Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cccc(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1cccc(CBr)c1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
3′-Methylacetophenone (5.00 g; 37.3 mmol), N-bromosuccinimide (6.63 g; 37.3 mmol), and benzoyl peroxide (100 mg) were added to carbon tetrachloride (70 ml), and the mixture was refluxed for 1 hour. The mixture was left to cool to room temperature, and crystals that precipitated were removed by filtration. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 3.08 g of the target compound (yield: 38.8%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([CH:30]1[CH2:32][CH2:31]1)[NH2:29]>>[CH:30]1([C:28]2[N:29]=[C:23]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH2:12]3)[O:25][N:27]=2)[CH2:32][CH2:31]1
Reactant: NC(=NO)C1CC1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
60 mg (0.17 mmol) of the compound from Example 38A and 27 mg (0.26 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 51 mg (70% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31](NC)=[O:32])[C:25]([Cl:39])=[CH:24][N:23]=1>>[CH:3]([O:2][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=1[NH:28][C:26]1[C:25]([Cl:39])=[CH:24][N:23]=[C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])[N:27]=1)([CH3:8])[CH3:4]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCCC(N1CCOCC1)C2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3C(=O)OC(C)C)n2)ccc2c1CCCC(N1CCOCC1)C2

Procedure:
The title compound was prepared from 1-methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (50 mg, 0.2 mmol) and 2-(2,5-dichloropyrimidin-4-ylamino)-N-methylbenzamide (60 mg, 0.2 mmol) in an analogous manner to Example 946 to afford a yellow foam (45 mg, 40%). Mp: 117-20° C. LCMS (m/e) 566 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.14 (s, 1H), 8.85 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.10 (d, J=8 Hz, 1H), 8.07 (d, J=8 Hz, 1H), 7.56 (t, J=8 Hz, 2H), 7.45 (s, 1H), 7.12 (t, J=8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 5.38 (m, 1H), 3.75 (m, 7H), 3.25 (m, 1H), 2.90 (m, 2H), 2.70 (m, 2H), 2.60 (m, 2H), 2.41 (m, 2H), 2.12 (m, 2H), 1.81 (m, 1H), 1.65 (m, 1H), 1.42 (d, J=6 Hz, 6H).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[C:4]([O:13][CH:14]([CH3:16])[CH3:15])[CH:3]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21]>>[CH:14]([O:13][C:4]1[CH:3]=[C:2]([O:21][CH2:20][CH2:19][O:18][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:12])[NH:7][CH:8]=[N:9]2)([CH3:16])[CH3:15]
Reactant: CC(C)Oc1cc(F)cc2nc[nH]c(=O)c12
Reactant: COCCO
Product: COCCOc1cc(OC(C)C)c2c(=O)[nH]cnc2c1
Temperature: 120 °C
Yield: 27.8 %

Procedure:
An analogous reaction to that described in example 137b, but starting with 7-fluoro-5-isopropoxyquinazolin-4(3H)-one (444 mg, 2 mmol) and 2-methoxyethanol (0.32 ml, 4.06 mmol) and heating at 120° C. for 1.5 hours yielded 5-isopropoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one (155 mg, 28% yield) as a beige solid:
Reaction SMILES: Cl([O-])(=O)(=O)=O.[C:6]([O-])(=O)[CH3:7].[C:10]1([CH3:17])[CH:15]=[CH:14][C:13]([Tl+2])=[CH:12][CH:11]=1.O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC=CC=1>[CH3:17][C:10]1[CH:15]=[CH:14][C:13]([C:10]2[CH:15]=[CH:14][C:6]([CH3:7])=[CH:12][CH:11]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)[O-]
Reactant: Cc1ccc([Tl+2])cc1
Agent: [Pd+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccc(C)cc2)cc1

