Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]2)=[CH:4][CH:3]=1.CN([CH:19]=[O:20])C>C1COCC1.C(OCC)C>[CH3:12][C:9]1([CH3:13])[O:8][CH:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([CH:19]=[O:20])=[CH:3][CH:4]=2)[CH2:11][O:10]1
Reactant: CC1(C)OCC(Cc2ccc(Br)cc2)O1
Reactant: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)OCC(Cc2ccc(C=O)cc2)O1
Reaction time: 0.5 h

Procedure:
At −78° C. buthyllithium (3.98 mL, 6.37 mmol, 1.6 M solution in hexanes) is added to a solution of 4-(4-bromo-benzyl)-2,2-dimethyl-[1,3]dioxolane (1.57 g, 5.79 mmol) in THF (50 mL). The reaction mixture is stirred at −78° C. for 2 h before DMF is slowly added (2.12 g, 28.95 mmol). Stirring is continued for 30 min at −78° C., then at rt for 1 h. The mixture is diluted with diethyl ether (200 mL) and washed with sat. aq. NaHCO3 and water. The organic layer is dried over MgSO4 and evaporated to leave 4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-benzaldehyde (1.29 g) as a pale brownish oil; LC-MS: tR=0.87 min; 1H NMR (CDCl3): δ 9.98 (s, 1H), 7.84-7.79 (m, 2H), 7.47-7.37 (m, 2H), 4.35 (p, J=6.4 Hz, 1H), 4.02 (dd, J=5.9, 8.2 Hz, 1H), 3.65 (dd, J=7.0, 8.2 Hz, 1H), 3.04 (dd, J=7.0, 14.1 Hz, 1H), 2.90 (dd, J=5.9, 13.5 Hz, 1H9, 1.44 8s, 3H), 1.36 (s, 3H).
Reaction SMILES: O.[OH-].[Li+].[CH:4]([C:7]1[S:8][C:9]([CH3:16])=[C:10]([C:12]([O:14]C)=[O:13])[N:11]=1)([CH3:6])[CH3:5]>O.CO>[CH:4]([C:7]1[S:8][C:9]([CH3:16])=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)c1nc(C(C)C)sc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1sc(C(C)C)nc1C(=O)O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of lithium hydroxide monohydrate (0.2 g) in water (3 mL) was added to a solution of methyl 2-isopropyl-5-methylthiazole-4-carboxylate (example 69, step a) (0.5 g) in methanol (7 mL) and the reaction mixture was stirred at 20° C. for 3 hours. The methanol was removed under reduced pressure and the remaining aqueous solution was washed with ethyl acetate. The aqueous layer was acidified by dropwise addition of concentrated aqueous HCl and this mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and the solvent was removed under reduced pressure. The resultant gum crystallised on standing. Trituration with a mixture of isohexane (4 mL) and ether (1 mL) afforded the subtitled compound. Yield 0.160 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:9]
Reactant: C[Mg]Br
Reactant: CC(=O)c1cccc(O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1cccc(O)c1
Reaction time: 2 h

Procedure:
3′-Hydroxyacetophenone (500 mg) was dissolved in tetrahydrofuran (10 ml), and the solution was slowly added dropwise with a 3 M solution of methylmagnesium bromide in diethyl ether (3.7 ml) under ice cooling. The mixture was stirred at the same temperature for 2 hours, and then added with saturated aqueous ammonium chloride, the mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1 to 1:1) to obtain the title compound (224.3 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])=O>C(C(C)=O)C>[CH2:10]([O:9][C:7]([C:5]1[N:6]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])[N:1]=[C:2]2[S:3][CH:4]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Solvent: CCC(C)=O
Product: CCOC(=O)c1csc2nc(-c3ccccc3[N+](=O)[O-])cn12
Temperature: 25 °C
Yield: 79.4 %

