Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[N:36]1([C:42]([CH:44]2[CH2:48][CH2:47][CH2:46][O:45]2)=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:39]3[CH2:40][CH2:41][N:36]([C:42]([CH:44]4[CH2:48][CH2:47][CH2:46][O:45]4)=[O:43])[CH2:37][CH2:38]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: O=C(C1CCCO1)N1CCNCC1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(C(=O)C3CCCO3)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazin-1-yl-(tetrahydro-furan-2-yl)-methanone (Aldrich) to give the title compound. LC-MS: 679.2 [(M+H)+]
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].[CH3:16][Si](C=[N+]=[N-])(C)C.N#N>CO.C1C=CC=CC=1>[CH3:16][O:4][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6]
Reactant: CC(C)(C(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Yield: 88.2 %

Procedure:
To a solution of 2-methyl-2-(4-nitrophenyl)-propionic acid (1.0014 g, 4.76 mmol) in 10% MeOH/benzene (20 mL) was added dropwise (trimethylsilyl)-diazomethane (2.0 M in hexanes, 3.5 mL, 7.0 mmol). The reaction mixture was stirred at rt until evolution of N2 ceased (<5 min) and then concentrated. The crude residue was purified (FCC) to give the title compound (937.6 mg, 88%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]([N:29]2[CH2:33][C@:32]3([CH:38]4[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]4)[CH2:34]3)[O:31][C:30]2=[O:41])[O:23][C:24]=1[Si](C)(C)C>O1CCCC1>[Br:19][C:20]1[CH:21]=[C:22]([N:29]2[CH2:33][C@:32]3([CH:38]4[CH2:37][CH2:36][N:35]([CH2:40][CH2:39]4)[CH2:34]3)[O:31][C:30]2=[O:41])[O:23][CH:24]=1
Reactant: C[Si](C)(C)c1oc(N2C[C@@]3(CN4CCC3CC4)OC2=O)cc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)co1
Temperature: 70 °C
Yield: 82.1 %

Procedure:
Tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 2.2 mL, 2.20 mmol) was added to a solution of (R)-3′-[4-bromo-5-(trimethylsilyl)furan-2-yl]spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one (577 mg, 1.44 mmol) in tetrahydrofuran (5 mL). The solution was heated at 70° C. (bath temperature) for 6 h. The reaction mixture was evaporated to dryness, and the residue was subjected to flash chromatography using a gradient of ammoniated methanol in chloroform as the eluant give the title compound as a pale brown solid (387 mg), m/z 327, 329 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:15]O>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[C:11]([C:12]#[N:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NO
Reactant: O=Cc1cc2ccccc2nc1Cl
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2ccccc2nc1Cl
Yield: 71.1 %

Procedure:
A mixture was prepared from 10 g of 2-chloro-3-quinolinecarboxaldehyde, 5.2 g of hydroxylamine hydrochloride and 100 ml of phosphoryl chloride and heated with a heat lamp. The mixture was heterogeneous until the temperature reached 90° C. and there was no noticeable exotherm or gas evolution. After heating at reflux for 30 minutes, the mixture was cooled for 16 hours. It was then quenched in 700 ml of water. The tan solid which formed was separated by filtration and dried to give 7 g of crude 2-chloro-3-cyanoquinoline.
Reaction SMILES: [CH2:1]([CH:6]1[CH:10]([CH:11](C(OCC)=O)[C:12](=[O:14])[CH3:13])[CH2:9][CH2:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5]>O>[CH2:1]([CH:6]1[CH:10]([CH2:11][C:12](=[O:14])[CH3:13])[CH2:9][CH2:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1C(=O)CCC1C(C(C)=O)C(=O)OCC
Solvent: O
Product: CCCCCC1C(=O)CCC1CC(C)=O
Yield: 86.9 %