Procedure:
A solution of 1000 parts by weight of p-tolyl thallium acetate perchlorate (p-CH3C6H4TlClO4CH3COO) in 6000 parts by weight of water and a solution of 2 parts by weight of palladium (II)-acetate [Pd(OAc)2 ] in 1500 parts by weight of benzene were stirred together vigorously for 2 hours at 60° C. Then the organic phase was separated and the benzene was distilled off under reduced pressure. 310 parts by weight of a residue remained which contained 297 parts by weight of p-tolyl acetate and 11 parts by weight of 4,4-dimethyl biphenyl in addition to palladium compounds. The reaction rate was 99% with a selectivity of 95%. The mixture was rectified over a short column at 10 m bar with the fraction passing over between 79° and 85° C. consisting of pure p-tolyl acetate. The distillation residue was taken up in acetone, and 4,4'-dimethyl biphenyl in pure form was obtained by addition of water.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:33].[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:33][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:34])=[O:2]
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4ccccn4)cc3)oc2C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(OCCc2nc(-c3ccc(-c4ccccn4)cc3)oc2C)ccc1CCC(=O)O
Temperature: 25 °C
Yield: 40 %

Procedure:
3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid methyl ester from step B is dissolved in tetrahydrofuran (1 mL) and 5N sodium hydroxide (1 mL) solution is added with stirring at room temperature. The reaction is heated to reflux and monitored by HPLC. Upon complete conversion, the reaction is allowed to cool to room temperature and neutralized with 5N hydrochloric acid (1 mL), diluted with ethyl acetate, and extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(2-methyl-4-{2-[5-methyl-2-(4-pyridin-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid (58 mg, 0.13 mmol, 40% yield for two steps) may also be obtained by recrystalization from ethyl acetate, MS (ES): 443.2 (M++1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:38][C@@H:37]2[C@:32]([CH3:46])([CH2:33][CH2:34][C@H:35]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH2:36]2)[C@@H:31]2[C@@H:10]1[C@H:11]1[C@:28]([CH3:47])([CH2:29][CH2:30]2)[C@@H:14]([C@H:15]([CH3:27])[CH2:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C@@H:9]1[CH2:38][C@@H:37]2[C@:32]([CH3:46])([CH2:33][CH2:34][C@H:35]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH2:36]2)[C@@H:31]2[C@@H:10]1[C@H:11]1[C@:28]([CH3:47])([CH2:29][CH2:30]2)[C@@H:14]([C@H:15]([CH3:27])[CH2:16][CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 90.4 %