Procedure:
In a typical run, ethyl 2-aminothiazole-4-carboxylate (2.1 g, 0.0123 mol) was taken up in methyl ethyl ketone (25 mL) along with 2-bromo-2′-nitroacetophenone (3.0 g, 0.0123 mol). The reaction mixture was stirred under reflux for 18 hours. It was then cooled to room temperature and filtered to remove some of the solids. The filtrate was concentrated to afford 3.10 g of 6-(2-nitro-phenyl)-imidazo[2,1-b]thiazole-3-carboxylic acid ethyl ester (Calc'd for C14H12N3O4S: 318.3, [M+H]+found: 319).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH2:19][OH:20].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[C:23]([O:22][C:18](=[O:21])[CH2:19][O:20][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 70 °C
Yield: 7.6 %

Procedure:
A suspension of 6-bromo-N-(4-fluorophenyl)nicotinamide (0.112 g, 0.38 mmol), tert-butyl glycolate (0.1 g, 0.76 mmol), and potassium tert-butoxide (0.85 g, 0.76 mmol) in THF (10 mL) was heated in a sealed tube at 70° C. After 6 h the reaction mixture was diluted with ethyl acetate and washed with water bicarbonate and dried over sodium sulfate. Removal of the solvents provided a solid. Purification by reverse phase chromatography gave 0.010 g (8%) of the titled product as a white solid; MS (EI) m/z 345.21 (M−H)−.
Reaction SMILES: [CH2:1]([C:5]1[N:14]=[C:13](O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:22])=O>C(Cl)Cl>[CH2:1]([C:5]1[N:14]=[C:13]([Cl:22])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1nc(O)c2cc(C(F)(F)F)ccc2n1
Solvent: ClCCl
Product: CCCCc1nc(Cl)c2cc(C(F)(F)F)ccc2n1
Yield: 121.7 %

Procedure:
Preparation D11, Step 2: 2-butyl-6-(trifluoromethyl)-quinazolin-4-ol (100 mg, 0.37 mmol, 1 eq) and phosphorus oxychloride (3.00 mL, 3.22 mmol, 87 eq) were mixed at room temperature under nitrogen then refluxed for 3 hours. The reaction was stripped 3 times from methylene chloride. The residue was dissolved in methylene chloride (25 mL) and rinsed 3 times with saturated sodium bicarbonate (25 mL), 1× with water (25 mL). The organic layer was dried (sodium sulfate) and stripped to give 2-butyl-4-chloro-6-(trifluoromethyl)quinazoline (130 mg) as a tan solid. LCMS of a an analytical sample prepared in MeOH detects (M-Cl+OMe)+=285.24.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26]>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH:14][S:25]([C:16]3[CH:17]=[CH:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=3)(=[O:27])=[O:26])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: CN1CCN(c2cccc(NS(=O)(=O)c3ccc4ccccc4c3)c2)CC1

Procedure:
The title compound (E132) was prepared from 3-(4-methylpiperazin-1-yl)benzenamine and naphthalene-2-sulfonyl chloride according to the method of Example 1 MH+=382.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-c1ccc(CBr)c(Br)c1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A solution of 1.0 g (3.7 mmol) of 3'-bromo-4'methyl-1,1'-biphenyl-2-nitrile (Step C) in 15 mL of carbon tetrachloride under a nitrogen atmosphere was treated with 0.720 g (4.04 mmol) of N-bromosuccinimide followed by 60 mg (0.37 mmol) of azobisisobutyronitrile (AIBN). The reaction mixture was heated at reflux for four hours, cooled to room temperature and filtered through Celite. The solvent was removed under vacuum and the residue was dissolved in methylene chloride and treated with decolorizing carbon. The solids were filtered through Celite and the solvent removed under vacuum. The resulting solid was triturated with cold ether, filtered and air dried to afford 920 mg (71 %) of the product as an off-white solid. 1H NMR (200 MHz, CDCl3): δ 4.64 (s, 2H), 7.4-7.8 (m, 7H). EI-MS: calculated for C14H9Br2N 351; found 351 (M+, 20%); 271 (M-Br, 100%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][N:11]([CH2:24][C:25](O)=[O:26])[C:10](=[O:28])[CH2:9]1)=[O:7].O[N:39]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>ClCCl>[F:34][C:32]([F:33])([F:35])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:31]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][N:11]([CH2:24][C:25](=[O:26])[NH2:39])[C:10](=[O:28])[CH2:9]1)=[O:7]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CN1C[C@@H](Cc2c[nH]c3ccccc23)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Product: NC(=O)CN1C[C@@H](Cc2c[nH]c3ccccc23)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 67.5 %

