Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[C:14]2[N:13]=[C:12]([CH:15]([CH3:17])[CH3:16])[C:11]3[C@@H:18]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[O:19][C:20]4([CH2:24][CH2:23][CH2:22][CH2:21]4)[C:10]=3[C:9]=2[C@@H:8]([OH:35])[CH2:7][C:6]1([CH3:37])[CH3:36])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:15]([C:12]1[C:11]2[C@@H:18]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=3)[O:19][C:20]3([CH2:21][CH2:22][CH2:23][CH2:24]3)[C:10]=2[C:9]2[C@@H:8]([OH:35])[CH2:7][C:6]([CH3:36])([CH3:37])[C@@H:5]([OH:4])[C:14]=2[N:13]=1)([CH3:17])[CH3:16]
Reactant: CC(=O)O[C@H]1c2nc(C(C)C)c3c(c2[C@@H](O)CC1(C)C)C1(CCCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCCC1)[C@@H](O)CC(C)(C)[C@H]2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
13 mg (3′R,6′R,9′S)-9′-hydroxy-4′-isopropyl-7′,7′-dimethyl-3′-(4-(trifluoromethyl)phenyl)-6′,7′,8′,9′-tetrahydro-3′H-spiro[cyclopentane-1,1′-furo[3,4-c]quinoline]-6′-yl acetate are dissolved in 1 ml methanol and treated with 14 mg potassium carbonate. Three drops water are added and the mixture is stirred for 3 hours at room temperature. Then the solvent is evaporated in vacuo and the residue is partitioned between water and dichloromethane. The organic phase is dried with sodium sulphate and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel (hexane/ethylacetate 4:1).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH3:10])=[C:6]([Cl:11])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH4+].[Cl-]>ClCCl>[Cl:11][C:6]1[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[N:3]=[C:2]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:7]=1[O:8][CH2:9][CH3:10]
Reactant: C1COCCN1
Reactant: CCOc1c(Cl)nc(-c2ccc([N+](=O)[O-])cc2)nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCOc1c(Cl)nc(-c2ccc([N+](=O)[O-])cc2)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
4,6-dichloro-5-ethoxy-2-(4-nitro-phenyl)-pyrimidine (0.50 g, 1.0 eq) was stirred in dichloromethane (10 mL) and a solution of morpholine (0.21 mL, 1.5 eq) in dichloromethane (5 mL) was added dropwise at 0° C. After stirring the resulting solution overnight at r.t., NH4Cl (aq) was added to the solution and the solution was extracted with dichloromethane. The combined organic layers were washed with brine, dried and evaporated in vacuo. A product was obtained as a white solid (0.57 g, 81%).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:18]([O:20]C)=O)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][OH:23].[OH-].[K+]>CO.C1COCC1>[OH:23][NH:22][C:18]([C:9]1[S:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20]
Reactant: NO
Reactant: COC(=O)c1sc(-c2ccccc2)nc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)c1sc(-c2ccccc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
A 100 mL round-bottomed flask was charged with methyl 2,4-diphenylthiazole-5-carboxylate 73 (420 mg, 1.422 mmol) in MeOH (2.844 ml) and THF (2.84 ml) and the solution was cooled down to 0° C. Then a 50% aqueous solution of hydroxylamine (4697 mg, 71.1 mmol) and 4M potassium hydroxide solution (0.427 ml, 1.706 mmol) were added and the reaction mixture was allowed to warm up to rt while stirring for 18 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with fresh EtOAc and the combined organic layers were washed with 1M HCl, sat NaHCO3, and brine, dried over MgSO4, filtered and concentrated. The resulting solid was triturated (Et2O) to afford the title compound 74 (0.303 g, 72% yield). 1H NMR: (DMSO-d6) d(ppm) 1H, 11.29 (s, 1H), 9.44 (s, 1H), 8.03 (dd, J=6.3, 2.7 Hz, 2H), 7.84 (d, J=7.0 Hz, 2H), 7.56-7.55 (m, 3H), 7.50-7.43 (m, 3H). LRMS (ESI): (calc.) 296.34 (found) 297.1 (MH)+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:38]1[C:27]2=[CH:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])=[CH:40][CH:39]=3)=[O:24])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]2[CH:36]=[CH:37]1
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2C=C3CC=CN3Cc3ccccc32)cc1)c1ccccc1F
Reaction time: 0.05 h
Yield: 88.4 %

