Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].I[C:17]1C=CC=C(C)C=1C(O)=O.FC1C=CC(I)=C(C=1)C(O)=O>>[CH3:17][C:10]1[CH:2]=[CH:3][CH:4]=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: Cc1cccc(I)c1C(=O)O
Agent: O=C(O)c1cc(F)ccc1I
Product: Cc1cccc(-n2nccn2)c1C(=O)O

Procedure:
The title compound was prepared in a manner analogous to Intermediate 1, substituting for 2-iodo-6-methyl benzoic acid for 5-fluoro-2-iodo-benzoic acid in Step A. 1H NMR (400 MHz, CD3OD): 7.89 (s, 2H), 7.72 (d, J=8.1 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 2.46 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[NH:22][CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[N:22]([C:33](=[O:34])[CH2:32][N:31]([CH3:36])[CH3:30])[CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc(OC[C@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CN(C)CC(=O)O
Product: COc1cc(OC[C@H]2C[C@@H](O)CN2C(=O)CN(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 72 %

Procedure:
The procedure described in Example 32 was repeated using (3R,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (209 mg) with N,N-dimethylglycine (57 mg) to give the title compound as a white solid in 72% yield; NMR spectrum (DMSO-d6) 10.03 (s, 1H), 8.46 (s, 1H), 8.19 (dd, 1H), 7.76-7.71 (m, 1H), 7.43 (t, 1H), 6.83 (d, 1H), 6.75 (d, 1H), 5.27-5.26 (m, 1H), 4.72-4.67 (m, 1H), 4.61-4.56 (m, 1H), 4.41-4.40 (m, 1H), 4.34-4.29 (m, 1H), 3.93 (s, 3H), 3.78 (dd, 1H), 3.52 (br d, 1H), 3.14 (d, 1H), 2.99 (d, 1H), 2.26-2.17 (m, 7H), 1.95-1.90 (m, 1H); Mass spectrum MH+ 504.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCN4CCCC4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.1 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (97 mg, 80%).
Reaction SMILES: C([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:17])[NH:8][C:7]1=[O:25])(=O)C.[ClH:26]>C(O)C>[ClH:26].[SH:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:17])[NH:8][C:7]1=[O:25]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)Nc2cccnc2)NC1=O
Agent: Cl
Solvent: CCO
Product: O=C1N[C@@H](C(=O)Nc2cccnc2)CCCCCC[C@@H]1CS
Reaction time: 1.5 h

Procedure:
3-{N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-amino}-pyridine (0.040 g, 0.11 mmol) is dissolved in ethanol (1.0 mL). An aqueous solution of nitrogen-degasded 1N sodium hydroxide (0.33 mL, 0.33 mmol) is added, and the reaction is stirred for 90 minutes. The reaction is quenched with 1N hydrochloric acid (0.33 mL, 0.33 mmol), and the solvent is evaporated. The residue is partitioned between ethyl acetate and water, and the aqueous layer is extracted several times with ethyl acetate. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The residue is dissolved in methylene chloride (5.0 mL), and anhydrous hydrochloric acid gas is bubbled through the reaction for 5 minutes. The solvent is evaporated to give 3-{N-[[trans 3-mercaptomethyl-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-amino}-pyridine hydrochloride, MS: M+1=322.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[N:13]=[C:12]([N:16]([CH3:18])[CH3:17])[N:11]([CH3:19])[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30]>CC(C)=O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH2:30][C:29]#[CH:28])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[N:13]=[C:12]([N:16]([CH3:17])[CH3:18])[N:11]([CH3:19])[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: CN(C)c1nc(=O)n(-c2cc(O)c(Cl)cc2F)c(=O)n1C
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(=O)nc(N(C)C)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2.80 g (8.90 mmol) of 3-[4-chloro-2-fluoro-5-(hydroxy)phenyl]-6-(dimethylamino)-1-methyl-1,3,5-triazine-2,4(1H,3H) -dione in 50 mL of acetone was added 1.47 g (10.7 mmol) of potassium carbonate and 1.98 mL (17.8 mmol) of an 80% solution of propargyl bromide in toluene. It was then warmed to reflux for 2 h. It was cooled to room temperature and the mixture was filtered and washed with excess ethyl acetate. The crude product was flash chromatographed over silica gel, eluting with a 3:7 v:v mixture of ethyl acetate and hexane to give 3.1 g of the title compound as a pale yellow solid, m.p.: 61°-65° C.; 1H-NMR (CDCl3, 200 MHz) ppm 7.0 (d, 1H), 4.75 (m, 2H), 3.45 (s, 3H), 3.1 (s, 6H), 2.6 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]2[NH:6][C:7]([C@@H:9]([NH:28][C:29](=[O:44])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:37])=[C:32]([CH3:43])[CH:31]=3)[CH2:10][CH2:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:46]=[CH:45][C:5]2[NH:6][C:7]([C@@H:9]([NH:28][C:29](=[O:44])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:37])=[C:32]([CH3:43])[CH:31]=3)[CH2:10][CH2:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH2:19][NH2:20])=[O:13])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCC[C@H]2CN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 100 %