Procedure:
To an ice-cooled solution of (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-1-(carboxymethyl)-5-(1H-indol-3-ylmethyl)piperazin-2-one (0.15 g) and 1-hydroxybenzotriazole (0.038 g) in dichloromethane (3 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.055 g). After the solution was stirred for 2 hours and 55 minutes at the same temperature, 28% aqueous ammonia solution (0.017 ml) was added into the mixture under ice-cooling. The mixture was stirred for 2 hours and 25 minutes at room temperature. After evaporation of the solvent, the residue was extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium bicarbonate solution, water and brine, and dried over magnesium sulfate. After evaporation in vacuo, the residue was purified by column chromatography on silica gel (10 g) eluting with a mixture of dichloromethane-methanol (from 0c to 5% gradient solution). To the eluate containing objective product was added diisopropyl ether and the resulting precipitates were collected by filtration, washed with diisopropyl ether, and dried to give (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-1-(carbamoylmethyl)-5-(1H-indol-3-ylmethyl)piperazin-2-one (0.10 g) as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([F:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1.[NH2:23][C:24]1[C:25]([C:31](O)=[O:32])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1>>[NH2:23][C:24]1[C:25]([C:31]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][C@H:12]([F:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:9]2)=[O:32])=[N:26][C:27]([Br:30])=[CH:28][CH:29]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(c2ccncc2N)C1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](F)CN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1

Procedure:
Following Method 11 of Example 305, tert-Butyl (3S,5R)-1-(3-aminopyridin-4-yl)-5-fluoropiperidin-3-ylcarbamate and 3-amino-6-bromopicolinic acid were coupled yielding after column chromatography tert-butyl (3S,5R)-1-(3-(3-amino-6-bromopicolinamido)pyridin-4-yl)-5-fluoropiperidin-3-ylcarbamate. LC/MS (m/z): 509.1/511.1 (MH+).
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O[C@@]1(C)C(=[N:21][C@H:22]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:23]([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])C[C@H]2C[C@@H]1C2(C)C>O1CCCC1>[CH3:30][CH:23]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@@H:22]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[NH2:21]
Reactant: CCOC(=O)CC(C)[C@H](N=C1C[C@H]2C[C@H](C2(C)C)[C@@]1(C)O)C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)[C@H](N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 10% aqueous solution of citric acid (11 ml, 5.6 mmol) was added to a solution of 1-(1,1-dimethylethyl) 5-ethyl N-[(1R,2R,5R)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylidene]-3-methylglutamate (2 g) in tetrahydrofuran (10 ml) and the mixture was stirred at room temperature for 4 days. The mixture was the evaporated and the residue suspended in water (50 ml) and washed with diethyl ether (100 ml). The aqueous phase was then adjusted to pH˜7 using aqueous sodium hydrogen carbonate solution and then extracted with diethyl ether (3×100 ml). The organic fractions were combined, dried over sodium sulphate, filtered and evaporated to give 1-(1,1-dimethylethyl) 5-ethyl 3-methylglutamate (1.1 g) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:22].CCCCCC.C(OCC)(=O)C>ClCCl>[CH:5]12[O:22][CH:4]1[CH2:3][CH2:2][N:1]([C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[CH2:6]2
Reactant: O=C(OCc1ccccc1)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC2OC2C1
Temperature: 25 °C