Procedure:
To a solution of 314 mg of 2-fluorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo-[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give 620 mg of the desired product as a crystalline solid, m.p. 257°-260° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH2:33][N:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)[CH:27]=4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:5]=[C:6]([F:15])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[N+](C1C=C[C:46]([O:49]C=O)=CC=1)([O-])=O.C(N(CC)CC)C>C1COCC1>[F:15][C:6]1[CH:5]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH:27]=4)[CH2:33][N:34]4[CH2:39][CH2:38][N:37]([CH:46]=[O:49])[CH2:36][CH2:35]4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:3]=[C:2]([F:1])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Cc1ccc(Nc2ncc3ccn(-c4cc(F)c(CN5CCOCC5)c(F)c4)c3n2)cc1CN1CCNCC1
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(Nc2ncc3ccn(-c4cc(F)c(CN5CCOCC5)c(F)c4)c3n2)cc1CN1CCN(C=O)CC1

Procedure:
The compound is obtained by treating [7-(3,5-difluoro-4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-(4-methyl-3-piperazin-1-ylmethyl-phenyl)-amine (Example 332) with formic acid 4-nitro-phenyl ester in presence of triethylamine in THF. HPLC: tR=6.84 min (Method B); MS-ES: (M+H)+=562
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=4)[CH:19]=3)=[C:14]([O:29][CH3:30])[CH:13]=2)(=O)=O)=CC=1.[OH-].[K+].O>C(O)C>[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]3)=[C:14]([O:29][CH3:30])[CH:13]=1
Reactant: COc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1-c1ccc2cc(O)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(O)ccc1-c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A solution of 4-(6-hydroxy-2-naphthyl)-3-methoxyphenyl 4-methylbenzenesulfonate (1.74 g, 4.05 mmol), potassium hydroxide (5 g), water (85 mL), and ethanol (85 mL) was stirred at 90° C. for 2 hr. The reaction was cooled to room temperature and concentrated to 50% volume, neutralized with acetic acid, and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, evaporation of the solvent, and purification by silica column (25% ethyl acetate—hexanes) yielded 1.01 g (94%) of the title compound as a tan solid. A sample was further purified by preparative reverse phase HPLC to yield a tan solid: mp 152-154° C.;
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.Cl.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C>C(#N)C>[CH3:22][O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][S:8]([C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
Pyridine-3-sulfonyl chloride hydrochloride (92c) (1.8 g, 5.0 mmol) was added to a solution of methyl 6-aminohexanoate hydrochloride (91) (1.82 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) in acetonitrile (30 ml). The mixture was stirred for 1 hour at ambient temperature, filtered and solvents were removed under reduced pressure. The oily product was dissolved in water (15 ml) and extracted with ethyl ether (50 ml). The extract was dried (Na2SO4) and the solvents were removed under reduced pressure. The title compound (1.09 g, 76%) was obtained as oil and was used for the next step without an additional purification. 1H NMR 5H (90 MHz, DMSO-d6) δ: 0.80-1.51 (6H, m, CH2); 1.83 (2H, t, J=6.5 Hz, CH2); 2.76 (2H, t, J=6.5 Hz, CH2N); 3.58 (3H, s, CH3); 7.54 (1H, dd, J=5.0 Hz, J=8.2 Hz, C5HN); 8.12 (1H, dt, J=2.0 Hz, J=8.2 Hz, C5HN); 8.61 (1H, dd, J=2.0 Hz, J=5.0 Hz, C5HN); 8.81 (1H, d, J=2.0 Hz, C5HN).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:22]O>>[OH:6][C:7]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:22])=[O:10]
Reactant: CO
Reactant: O=C(O)c1cccc(-c2ccccc2)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(-c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanol (50 ml) was treated with concentrated sulphuric acid (4.9 g, 2.66 ml) cautiously. 2-Hydroxy-3-phenylbenzoic acid (10.7 g, 50 mmol) was added and the reaction mixture stirred at ambient temperature for 18 hours. The mixture was then heated at reflux for 4 hours, cooled to ambient temperature and evaporated. The residue was partitioned between ethyl acetate/and water, the organic layer washed twice with water, dried (MgSO4) and evaporated to give methyl 2-hydroxy-3-phenylbenzoate.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.CCN(C(C)C)C(C)C.[SH:30][C:31]1[CH:32]=[C:33]([C:37]2([OH:43])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[N:8]2[C:9]3[C:4]([CH:5]=[CH:6][C:7]2=[N:14][N:13]=1)=[CH:3][C:2]([S:30][C:31]1[CH:32]=[C:33]([C:37]2([OH:43])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1)=[CH:11][CH:10]=3
Reactant: OC1(c2cccc(S)c2)CCOCC1
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: OC1(c2cccc(Sc3ccc4c(ccc5nnc(-c6ccccn6)n54)c3)c2)CCOCC1
Temperature: 90 °C