Procedure:
Compound 2007 (0.0527 g, 0.079 mmol) in anhydrous THF (4 ml) under Ar was treated with tetrabutylammonium fluoride (TBAF) (0.237 ml, 1M in THF, 0.237 mmol). The solution was stirred until no starting material remained by TLC. The solvent was removed in vacuo, the residue taken up in 5 ml CH2Cl2, washed with 5 ml aqueous saturated NaHCO3 solution, and the aqueous layer was extracted 2x with 5 ml CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo. Flash chromatography (SiO2, 8:1 hexanes:EtOAc) gave compound 2008 (0.0395 g, 90%) as a white solid foam. 1H NMR (500 MHz, CDCl3) δ: 7.35-7.34 (m, 5H, benzyl Ar--H), 4.71-4.69 (m, 1H, THP ether methine H), 4.585 (d, J=11.8 Hz, 1/2H, benzyl-CH2), 4.58 (d, J=11.8 Hz, 1/2H, benzyl-CH2), 4.315 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 4.29 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 3.94-3.90 (m, 1H, THP OCH2), 3.62-3.58 (m, 3H, C-24 H & THP OCH2), 3.50-3.48 (m, 1H, C-3 H), 3.45 (s, 1H, 7-H), 0.92 (d, J=6.6 Hz, 3H, C-21 H), 0.81 (s, 3H, C-19 H), 0.63 (s, 3H, C-18H) (Note: product is a mixture of diastereomers); IR (CHCl3) 3600, 2900 cm-1 ; MS (CI/isobutane) m/z 554 (M+1, 2%), 361 (M+1-THP-HOBn, 42%), 343 (M+1-THP-HPBn, H2O, 100%); m.p. 52°-56° C.; Anal. calcd. for C36H56O4 : C=78.21, H=10.21; Found: C=77.93, H=10.39.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CS(C)=O.CCOC(C)=O>[N:10]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccc(Br)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of 4-bromobenzylbromide 1 (2.95 g, 11.8 mmol) in DMSO (5 mL) at room temperature, was added NaN3 (1.53 g, 23.5 mmol). The solution was heated to 80° C. and stirred for 1 h at this temperature. The reaction mixture was diluted with EtOAc, and washed with H2O and brine. The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using EtOAc/hexanes (10%) to give 1.88 g (76%) of 2 as a colorless oil. 1H NMR spectra was consistent with literature data. Shi, H.; Liu, J.; Geng, J.; Tang, B. Z.; Liu, B. J. Am. Chem. Soc. 2012, 134, 9569.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S-:9])[CH:6]=[CH:7][CH:8]=1.[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: COc1cccc([S-])c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A solution of potassium 3-methoxybenzenethiolate (6.37 g, 35.7 mmol) and 4-chloronitrobenzene (5.11 g, 32.5 mmol) in dimethylformamide (30 mL) was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and a yellow solid was collected by filtration. Recrystallization from 90% ethanol yielded the title anisole (7.79 g, 92%) as a yellow solid; mp 81°-83° C. 1H--NMR (250 MHz, d6 --DMSO): 3.80 (s, 3H, OCH3) 7.10-7.19 (m, 3H, aromatic) 7.32 (d, 2H, J=7.1 Hz, aromatic) 7.43-7.49 (m, 1H, aromatic) 8.15 (d, 2H, J=7.0, aromatic). MS (CI, CH4): 262 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl[CH:13](Cl)C.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[CH:3]=1
Reactant: CC(Cl)Cl
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(O)c(O)c1

Procedure:
A mixture of 180 g of 3,4-dihydroxybenzoic acid, 360 ml of dichloroethane, 142 ml of methanol and 18 g of p-toluenesulfonic acid was boiled on a water separator, until distillate is clear. The solvent was evaporated, and the residue was admixed with 1.5 liters of diethyl ether, washed with 1 liter of a saturated aqueous sodium bicarbonate solution and twice with each 0.4 liter of aqueous sodium chloride solution. After evaporation again, the residue was recrystallized from 3 liters of toluene to obtain the product. m.p. 136°-137° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[C:29]4[CH:28]=[CH:27][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:25][C:24]=4[C:8]4[CH:9]=[C:10]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:11]=[C:12]([C:13]([CH3:17])([CH3:16])[C:14]=2[CH:15]=1)[C:7]3=4.C([Li])CCC.[B:41]([O:46]C)(OC)[O:42]C>C1COCC1.C1CCCCC1>[CH3:16][C:13]1([CH3:17])[C:12]2[C:7]3=[C:8]([C:24]4[CH:25]=[C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:27]=[CH:28][C:29]=4[N:6]3[C:5]3[CH:4]=[CH:3][C:2]([B:41]([OH:46])[OH:42])=[CH:15][C:14]1=3)[CH:9]=[C:10]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:11]=2
Reactant: CC1(C)c2cc(Br)ccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC1(C)c2cc(B(O)O)ccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32
Temperature: 25 °C

Procedure:
133 g (259 mmol) of 10-bromo-8,8-dimethyl-3,6-diphenyl-8H-indolo-[3,2,1-de]acridine are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., after 1 h 37 ml of trimethyl borate (336 mmol) are added dropwise, the mixture is warmed to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH:9]([F:27])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].N.CO>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[C@H:9]([F:27])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC(F)C2NC(=O)Nc1cccc2[nH]ncc12
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)C[C@@H](F)[C@H]2NC(=O)Nc1cccc2[nH]ncc12