Procedure:
A stirred solution of benzyl 3,6-dihydropyridine-1(2H)-carboxylate (20.0 g, 92.0 mmol) in dichloromethane (280 ml) was cooled to 0° C. A solution of m-chloroperoxybenzoic acid (22.5 g, approx. 130 mmol) in dichloromethane (560 ml) was added drop-wise and the resulting colourless reaction mixture warmed to room temperature. After an additional 4 h at room temperature (reaction complete by tlc using 50:50 hexane:ethyl acetate as eluent.) the reaction mixture was washed with aqueous potassium carbonate solution (5 wt %, 3×200 ml) and brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to furnish benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate as a yellow oil (22.0 g; 100%).
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][C:11]([C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=O)([C:14]#[N:15])[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.B.C1COCC1>>[CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][C:11]([CH2:14][NH2:15])([CH2:16][N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: N#CC1(C(=O)N2CCCC2)CCC(S(=O)(=O)CC2CC2)CC1
Agent: B
Solvent: C1CCOC1
Product: NCC1(CN2CCCC2)CCC(S(=O)(=O)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-cyclopropylmethanesulfonyl-1-(pyrrolidine-1-carbonyl)-cyclohexanecarbonitrile (246 mg; 0.0758 mmol) and borane-THF complex (1.0 M solution in THF; 10 ml; 10 mmol) were stirred at room temperature overnight. LC-MS indicated that the reaction had not gone to completion. The mixture was heated at reflux for 2 hours then allowed to cool to room temperature. The mixture was cooled in an icebath and quenched with MeOH (3 ml) then evaporated to dryness in vacuo. The residue was dissolved in MeOH (7 ml) and acidified with concentrated HCl. The mixture was stirred at room temperature for 18 hours. The mixture was poured on to a SCX cartridge. The cartridge was washed with several column lengths of MeOH followed by 2M ammonia in methanol solution to elute the amine. The desired product was obtained as a colourless oil upon evaporation of the appropriate fractions (44 mg). m/z=315 (M+H+).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:17][C:18]1[CH:19]=[C:20](I)[CH:21]=[CH:22][CH:23]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[Br:17][C:18]1[CH:23]=[C:22]([NH:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: Brc1cccc(I)c1
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Solvent: CCCCCC
Product: Brc1cccc(NCc2ccccc2)c1
Yield: 82.8 %

Procedure:
The general procedure under argon or air was followed using copper(I) iodide (10 mg, 0.05 mmol or 2.0 mg, 0.01 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μl, 1.20 mmol), 3-bromoiodobenzene (128 μL, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rf=0.4) afforded N-(3-bromophenyl)benzylamine (217 mg, 83% isolated yield) as colorless liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Beletskaya, I. P.; Bessmertnykh, A. G.; Guilard, R. Synlett 1999, 1459-1461.
Reaction SMILES: [C:1]([C:3]([NH:8][C:9](=O)[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13])([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2].[OH-:20].[Na+].OO.[ClH:24]>C(O)(C)C.O>[ClH:24].[CH:4]([C:3]1([CH3:7])[NH:8][C:9]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[N:2][C:1]1=[O:20])([CH3:6])[CH3:5]
Reactant: [OH-]
Reactant: CC(C)C(C)(C#N)NC(=O)c1ccccc1C(=O)O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)C1(C)NC(c2ccccc2C(=O)O)=NC1=O
Temperature: 80 °C
Yield: 60.3 %

Procedure:
To 5.22 g (0.020 mol) of N-(1-cyano-1,2-dimethylpropyl)phthalamic acid in a mixture of 35 mL isopropyl alcohol and 10 mL of water is added 6.41 g (0.080 mol) of aqueous 50% sodium hydroxide. External cooling is applied to hold the temperature at 20°-30° C. and 4.80 g (0.042 mol) of aqueous 30% hydrogen peroxide is added. The mixture is heated at 80° C. for five hours then cooled to 20°-25° C. Aqueous 36% hydrochloric acid is added to adjust the pH to 1. The volatile solvent is removed in vacuo to give 8.35 g of solid 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)benzoic acid, hydrochloride salt. The solid is analyzed by high performance liquid chromatography. The real yield is 60.3%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O1CCCC1>[C:12]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)COC2=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)COC2=O