Procedure:
5k (201 mg, 0.54 mmol) was suspended in 1,4-dioxane (4.5 mL) and degassed with N2 for 5 minutes. iPr2NEt (0.19 mL, 1.08 mmol) was added, followed by 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-ol (51, 131 mg, 0.60 mmol) in 1,4-dioxane (1 mL). Pd2dba3 (13 mg, 0.01 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (16 mg, 0.03 mmol) were added, and the reaction was sealed and heated to 90° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (20-100% EtOAc in hexanes, followed by 0-10% MeOH in EtOAc) to obtain the desired product, 5p. Further purification by preparative HPLC was required, followed by standard aqueous workup of the combined fractions using EtOAc and saturated aqueous NaHCO3 to give clean product.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:18][C:19]1[C:20]([NH:29][C:30]2[C:35]([Cl:36])=[CH:34][N:33]=[C:32](Cl)[N:31]=2)=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([NH:24][CH3:25])=[O:23]>>[Cl:18][C:19]1[C:20]([NH:29][C:30]2[C:35]([Cl:36])=[CH:34][N:33]=[C:32]([NH:1][C:2]3[CH:17]=[CH:16][C:5]4[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[NH:14][CH3:15])[CH2:9][CH2:10][C:4]=4[CH:3]=3)[N:31]=2)=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([NH:24][CH3:25])=[O:23]
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Reactant: CNC(=O)CN1CCc2ccc(N)cc2CC1
Product: CNC(=O)CN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(Cl)cccc4C(=O)NC)n3)cc2CC1

Procedure:
3-Chloro-2-[5-chloro-2-(3-methylcarbamoylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and 3-chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (53 mg, 23%). LCMS (m/e) 528 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H, J=8.0 Hz), 7.50 (d, 1H, J=7.7 Hz), 7.34-7.26 (m, 1H), 7.16 (s, 1H), 7.06 (d, 1H, J=7.3 Hz), 6.90 (d, 1H, J=8.0 Hz), 6.85 (s, 1H), 6.13-6.06 (m, 1H), 3.12 (s, 2H), 2.88 (d, 3H, J=5.0 Hz), 2.87-2.82 (m, 2H), 2.80 (d, 3H, J=4.9 Hz), 2.77-2.72 (m, 2H), 2.71-2.62 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH2:21][CH:22]([F:24])[F:23])=[N:13][C:12]=2OCC(F)F)[CH2:5][CH2:4]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[F:1][C:2]([F:32])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH2:21][CH:22]([F:24])[F:23])=[N:13][C:12]=2[N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:5][CH2:4]1
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(NCC(F)F)nc1OCC(F)F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(NCC(F)F)nc1N1CCOCC1

