37]3[CH2:36][CH2:35][NH:34][C@@H:33]([CH2:32][CH2:31][C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)[CH2:38]3)[C:13]=2[CH:12]=1
Reactant: c1cc(CC[C@H]2CNCCN2)cs1
Reactant: Cc1cc2c(s1)Nc1ccccc1NC2=S
Agent: COS(=O)(=O)C(F)(F)F
Agent: c1csc(CC[C@H]2CNCCN2)c1
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccsc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Add methyl trifluoromethanesulfonate (241 μL, 2.13 mmol) to a 0° C. slurry of 2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (437 mg, 1.77 mmol) in dichloromethane (5 mL). Stir 2 h at 0° C. then warm to ambient temperature and stir 16 h. Concentrate the reaction to an orange powder. Add a 6:1 mixture of (S)-2-(2-thiophen-3-yl-ethyl)-piperazine and (S)-2-(2-thiophen-2-yl-ethyl)-piperazine (346 mg, 1.76 mmol) and pyridine (5 mL). Heat to reflux for 7.5 h and stir at ambient temperature for 18 h. Concentrate the reaction, dissolve the residue in methanol-dichloromethane, apply to a SCX column. Wash the column with methanol-dichloromethane to remove impurities then elute the product with 2N ammonia in methanol-methanol (10%). Concentrate and purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (1%–4%) as the eluent to give 333 mg of a brown foam. Purify by radial silica gel chromatography using a 4 mm plate and 1% isopropylamine in tetrahydrofuran-hexanes (10%–20%) as the eluent to give 218 mg (30%) of the title compound: mass spectrum (ion spray): m/z=409 (M+1), 407 (M −1). HR-MS calculated for C22H25N4S2: 409.1521. Found 409.1540. 1H NMR (DMSO-d6): δ 7.56 (s, 1H), 7.43 (dd, 1H), 7.13 (s, 1H), 6.99 (d, 1H), 6.87–6.74 (m, 3H), 6.67 (d, 1H), 6.31 (s, 1H), 3.88 (br d, 1H), 3.76 (br d, 1H), 2.88 (br d, 1H), 2.80–2.53 (m, 5H), 2.45–2.38 (m, 1H), 2.27 (s, 3H), 1.61 (dd, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O>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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:25]4[S:26][CH:27]=[CH:28][C:24]=4[CH3:23])[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: Cc1ccsc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3sccc3C)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 3-methylthiophene-2-boronic acid pinacol ester (125 mg, 0.557 mmol) and K2CO3 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(3-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.52-7.71 (m, 2H), 7.42 (s, 1H), 7.4 (m, 2H), 7.35 (s, 1H), 7.18 (d, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.82 (m, 1H), 3.58 (m, 1H), 3.2 (m, 4H), 3.0 (m, 1H), 2.42 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([O:22]CC)=[CH2:21])[CH:14]=[N:13]2>C1COCC1.O.CO>[Br:8][CH2:22][C:20]([C:15]1[CH:14]=[N:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([Br:9])[CH:11]=2)[N:16]=1)=[O:21]
Reactant: C=C(OCC)c1cnc2cc(Br)ccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CBr)c1cnc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
NBS (55.1 mg, 0.310 mmol) was added to a solution of 6-bromo-2-(1-ethoxyvinyl)quinoxaline (72 mg, 0.26 mmol) in THF (2 mL) and water (0.500 mL) and the mixture was stirred at rt for 2 h. The reaction was diluted with MeOH and purified by prep HPLC (H2O-MeOH with 10 mM NH4OAc buffer) to yield 2-bromo-1-(6-bromoquinoxalin-2-yl)ethanone (50 mg, 0.15 mmol, 59% yield) as white solid. LC-MS retention time 2.40 min; m/z 329 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water: 10% methanol: 0.1% TFA. Solvent B=10% water: 90% methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([S:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19](=O)[CH3:20]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([S:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)=[C:19]([CH3:20])[NH:13]2
Reactant: COC(=O)C(Sc1ccc(Cl)cc1)C(C)=O
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Solvent: C1COCCO1
Product: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Sc3ccc(Cl)cc3)c(=O)c12
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (2.1 g), 2-(4-chlorophenylsulfanyl)-3-oxobutyric acid methyl ester (2.5 g), polyphosphoric acid (10 g) and dioxane (30 mL) was heated at 130° C. for 2 days. The mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was diluted with water and the resulting precipitate collected by filtration, washed with water and dichloromethane and dried to afford title compound, 1.6 g.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH:27]1([CH2:32][N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH:27]1([CH2:32][N:33]2[CH:37]=[C:36]([C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]5[CH:17]=[C:16]([N:18]6[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]6)[N:15]=[C:14]([NH2:25])[N:13]=5)[CH2:9]4)=[CH:4][CH:3]=3)[CH:35]=[N:34]2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CC3CCCC3)c2)OC1(C)C
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: C1COCCO1
Solvent: O
Solvent: CO
Product: CC1Cc2ccc(-c3cnn(CC4CCCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(cyclopentylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.3 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. It was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (4.1 mg). LCMS (M+H)+: m/z=487.3.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:25]([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[O:8])=[CH:9][CH:10]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N(C(=O)c1ccc(O)cc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 4-hydroxybenzoic acid (5 g, 36.2 mmol) in 50 mL of dichloromethane is treated at 0° C. with oxalyl chloride (6.3 mL, 72.4 mmol) and N,N-dimethylformamide (5.6 mL, 72.4 mmol). This solution is stirred at room temperature for 2 hours and treated with diisopropylamine (40 mL, 286 mmol) at 0° C. After stirring at room temperature for overnight, the reaction is partitioned between ethyl acetate and 1N hydrochloride solution. The organic phase is washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 4-hydroxy-N,N-bis(1-methylethyl)benzamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH:2]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[Br-:12].[CH2:13]([N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:8])[CH2:9][CH2:10][CH3:11])[CH:2]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(=O)c1cccnc1
Reactant: CCCCBr
Product: CCCC[n+]1cccc(C(=O)CCC)c1
Product: [Br-]

Procedure:
Propyl 3-pyridyl ketone was reacted with 1-bromobutane according to the procedure of Part a) of Example 6 to give 1-butyl-3-butyryl pyridinium bromide as a tan coloured crystalline solid.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2CN2CCCC2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O.[CH3:45][N:46](C)[CH:47]=O>>[F:1][C:2]1([F:32])[CH2:3][CH2:4][N:5]([C:8]([C:10]2[N:11]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([N:46]([CH3:47])[CH3:45])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]1
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Product: CN(C)[C@H]1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC(F)(F)F)C1
Yield: 85 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 42), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a white foam (85%).