Procedure:
3 g of 5-amino-phthalide, 10 ml of acetic anhydride and 30 ml of tetrahydrofuran are refluxed for 1 hour. The crystals that are precipitated after cooling are suctioned off and washed with isopropylether. 3.3 g of the title compound is obtained, flash point >300° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:24][C@:23]3([CH3:37])[C@@H:25]([CH3:36])[CH2:26][CH2:27][C@H:28]4[C:29]([CH3:35])([CH3:34])[C@@H:30]([OH:33])[CH2:31][CH2:32][C@@:22]34[O:21][C:11]=2[C:12]2[CH:13]([O:19]C)[NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:10]2[CH2:24][C@:23]3([CH3:37])[C@@H:25]([CH3:36])[CH2:26][CH2:27][C@H:28]4[C:29]([CH3:35])([CH3:34])[C@@H:30]([OH:33])[CH2:31][CH2:32][C@@:22]34[O:21][C:11]=2[C:12]2[CH:13]([OH:19])[NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1NC(=O)c2cc(OCc3ccccc3)c3c(c21)O[C@@]12CC[C@H](O)C(C)(C)[C@@H]1CC[C@H](C)[C@@]2(C)C3
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2C(O)NC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a solution of the above Compound (29b) (439 mg, 0.87 mmol) in dioxane (15 ml) was added 0.15 ml of 0.1N HCl, and the mixture stirred at room temperature for 2 hours. Water was added to the reaction, and extracted with ethyl acetate. The extract was washed with 5% sodium carbonate aqueous solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by a silica gel column chromatography (silica gel 15 g; toluene:ethyl acetate=1:2) to give 276 mg (62%) of Compound (29a).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=O.[C:30](O)(=O)[CH2:31][CH:32](C)C.C[O-].[Na+]>CO.[Pt]>[OH:25][C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[CH:19]([CH2:18][C@@H:17]([OH:27])[C@@H:16]3[C@@H:15]2[CH2:14][C@H:13]([OH:28])[C@@:12]2([CH3:29])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:31]([CH3:32])[CH3:30])[CH2:24]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CC(C)CC(=O)O
Agent: [Pt]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 24 h

Procedure:
The product was synthesized by the electrochemical oxidative decarboxylation of carboxylic acids (Kolbe electrolysis) according to a literature procedure (Bergström, S. and Krabisch, L., Acta Chem. Scand. 1957, 11, 1067). To a solution of cholic acid (10 g, 24.5 mmol) and isovaleric acid (70 mL, 644 mmol) in methanol (400 mL) was added sodium methoxide (2.5 g). The solution was placed in a beaker surrounded by ice. The electrolysis was run for 24 hours with 1.0 A between platinum electrodes. After work up, the product was crystallized from acetone (6.2 g, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([S:10][CH2:11][CH3:12])[N:3]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([S:10][CH2:11][CH3:12])[N:3]=1
Reactant: CCSc1ncc(CO)c(N)n1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCSc1ncc(C=O)c(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-5-hydroxymethyl-2-(ethylthio)pyrimidine (6-1) (9.6 g, 51.89 mmol) in CHCl3 (1 L) was added MnO2 (86.9 g, 415 mmol, 8 equiv). The suspension was stirred at rt overnight. The mixture was filtered through celite and washed with CHCl3. The combined filtrate was concentrated to give the titled compound (6-2). LRMS m/z (M+H) Calcd. 184.1, found 184.1.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH2:35]1[CH2:41][O:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:37]4[CH2:36][CH2:35][CH2:41][O:40][CH2:39][CH2:38]4)[C:17]=23)=[CH:20][C:21]=1[CH3:34]
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Reactant: C1CNCCOC1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCCOCC4)c23)ccc1OCc1cccc(F)c1
Yield: 25 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate (prepared as described in Example 21) and homomorpholine to give the title compound in 25% yield; NMR Spectrum: 1.74-1.79 (m, 2H), 2.23 (s, 3H), 2.76-2.79 (m, 4H), 2.98 (t, 2H), 3.57-3.59 (m, 2H), 3.62-3.64 (m, 2H), 4.40 (t, 2H), 5.16 (s, 2H), 7.00 (d, 1H), 7.16 (td, 1H), 7.28-7.33 (m, 2H), 7.44-7.47 (m, 3H), 8.17 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 493 (MH+).