Procedure:
513 g of 2-n-pentyl-3-(1-carbethoxy-2-oxopropyl)-1-cyclopentanone were mixed in an autoclave with an equal weight of water. The autoclave was then purged of the air which it contained, closed and heated up to a temperature of 140°-150° C. for 2 hours. After cooling, extraction, washing and distillation, there was obtained 332 g of 2-n-pentyl-3-(2-oxopropyl)-1-cyclopentanone (yield=90.6%) having nD20 =1.432 and d420 =0.961.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)[CH2:54][CH2:53][O:52]1.C(O)CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:54][CH2:53][OH:52])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: OCCO
Product: COc1cc(C(=O)OCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a suspension of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (US20100152190A1, 197 mg, 0.320 mmol,) in methylene chloride (8 mL) was added triethylamine (97.0 mg, 0.14 mL, 0.959 mmol) followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (Aldrich, 114 mg, 0.447 mmol). The mixture was stirred at room temperature for 10 min before ethane-1,2-diol (Aldrich, 122 mg, 0.11 mL, 1.97 mmol) was added. This reaction mixture was stirred at room temperature overnight. It was then diluted with methylene chloride and washed with water, brine and concentrated to dryness. The crude material was purified by flash chromatography (eluting with hexane/ethyl acetate, 80/20 to 10/90) to give chiral 2-hydroxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (112.2 mg, 53% yield). MS (ES+) m/z calcd. for C33H34Cl2F2N3O5 [(M+H)+]: 660. found: 660.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:3]#[CH:4].C([Mg]Cl)C.COC1C=CC(C=O)=CC=1.Br[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1/[C:30](=[CH:38]/[C:39]1[NH:40][CH:41]=[CH:42][C:43]=1[O:44][CH3:45])/[C:31](=[O:37])[NH:32]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:3]#[C:4][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1/[C:30](=[CH:38]/[C:39]1[NH:40][CH:41]=[CH:42][C:43]=1[O:44][CH3:45])/[C:31](=[O:37])[NH:32]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC[Mg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1

Procedure:
Using Method D above, 3-hydroxy-3-(4-methoxyphenyl)-1-propyne (115 mg, 0.70 mmol) (prepared by the addition of ethylmagnesium chloride (Aldrich) to 4-methoxybenzaldehyde (Aldrich) according to Method A above), was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1) (174 mg, 0.55 mmol) using (Ph3P)2PdCl2 (18 mg) (Aldrich) and CuI (10 mg) (Aldrich) as catalyst in DMF (2.5 mL) and Et3N (2.5 mL) as solvent at 70° C. for 15 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(4-methoxyphenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 32 mg, 32%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O>>[F:23][C:15]1[CH:14]=[C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:25]4[O:24][CH:28]=[CH:27][CH:26]=4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=[N:11]2)[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Br)cc2)cc1F
Reactant: OB(O)c1ccco1
Product: CS(=O)(=O)c1ccc(-n2nccc2-c2ccc(-c3ccco3)cc2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 5 using 5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazole instead of 4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide, 2-furanboronic acid instead of 3-thienylboronic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6]([SH:11])=[N:5][N:4]=1.IC.[CH2:14](N(CC)CC)C>C(O)C>[OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6]([S:11][CH3:14])=[N:5][N:4]=1
Reactant: CCN(CC)CC
Reactant: CCCn1c(S)nnc1CO
Solvent: CCO
Solvent: CI
Product: CCCn1c(CO)nnc1SC

Procedure:
A solution of 3-hydroxymethyl-4-propyl-5-mercapto-4H-1,2,4-triazole (2.0 g), iodo methane (1.1 ml) and triethylamine (2.5 ml) in ethanol (20 ml) was stirred for 2 days at 50° C. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:5→1:4), to give 3-hydroxymethyl-5-methylthio-4-propyl-4H-1,2,4-triazole (2.13 g) as pale yellow oil. To a solution of 3-hydroxymethyl-5-methylthio-4-propyl-4H-1,2,4-triazole (2.13 g) in chloroform (6 ml), thionyl chloride (16 ml) was slowly added at 0° C. The mixture was heated to reflux for 2 hours, and concentrated under reduced pressure. To the residue were added small amount of ethanol and ethyl acetate, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate and diethylether, to give 3-chloromethyl-5-methylthio-4-propyl-4H-1,2,4-triazole hydrochloride (1.06 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([OH:12])[CH:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:11])[CH3:10])=[C:4]([O:12][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: CC(=O)c1cc(C)c(Cl)cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc(Cl)c(C)cc3C(C)=O)c2cc1OC
Temperature: 140 °C
Reaction time: 24 h
Yield: 10 %