Procedure:
Prepared from N-{(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-[(2S)-2-tert-butoxycarbonylaminomethylpyrrolidin-1-ylcarbonyl]propyl}-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide followed by treatment with trifluoroacetic acid analogously to Example 17. Yield: 100%; Rf value: <0.1 (silica gel; ethyl acetate); C29H35ClN6O5 (551.09); mass spectrum: (M+H)+=551/553 (chlorine isotope).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][CH:6]([CH3:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[N+]([O-])(O)=O.S(=O)(=O)(O)O>S(=O)(=O)(O)O>[CH3:5][CH:6]([CH3:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[CH:10]=1)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CC(C)C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CC(C)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Concentrated nitric acid (20 ml) was added cautiously with cooling to concentrated sulphuric acid (50 ml) maintaining a temperature of −5° C. Another solution of 2-methyl-1-phenyl-1-propanone (29.6 g, 0.2 mol) in concentrated sulphuric acid (70 ml) was made up with shaking, keeping the temperature at −5° C. The former nitric acid/sulphuric acid solution was added portionwise over 30 min to the latter solution of ketone in sulphuric acid keeping the temperature at −10° C.+/−5° C. during the addition and for a subsequent 30 min. The reaction mixture was poured onto crushed ice (1 l) and then extracted with diethyl ether (3×100 ml). The organic extracts were washed with water (300 ml) and then brine (300 ml), dried (Na2SO4) and then concentrated in vacuo. The crude product was obtained as an orange oil (40 g) which was purified by chromatography on silica gel (450 g) eluting with hexane: diethyl ether (9:1) to give the title compound as a pale yellow solid (16.3 g, 42%), m.p.33–35° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8](F)=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]([F:30])([F:29])[CH2:27][OH:28]>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([O:28][CH2:27][C:26]([F:30])([F:29])[F:25])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(F)c(-c2ccc(Cl)cc2)n1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1ncc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of 0.143 g 4-(4-chloro-phenyl)-5-fluoro-pyrimidine-2-carboxylic acid methyl ester in 1.5 ml dried DMSO was added 192 mg of cesium carbonate and 0.059 g of 2,2,2-trifluoroethanol and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase was dried with MgSO4 and purified by chromatography on silica gel with a gradient of heptane:ethyl acetate=9:1 to 1:1 to yield 161 mg (86.60%) of the title compound as white solid, MS 347.1 (M+H)+.
Reaction SMILES: [C:1]([O-])(O)=O.[Na+].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([I:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].CN(C=O)C.CI>O.CCOC(C)=O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([I:16])=[C:11]([CH:15]=1)[C:12]([O:14][CH3:1])=[O:13]
Reactant: O=C(O)c1cc(Cl)ccc1I
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a round bottomed flask was added NaHCO3 (22.31 g, 266 mmol), 5-chloro-2-iodobenzoic acid (25 g, 89 mmol), DMF, and MeI (11.07 mL, 177 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water (3×) and brine before being dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage to afford the titled compound (25.81 g, 87 mmol). LC/MS m/z 297 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30]([NH:34][C:35](=[O:39])[C:36](O)=[O:37])([CH3:33])([CH3:32])[CH3:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:35]([NH:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:39])=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CC(C)(C)NC(=O)C(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(=O)NC(C)(C)C)c1

Procedure:
Prepared as described in Example 76 using (1R,2S)-1-[1-(4-fluorophenyl)-indazol-5-yl]oxy-1-(3-methoxyphenyl)-propan-2-amine (51 mg, 0.13 mmol) and 2-(tert-butylamino)-2-oxoacetic acid (19 mg, 0.13 mmol). Yield 53 mg (78%).
Reaction SMILES: [OH:1][CH:2]1[C:7](/[CH:8]=[CH:9]/[C:10]#[C:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:6]([CH3:23])[CH2:5][CH2:4][CH2:3]1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([O:1][CH:2]1[C:7](/[CH:8]=[CH:9]/[C:10]#[C:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:6]([CH3:23])[CH2:5][CH2:4][CH2:3]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1ccc(C#C/C=C/C2=C(C)CCCC2O)cc1
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)c1ccc(C#C/C=C/C2=C(C)CCCC2OC(=O)c2ccccc2)cc1