Procedure:
The title compound was prepared by chiral separation of the corresponding racemic compound N-(5-tert-butyl-2-fluoro-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea (Ex. 39) using a chiral column ChiralCel OD. 1H NMR (300 MHz, d6-DMSO) 13.01 (broad s, 1H), 8.87 (s, 1H), 8.08 (s, 1H), 7.71 (d, 1H), 7.33 (s, 1H), 7.30 (d, 1H), 7.21 (m, 2H), 7.09 (d, 1H), 6.87 (d, 1H), 5.33-5.46 (m, 2H), 3.05-3.27 (m, 2H), 1.27 (s, 9H). MS (DCI/NH3) m/e 367 (M+H)+. [α]D +2.67° (c=0.935, 1:1 MeOH:CH2Cl2). Structure is cis by ROESY NMR, absolute stereochemistry assigned arbitrarily. Contains 17% of trans (−) diastereomer.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=O)[S:7][CH:8]=[C:4]2[CH2:3]1.[CH2:15](OCC)C>C1COCC1.C[Li]>[CH3:14][C:2]1([CH3:1])[CH2:13][CH2:12][C:5]2=[C:6]([C:9](=[O:11])[CH3:15])[S:7][CH:8]=[C:4]2[CH2:3]1
Reactant: CCOCC
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1scc2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (1051 mg, 5.0 mmol) in diethyl ether (15 mL) and THF (8 mL), methyllithium (7 mL of a 1.6 M solution in diethyl ether) is added. The mixture is stirred at rt for 15 min before the reaction is quenched with ethanol. The mixture is diluted with 10% aq. citric acid and extracted with TBME. The organic extract is washed three times with sat. aq. NaHCO3, dried over Na2SO4 and evaporated to give crude 1-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (1.0 g) as a brownish oil; LC-MS: tR=1.03 min, [M+1]=209.07.
Reaction SMILES: [CH3:1][N:2]1[C@:6]2([CH2:18][C:9]3=[N:10][CH:11]=[C:12]([C:14]([O:16]C)=[O:15])[CH:13]=[C:8]3[CH2:7]2)[C:5](=[O:19])[NH:4][C:3]1=[O:20].[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][N:2]1[C@:6]2([CH2:18][C:9]3=[N:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=[C:8]3[CH2:7]2)[C:5](=[O:19])[NH:4][C:3]1=[O:20]
Reactant: COC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)NC(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)NC(=O)[C@]12Cc1cc(C(=O)O)cnc1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (6R)-3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylate (450 mg, 1.64 mmol) in THF (8 mL) and H2O (2 mL) was added 1 N aqueous lithium hydroxide (1.96 mL, 1.96 mmol). The reaction was stirred at ambient temperature for 2 h, adjusted to pH≈4 by addition of 1 N hydrochloric acid, and concentrated in vacuo to provide the title compound. MS: m/z=262.1 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.96 (s, 1H), 8.24 (s, 1H), 3.54 (d, 1H, J=18.1 Hz), 3.52 (d, 1H, J=17.3 Hz), 3.40 (d, 1H, J=17.3 Hz), 3.39 (d, 1H, J=18.1 Hz), 2.71 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)C.CN(C=O)C.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)#[N:28]>O>[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH2:9][CH2:10][C:11](=[O:17])[NH:12]4)[CH2:2][CH2:3]2)=[O:34])=[CH:31][CH:30]=1)#[N:28]
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)N2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
5-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 2 ml of trimethylamine were added to 40 ml of DMF. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.4 g of 4-cyanobenzoyl chloride. After completion of addition, the reaction mixture was stirred at 40° to 50° C. for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 1.9 g of 5-[4-(4-cyanobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 266°-269° C., colorless granules.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: BrCCCCBr
Reactant: CCOC(=O)COc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(OCCCCBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 2-(4-hydroxy-2-nitrophenoxy)acetate 12 (0.17 g, 0.0007 mol) in 10 mL acetone was added potassium carbonate (0.39 g, 0.0028 mol). The reaction mixture was stirred at room temperature for 10 min. Then 1,4-dibromobutane 13 (0.33 mL, 0.0028 mol) was added. The resulting mixture was heated at reflux for 12 h. The progress of the reaction was monitored by thin layer chromatography (TLC). Acetone was evaporated and the residue was diluted with water, extracted with ethyl acetate and dried over sodium sulfate to give ethyl 2-(4-(4-bromobutoxy)-2-nitrophenoxy)acetate 14 which was purified by silica gel column chromatography using 0-20% gradient of hexane and ethyl acetate. Yellow oil (0.52 g, 92%). 1H NMR (400 MHz, CDCl3): δ 1.26 (t, J=6.8 Hz, 3H); 1.91-1.98 (m, 2H); 2.02-2.09 (m, 2H); 3.48 (t, J=6.8 Hz, 2H); 3.99 (t, J=6.0 Hz, 2H); 4.26 (q, J=6.8 Hz, 2H); 4.70 (s, 2H); 6.99-7.02 (m, 2H); 7.38 (d, J=3.2 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4].[C:6]([N:10]=[C:11]=[S:12])([CH3:9])([CH3:8])[CH3:7]>C(O)C.C(OCC)C>[OH:5][C@@H:3]([CH3:4])[CH2:2][NH:1][C:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[S:12]
Reactant: CC(C)(C)N=C=S
Reactant: C[C@H](O)CN
Solvent: CCOCC
Solvent: CCO
Product: C[C@H](O)CNC(=S)NC(C)(C)C
Temperature: 20 °C
Reaction time: 5 h
Yield: 93.6 %