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-6-(2,2-difluoroethylamino)-5-nitro-2-(2,2-difluoroethoxy)-nicotinic acid amide (0.40 g, 0.83 mmol), morpholine (87 mg, 1.0 mmol), K2CO3 (170 mg, 1.24 mmol) and 2.5 mL DMSO is irradiated in a microwave apparatus at 100° C. for 30 min. The mixture is poured into water and the precipitate is collected by filtration and dried. Yield 0.34 g
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.[Li+].[CH3:22]C([N-]C(C)C)C.IC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]([CH3:22])=[CH:10][C:3]=12
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)ccnc32)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3c(Br)ccnc32)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of 4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (D20) (6 g, 17.08 mmol) in THF (100 ml) was cooled to −78° C. LDA (2M in THF) (21.35 mL, 42.7 mmol) was added at −78° C. and stirred at this temperature for ca. 1 hour. Iodomethane (2.136 ml, 34.2 mmol) was then added. After stirred at −78° C. for further ca. 30 min, the mixture was quenched by addition of saturated NH4Cl solution (150 mL), extracted with ethyl acetate (100 mL×3). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified on normal phase chromatography eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give the title compound containing impurities (5.4 g). LCMS (A): m/z (M+H)+ 365/367, C15H13BrN2O2S requires 364/366 (acidic).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1.Br[CH2:13][CH2:14][OH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:15][CH2:14][CH2:13][CH:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1
Reactant: C1=CC2(CCC1)CCCNC2
Reactant: OCCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCCC1NCCCC12C=CCCC2
Yield: 72 %

Procedure:
A mixture of 2-azaspiro-[5.5]-undec-7-ene (30.2 g.; 0.20 mole), 2-bromoethanol (25 g.; 0.20 mole) and triethylamine (20.2 g.) in toluene (250 ml.) is heated under reflux for 5 hours. The solution is cooled, filtered to remove triethylamine hydrobromide and the filtrate concentrated under reduced pressure. The residual liquid was distilled under reduced pressure to afford 28 g. (72% yield) of 2-hydroxyethyl-2-azaspiro-[5.5]-undec-7-ene, b.p. 90°-91° C./0.45 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:13]3[CH2:14][CH:10]([CH2:11][N:12]3C(OC(C)(C)C)=O)[CH2:9][CH:8]=2)[O:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:13]3[CH2:14][CH:10]([CH2:11][NH:12]3)[CH2:9][CH:8]=2)[O:4][N:3]=1
Reactant: Cc1cc(C2=CCC3CC2N(C(=O)OC(C)(C)C)C3)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2=CCC3CNC2C3)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A solution of tert-butyl 4-(3-methyl-5-isoxazolyl)-6-azabicyclo[3.2.1] oct-3-ene-6-carboxylate (80 mg, 0.28 mmol) in 10 mL of dichloromethane was treated with trifluoroacetic acid (2 mL) with ice bath cooling. After stirring 2 h and warming to ambient temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was made basic with 10% potassium hydroxide solution and extracted with chloroform (2×10 mL). The extracts were dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product as a viscous oil (30 mg, 58%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([Cl:16])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCc1ccccc1F
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccccc1F
Temperature: 25 °C

Procedure:
To a mixture of 3-(2-fluorophenyl)propionic acid (18.64 g, 0.111 mol) and dimethylformamide (5 drops) at room temperature was added dropwise oxalyl chloride (60 mL). The mixture was stirred at room temperature until gas evolution had ceased. The excess oxalyl chloride was removed by distillation to give 3-(2-fluorophenyl)propionyl chloride. A solution of the 3-(2-fluorophenyl)propionyl chloride in dichloromethane (230 mL) was added dropwise to a mixture of aluminum chloride (16.25 g, 0.12 mol) in dichloromethane (230 mL), and the mixture was refluxed for 3.5 h. The reaction mixture was poured into ice water (1200 mL), and the two phases were separated. The dichloromethane phase was washed successively with 0.1N aqueous sodium hydroxide (2×100 mL), water (200 mL), and brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residual oil was chromatographed on silica gel eluting with hexane:dichloromethane (9:1) to give 11.0 g of crude 4-fluoro-1-indanone as a yellow solid. Recrystallization from acetone: water mixtures gave 8.02 g (48%) of 4-fluoro-1-indanone as a pale yellow solid: m.p., 71°-72° C.; NM (DMSO-d6): d 7.51 (m, 3H, Ar), 3.13 (t, 2H, CH2), 2.74 (t, 2H, CH2).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([O:5][CH3:6])=[O:4].Cl[CH2:10][CH2:11][OH:12].CS(C)=O.[H-].[Na+]>O>[CH3:6][O:5][C:3]1([C:2]([F:8])([F:7])[F:1])[O:12][CH2:11][CH2:10][O:4]1
Reactant: OCCCl
Reactant: COC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC1(C(F)(F)F)OCCO1
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A mixture of 42.0 g (0.33 mol) of methyl trifluoroacetate, 26.6 g (0.33 mol) of 2-chloroethanol, and 150 mL of dimethylsulfoxide (DMSO) was stirred at 10°-20° while 15.8 g (0.33 mol) of 50% NaH in mineral oil was added portionwise. The resulting mixture was stirred at 20° for 2 h, at 25° for several days, and then poured into 1 L of water. The resulting aqueous layer was extracted with 100 mL of ether. The organic layers were combined, then washed twice with water, dried over CaSO4, and distilled to give 35.6 g (63% yield) of 2-methoxy-2-trifluoromethyl-1,3-dioxolane, b.p. 60°-65° at 3.3 kPa (25 mm), and a residue containing about 4.8 g (7% yield) of by-product 2-(2-chloroethoxy)-2-trifluoromethyl-1,3-dioxolane (estimated by GC).
Reaction SMILES: FC(F)(F)C1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2C=1.Br[CH2:15][C:16](=O)[C:17]([CH3:20])([CH3:19])[CH3:18].C(O)C>[Pt](=O)=O.CO>[CH3:18][C:17]([C:16]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:15]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)CBr
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CO
Product: CC(C)(C)c1cn2c(n1)CNCC2