Procedure:
The title compound, a colorless oil, was prepared from ethyl (+)-(E)-4-(4-(6-hydroxy-2-methylcyclohex-1-enyl)but-3-en-1-ynyl)benzoate (Compound 1b, 30 mg, 0.097 mmol) and benzoyl chloride (0.041 mL, 0.35 mmol) as described in General Procedure D. [α]D=+97 (EtOAc), PNMR (300 MHz, CDCl3) δ 1.37 (t, 3 H, J=7.1 Hz), 1.66 (m, 3 H), 1.97 (s, 3 H), 2.10(m, 1 H), 2.28 (m,2 H),4.36 (q, 2 H, J=7.1 Hz), 5.78 (d, 1 H, J=16 Hz), 5.92 (s, 1 H), 7.41-7.45 (several ds, 4 H), 7.54 (m, 1 H), 7.95 (dd, 2 H, J=8.4, 1.8 Hz), 8.05 (dd, 2 H, J=8.6, 1.5 Hz). (Trimethylsilyl)ethyl (−)-(E)-4-(4-(6-Hydroxy-2-methylcyclohex-1-enyl)but-3-en-1-ynyl)benzoate (Compound 2a) and (Trimethylsilyl)ethyl (+)-(E)-4-(4-(6-Acetoxy-2-methylcyclohex-1-enyl)but-3-en-1-ynyl)benzoate (Compound 8b).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][NH2:10])[CH2:2][CH2:3][CH3:4].[OH2:25]>N1C=CC=CC=1.C(O)(=O)C>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([S:21](=[O:24])(=[O:23])[NH2:22])[C:13]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][NH:10][C:15]([O:14][CH2:13][CH3:6])=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCCCNc1cc(CNC(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine (1.05 g; prepared as described in Example 289) in pyridine (7ml) ethyl chloroformate (0.3 ml) is dropwise added at 22°-25° C., and the mixture is stirred for a further 1.5 hours. The mixture is then diluted with water (30 ml) and acetic acid (10 ml) to precipitate crude N-(3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)urethan. After filtration and recrystallization from ethanol it is obtained with a melting point of 105°-107° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:3]1=[O:23].[CH2:24]([O:26][C:27](=[O:50])[C@H:28](OS(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:25].CN1CCOCC1.Cl>C(OCC)(=O)C.C(OCC)(=O)C.O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH2:24]([O:26][C:27]([C@@H:28]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=2)[C:3]1=[O:23])[CH2:29][CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:50])[CH3:25]
Reactant: CCOC(=O)[C@@H](CCC1CCCCC1)OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)c1ccc(CN2C(=O)C(N)CCc3ccccc32)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CCC1CCCCC1)NC1CCc2ccccc2N(Cc2ccc(C(C)C)cc2)C1=O
Temperature: 75 °C