Procedure:
1-(4-Chloro-2-hydroxy-5-methyl-phenyl)-ethanone (193 mg), 4-chloro-6,7-dimethoxyquinoline (468 mg), and 4-dimethylaminopyridine (385 mg) were suspended in o-dichlorobenzene (5 ml) to prepare a suspension which was then stirred at 140° C. for 24 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (39 mg, yield 10%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[F:26].[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1.CCOC(C)=O>ClCCl.CCCCCCC>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)=[CH:21][C:20]=1[F:26]
Reactant: C1=COCCC1
Reactant: Oc1ccc(Br)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Fc1cc(OC2CCCCO2)ccc1Br
Yield: 33 %

Procedure:
Pyridinium p-toluene sulfonic acid (789 mg, 3.1 mmol) was added to a solution of 4-bromo-3-fluorophenol (4.00 g, 20.9 mmol) and 3,4-dihydro-2H-pyran (3.52 g, 41.9 mmol) in dichloromethane (105 mL, 0.2M). After 2 h the reaction was quenched with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted with dichloromethane (2×). The organic layers were combined, dried (Na2SO4), filtered and concentrated to give a colorless oil. The material was loaded onto a 25 g silica guard column and run on a 330 g column with 0-5% EtOAc in heptane. Desired material was concentrated down yielding 1900 mg (33%) of a clear colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.56-1.77 (m, 3H) 1.82-1.89 (m, 2H) 1.89-2.07 (m, 1H) 3.62 (m, J=11.37, 4.07, 4.07, 1.37 Hz, 1H) 3.85 (ddd, J=11.32, 10.05, 3.02 Hz, 1H) 5.38 (dd, J=3.12 Hz, 1H) 6.76 (ddd, J=8.88, 2.73, 1.07 Hz, 1H) 6.89 (dd, J=10.34, 2.73 Hz, 1H) 7.35-7.46 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1

Procedure:
2-Chloro-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (see Example 19 for preparation), 4-methoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH3:39])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]>>[CH:29]([N:32]1[CH2:33][CH2:34][CH:35]([N:38]([CH3:39])[CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:36][CH2:37]1)([CH3:31])[CH3:30]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CNC1CCN(C(C)C)CC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN(C)C3CCN(C(C)C)CC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-isopropyl-N-methylpiperidin-4-amine via General Procedure E to give 22.1 mg of 295 following reverse phase purification. MS (Q1) 518.3 (M)+
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH2:11][CH2:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17]O)=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[C:5]1([CH2:11][CH2:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][Br:2])=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCc1ccc(CCc2ccccc2)cc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: BrCc1ccc(CCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
3.14 ml (33.4 mmol) of phosphorus tribromide in 11 ml of toluene are added dropwise, while cooling and under an N2 atmosphere, to 8.36 g (85%; 33.4 mmol) of p-(2-phenylethyl)benzyl alcohol in 100 ml of toluene. After 2 h at RT, the mixture is poured onto ice-water and the organic phase is separated off; it is washed with sat. NaHCO3 solution, water and saline. The aqueous phases are extracted 2× with ether, and the combined organic phases are dried with Na2SO4 and evaporated: TLC Rf (A)=0.77; 1H-NMR (200 MHz, CDCl3): 2.92 (s, 4H), 4.50 (s, 2H), 7.15-7.35 (m, 9H; additional signals of approximately 20% p-(2-phenylethyl)toluene.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32]>C1COCC1>[F:29][C:30]([F:37])([F:36])[C:31](=[O:32])[CH2:17][C:16]([C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2ccc(C(=O)CC(=O)C(F)(F)F)s2)c1
Temperature: 1.5 °C