Procedure:
2-(1,1-Dimethylethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was prepared in an analogous manner to that described above for 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Intermediate 4) but starting from 1-bromo-3,3-dimethyl-2-butanone instead of 3-bromo-1,1,1-trifluoro-2-propanone and using platinum (IV) oxide and ethanol in the place of 10% palladium on carbon paste and methanol for the hydrogenation step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:22][CH2:21][C:11]3([O:16][CH2:15][C:14](=[O:17])[N:13]([CH:18]([CH3:20])[CH3:19])[CH2:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br.Br[CH2:25][CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH3:33]>>[CH:18]([N:13]1[CH2:12][C:11]2([CH2:21][CH2:22][N:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH2:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][C@H:29]4[CH3:33])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[O:16][CH2:15][C:14]1=[O:17])([CH3:20])[CH3:19]
Reactant: C[C@@H]1CCCN1CCCBr
Reactant: CC(C)N1CC2(CCN(c3ccc(O)cc3)CC2)OCC1=O
Agent: Br
Product: CC(C)N1CC2(CCN(c3ccc(OCCCN4CCC[C@H]4C)cc3)CC2)OCC1=O

Procedure:
The entitled compound was obtained as a white solid according to the same method as in Example 4-(c) or according to a method similar to it but using 9-(4-hydroxyphenyl)-4-isopropyl-1-oxa-4,9-diazaspiro[5,5]undecan-3-one obtained in Example 4-10-(b) and (2R)-1-(3-bromopropyl)-2-methylpyrrolidine hydrobromide produced in Reference Example 4-2.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3](=[O:10])[NH:4][C:5](=[NH:9])[S:6][CH2:7][CH3:8].[CH3:12][N:13]=[C:14]=[O:15]>C(Cl)Cl>[CH3:11][N:2]([CH3:1])[C:3]([N:4]=[C:5]([S:6][CH2:7][CH3:8])[NH:9][C:14]([NH:13][CH3:12])=[O:15])=[O:10]
Reactant: CN=C=O
Reactant: CCSC(=N)NC(=O)N(C)C
Solvent: ClCCl
Product: CCSC(=NC(=O)N(C)C)NC(=O)NC

Procedure:
A solution of 5 parts of ethyl 4,4-dimethylthioallophanimidate and 1.8 parts of methylisocyanate in 70 parts of methylene chloride was refluxed for 2 hours. After evaporation of the solvent, the residue was recrystallized from ethylacetate to give ethyl N-dimethylcarbamoyl-4-methylthioallophanimidate (a compound of formula I), m.p. 109°-111.5° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].[OH-].[Na+]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:35][CH:36]=2)=[CH:27][CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: CC(C)(C)c1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4′-tert-Butyl-biphenyl-4-ol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C29H34O5 [M+NH4]+: 480, [M+Na]+: 485.