Procedure:
The process is performed as in Example 1, starting with 5 g of (+)-(S)-1-amino-2-propanol and 8.43 g of tert-butyl isothiocyanate in 60 cm3 of ethanol. After stirring the reaction medium for 5 hours at a temperature in the region of 20° C. and then concentration under reduced pressure (5 kPa) at a temperature in the region of 50° C., the white solid obtained is taken up in diethyl ether. The suspension is again concentrated under the same conditions as above. 11.86 g of N-[(2S)-2-hydroxypropyl]-N′-tert-butylthiourea are obtained in the form of a white solid melting at 106° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH: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])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:65][S:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([NH2:73])[CH:68]=1>C(Cl)Cl>[CH3:65][S:66][C:67]1[CH:68]=[C:69]([NH:73][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])[CH:70]=[CH:71][CH:72]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CSc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (250 mg, 0.44 mmol) in methylene chloride (10 mL), HATU (Aldrich, 332 mg, 0.88 mmol) was added followed by the addition of DIPEA (0.230 mL, 1.31 mmol) and 3-amino-phenyl methyl sulfide (Aldrich, 122 mg, 0.88 mmol). The mixture was stirred at rt for 2 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (50 g column, eluent EtOAc/Hexanes, 5-10%) to give a white solid. 178 mg.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:24][N:25]([C:27](=[O:29])[CH3:28])[OH:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.Cl>>[ClH:23].[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)[CH2:24][N:25]([OH:26])[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)N(O)C[C@H](Cc1ccc(Oc2ccc(Cl)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N(O)C[C@@H](N)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 234.2 %

Procedure:
To a 40 ml vial was charged with {(S)-1-[(Acetyl-hydroxy-amino)-methyl]-2-[4-(4-chloro-phenoxy)-phenyl]-ethyl}-carbamic acid tert butyl ester (20 mg, 0.046 mmol, 1 eq.) followed by 4 N HCl (1 ml, 4 mmol, 86 eq.). The mixture was stirred at room temperature for 2 hr. The volatile material was removed under reduced pressure to give the desired product (20 mg, 100% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.02 (s, 3H), 2.83-2.87 (dd, J=6.4, 11.2 Hz, 1H), 3.17-3.20 (dd, J=4.8, 11.2 Hz, 1H), 3.46-3.87 (m, 4H), 7.0-7.03 (m, 4H), 7.32-7.33 (d, J=6.8 Hz, 2H), 7.42-7.44 (m, 2H), 8.06 (s, brs, 3H); LCMS (UV, ESI), 335 (M+1), 86% purity.