Procedure:
Into a 250 mL flask was weighed 5.42 g (19.3 mmol) of 1-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)ethanone and 42 mL of THF. The resulting suspension was stirred and cooled to 0-3° C. in an ice bath and 23 mL of a lithium bis(trimethylsilyl)amide solution (1.0 M in THF) was added. The resulting thick yellow suspension was stirred and allowed to warm to room temperature then ethyl trifluoroacetate (3.46 mL, 29 mmol) was added. After stirring at room temperature overnight the reaction was concentrated in vacuo to remove THF. The residue was washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting amorphous yellow powder was pure enough for further synthetic transformations, yield: 72 g (99%). 1H NMR (400 MHz, DMSO-d6): δ 8.20 (d, J=7 Hz, 1H), 8.08 (t, J=7 Hz, 1H), 7.95 (d, J=4.0 Hz, 1H), 7.89 (d, J=7 Hz, 1H), 7.78 (d, J=4 Hz, 1H), 7.69 (t, J=7 Hz, 1H), 6.22 (broad s, 1H), 3.26 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH:10]([N:23]1[C:19](=[O:29])[C:20]2[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22]1=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCC(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
To a solution of (3-hydroxy-3-phenyl-propyl)-carbamic acid tert-butyl ester (10.4 g, 41.4 mmol), phthalimide (5.2 g, 36.6 mmol), and PPh3 (14.6 g, 55.5 mmol) in THF (204 mL) was added dropwise DEAD (8.9 mL, 55 mmol) with stirring at 0° C. Then the resulting mixture was warmed to room temperature for an additional 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate, 3:1) to give [3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propyl]-carbamic acid tert-butyl ester. (Yield 10.5 g, 66.8%).
Reaction SMILES: [N:1]1([C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH3:24])=[O:22])=[N:19][CH:20]=3)[CH2:11]2)=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:25]=O>CC#N>[CH3:25][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([N:10]2[CH2:11][CH:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH3:24])=[O:22])=[N:19][CH:20]=3)[CH2:13]2)=[O:9])[CH2:2][CH2:3]1
Reactant: C=O
Reactant: CNC(=O)c1ccc(OC2CN(C(=O)N3CCCNCC3)C2)cn1
Solvent: CC#N
Product: CNC(=O)c1ccc(OC2CN(C(=O)N3CCCN(C)CC3)C2)cn1
Yield: 20 %

Procedure:
In a similar fashion (Route 1, GP A; except that MeCN was used as solvent), 5-{[1-(1,4-diazepan-1-ylcarbonyl)azetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (25 mg, 0.075 mmol) and formaldehyde (6.1 μl of a 37% aq solution, 0.075 mmol) gave the title compound as colourless oil (5.3 mg, 20%) after purification by preparative HPLC.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.CO>C(O)C.ClCCl.[Pd]>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Reaction time: 8 h

Procedure:
A mixture of 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (400 mg, 1.67 mmol) and 10%Pd/C (400 mg) in ethanol (15 mL) was stirred under H2 overnight. The reaction mixture was filtered and the filtrate concentrated and purified by column chromatography. Elution with 5% methanol (2M/NH3) in dichloromethane gave the less polar isomer (297.7 mg, 73.5%) and with 10% methanol (2M/NH3) in dichloromethane gave the more polar isomer (73 mg, 18.1%).
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([NH:18][CH2:13][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1ccc(OCC2CO2)cc1
Reactant: CCCCN
Product: CCCCNCC(O)COc1ccc(C=O)cc1

Procedure:
To 4-(2,3-epoxypropoxy)benzaldehyde (8.9 gms., 0.05 m) is added n-butylamine (30 ml.) and the resulting solution is refluxed 17 hours. The excess n-butylamine is removed under reduced pressure (20 mm). The oil is dissolved in 6N hydrochloric acid (30 ml.) and the solution is heated on a steam bath for 40 minutes. The hot acidic solution is poured into a hot saturated aqueous sodium carbonate solution with nitrogen bubbling through it. The basis solution is extracted with chloroform. The chloroform is dried over sodium sulfate and concentrated to yield 4-(3-n-butylamino-2-hydroxypropoxy)benzaldehyde, as an oil.