Procedure:
1.5 g of 3-(R/S)-amino-1-(p-isopropylbenzyl)-2,3,4,5-tetrahydro-benzazepin-2-one and 2.23 g of (R)-alpha-[[(4-nitrophenyl)-sulfonyl]oxy]-4-cyclohexylbutyric acid ethyl ester (Helv. Chim. Acta 71 (2), 337, 1988) are combined and, at 40° C., 0.67 ml of N-methylmorpholine is added. The mixture is heated at 75° C. for 15 h, cooled, diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and water and finally with dilute hydrochloric acid and brine. Flash chromatography (80 g of silica gel, eluant ethyl acetate/hexane 1:2) yields the two diastereoisomers which, after being dissolved in ethyl acetate/tetrahydrofuran, were each converted separately into the corresponding hydrochloride with 3 equivalents of 1N hydrochloric acid. Rf values of the free bases (eluant: ethyl acetate/hexane 1:2):
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8]([O:14][CH2:15][CH:16]2[CH2:23][CH2:22][C:19]3([CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:9][C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3].[C-]#N.[K+].C1N2CC[N:29](CC2)[CH2:28]1.O>CS(C)=O>[CH2:1]([O:4][C:5]([C:7]1[C:8]([O:14][CH2:15][CH:16]2[CH2:23][CH2:22][C:19]3([CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:9][C:10]([C:28]#[N:29])=[N:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C1CN2CCN1CC2
Reactant: C=CCOC(=O)c1cnc(Cl)nc1OCC1CCC2(CC1)CC2
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOC(=O)c1cnc(C#N)nc1OCC1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the 2-chloro-4-(spiro[2.5]oct-6-ylmethoxy)pyrimidine-5-carboxylic acid allyl ester (0.62 mmol) in DMSO (1.0 mL) are added KCN (0.94 mmol), DABCO (0.19 mmol), and H2O (0.10 mL) at room temperature. The reaction mixture is stirred at room temperature for 0.5 h and the reaction is quenched by the addition of water. The mixture is extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give the titled compound; 1H NMR (CDCl3) δ 0.19-0.20 (m, 2H), 0.21-0.33 (m, 2H), 0.91-0.96 (m, 2H), 1.23-1.33 (m, 3H), 1.72-1.85 (m, 4H), 4.38 (d, 2H), 4.84 (d, 2H), 5.31-5.45 (m, 1H), 9.01 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]=[C:5]([OH:14])[CH:4]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH:23]([OH:30])[CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.[OH-].[Na+].Cl.N>O.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CCOCC.O1CCCC1>[ClH:13].[Cl:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([OH:14])[CH:4]=[C:3]2[CH2:2][O:30][CH:23]([C:17]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=1[Cl:15])[CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: Oc1cc(CBr)c2cc(Cl)ccc2n1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: N
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Oc1cc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c2cc(Cl)ccc2n1

Procedure:
4.1 g of 4-bromomethyl-6-chloro-2-hydroxyquinoline (0.015 mol), 3.9 g of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (0.015 mol), 15.2 g of sodium hydroxide (0.38 mol) in 15 ml of water, 0.25 g of benzyltrimethylammonium chloride and 50 ml of tetrahydrofuran are reacted in a manner similar to the procedure of Example 1. After work up of the mixture, the oily product is treated with water and ether. To the aqueous layer is added half concentrated hydrochloric acid (pH 5) and subsequently aqueous ammonia (10%) for neutralization of the hydrochloride. The deposited oily product is extracted with chloroform and the chloroform layer is washed with water, dried and charcoaled. Then the solvent is removed in vacuo, the solid product dissolved in ethyl acetate and to the clear solution is added etheral hydrochloric acid. The precipitated hydrochloride (3.4 g) is washed with ethyl acetate, treated with boiling acetonitrile and then with anhydrous ether. The filtered off product, which contains two moles of crystal water, is dried at 70°-75° C.; m.p. 176°-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([C:16]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:19]3[C:20]([C:30]([NH:32][CH3:33])=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>[Pt].C1COCC1.CO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]([C:16]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:19]3[C:20]([C:30]([NH:32][CH3:33])=[O:31])=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:3][C:2]=1[Cl:1]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 99 %

Procedure:
A solution of 6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (11.0 g, 19.7 mmol) in 1:1 THF/MeOH (75 mL) was subjected to hydrogenation at 40 psi in the presence of 5% sulfided platinum on carbon (0.560 g). After 4 hours an additional portion of catalyst was added (0.250 g). After another 16 hours the reaction vessel was purged with nitrogen, catalyst removed by filtration through celite, and the filtrate concentrated to dryness at reduced pressure. The residue was recrystallized from hexane/EtOAc to afford the title compound (10.3 g, 99%) as a white solid. LCMS (m/z, ES+)=528 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12].S(=O)(=O)(O)O.[Cl-].[Na+]>CCOCC>[Cl:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:12]
Reactant: NCC(=O)O
Reactant: CC(C)(CCl)C(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(CCl)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
By the method of M. Shimazaki, et al., Chem. Pharm. Bull., 30(9), 3139-3146 (1982), 2.27 g glycine in a solution of 31 mL of 2 M sodium hydroxide was stirred with commercially available chloropivaloyl chloride (4.65 g) in 5 mL ether. After one hour at 0° C., the reaction mixture was warmed to ambient temperature, acidified (pH 2) with sulfuric acid and saturated with sodium chloride. After extraction with 3×30 mL ethyl acetate, the extracts were dried (MgSO4) and evaporated in vacuo to give 3.0 g of the title compound as a white solid. This material was used as obtained in the following transformation.