Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH:3]12[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH:4]2[C:18]([O:20]C)=[O:19].Cl>CO.O>[C:14]([O:13][C:11]([N:10]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]([C:18]([OH:20])=[O:19])[CH2:5][CH2:6]2)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1CCC2CCC1N2C(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC(C(=O)O)C1CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium hydroxide (0.44 g, 7.8 mmol) was added into a solution of 8-tert-butyl 2-methyl 8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (840 mg, 3.12 mmol) in methanol (2 ml) and water (2 ml). The reaction solution was stirred at room temperature for 16 h, and 1.0 N HCl solution was added dropwise to adjust pH to 4. The resulting solution was extracted with EtOAc (50 ml, twice). The combined organic layers were washed with water (10 ml). The organic layer was separated, and dried over sodium sulfate. The solution was filtered, concentrated, and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[OH:26][C@@H:27]1[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:33]([C@H:30]3[CH2:31][CH2:32][C@@H:27]([OH:26])[CH2:28][CH2:29]3)=[O:34])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)[C@H]2CC[C@@H](O)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(cis-4-hydroxy-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using cis-4-hydroxycyclohexanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a an off-white foam. MS m/e: 509.2 [M]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:6]=1)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([NH:25]N)[CH:21]=[CH:22][C:23]=1[F:24]>>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:21]3[C:20](=[CH:19][C:18]([Cl:17])=[C:23]([F:24])[CH:22]=3)[NH:25][C:13]=2[CH3:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1
Reactant: NNc1ccc(F)c(Cl)c1
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)c(F)cc23)c1

Procedure:
Prepared according to the procedure described in Example 2, step 1, using the following starting materials: 3-(2-Oxo-propylsulfanyl)-benzoic acid ethyl ester and (3-Chloro-4-fluoro-phenyl)-hydrazine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[C:19]3[C:24](=[N:25][CH:26]=2)[NH:23][CH2:22][CH2:21][CH2:20]3)[CH:14]=[N:15][CH:16]=1.[C:27]([N:35]=C=O)(=[O:34])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[C:19]3[C:24](=[N:25][CH:26]=2)[N:23]([C:27]([NH2:35])=[O:34])[CH2:22][CH2:21][CH2:20]3)[CH:14]=[N:15][CH:16]=1
Reactant: Cn1c(-c2cncc(-c3cnc4c(c3)CCCN4)c2)cc2ccccc21
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cn1c(-c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2)cc2ccccc21
Yield: 60.3 %

Procedure:
To a solution of 6-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridine (110 mg; 0.32 mmol) in anhydrous DCM (5.0 mL) is added benzoyl isocyanate (71 mg; 0.48 mmol). The mixture is heated to reflux for 3 hrs. The solvent is removed and the residue is dissolved in EtOH (5.0 ml). K2CO3 (76 mg; 0.55 mmol) is added and the mixture is heated to reflux for 1 hr. Then the solvent is removed and the residue is purified by preparative HPLC to give 74 mg of the titled product.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[NH:13][N:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH:22]O.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]([NH2:21])=[O:22])[CH:18]=4)[NH:13][N:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc2[nH]nc(-c3ccc4c(c3)OCCO4)c2c1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc2[nH]nc(-c3ccc4c(c3)OCCO4)c2c1
Temperature: 45 °C
Yield: 50 %

Procedure:
A mixture of 3-(2H,3H-benzo[e]1,4-dioxin-6-yl)-1H-indazole-5-carbonitrile (0.230 g, 0.83 mmol), 95% ethanol, aqueous 30% hydrogen peroxide (3 mL), and 6.0 N aqueous sodium hydroxide (1 mL) was heated at 45° C. for 3 h. The reaction mixture was diluted with water (80 mL) and acidified to pH 6 with 3 N hydrochloric acid. The solid was filtered and dried in a vacuum oven and gave the title compound (0.098 g, 50% yield): 1H NMR (DMSO-d6) δ 13.31 (s, 1H), 8.55 (s, 1H), 8.17 (br s, 1H), 7.92 (d, 1H), 7.57 (d, 1H), 7.52 (m, 2H), 7.31 (br s, 1H), 7.02 (d, 1H), 4.32 (s, 4H); ES-MS (m/z) 296 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[I:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1[OH:41]>>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:41][C:32]2[CH:33]=[CH:34][C:35]([C:37]([F:38])([F:39])[F:40])=[CH:36][C:31]=2[I:30])=[CH:12][C:11]=1[F:18])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(C(F)(F)F)cc1I
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(C(F)(F)F)cc3I)cc2F)c(OC)c1
Yield: 67 %

Procedure:
Prepared according to Preparation 255 using N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 647, 1000 mg, 2.26 mmol) and 2-iodo-4-(trifluoromethyl)phenol (Preparation 224, 975 mg, 3.38 mmol) to afford the title compound, 1080 mg, 67% yield.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>>[O:28]=[S:20]1(=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[CH:9]=2)[N:19]1[CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[C:32]([C:31]([F:30])([F:40])[F:41])[CH:33]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: Cc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Product: Cc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1Cc1cccc(C(F)(F)F)c1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 2, step c) and 3-trifluoromethyl benzyl bromide. MS: ESI (negative): 513 (M−H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)/[C:8]([O:10]CC)=[O:9])[N:6]=1.O.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OC1CCCCC1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(/C(=N/OC2CCCCC2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(cyclohexyloxyimino)acetate (0.536 g) was dissolved in ethanol (15 ml), and water (5 ml) and aqueous sodium hydroxide (1N, 6.4 ml) added. The mixture was stirred at room temperature for 24 h. Ethanol was removed and the residue diluted with water (25 ml), washed with ethyl acetate, and acidified to pH 2.8. The precipitate was collected by filtration, washed with cold water and dried in vacuo to give the title compound as a cream solid (0.335 g; 69%), νmax (nujol) 1630 cm-1 δH (D6DMSO) 1.2-2.0 (10H, br m), 6.78 (1H, d), and 7.14 (2H, s, exch. D2O).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:13][C:14](=[O:36])[CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][C:19]=2[N:18]=[C:17]1[CH2:33][CH2:34][CH3:35])([CH3:12])([CH3:11])[CH3:10].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:9]([O:13][C:14](=[O:36])[CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([N:25]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])=[CH:24][C:19]=2[N:18]=[C:17]1[CH2:33][CH2:34][CH3:35])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C(Cl)C1CCCC1
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C3CCCC3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopentanecarbonyl chloride (43 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C29H37N3O3+H: 476, observed: 476.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]([N:21]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([Br:27])=[CH:29][CH:30]=1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2ccsc2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(c1nc2ccsc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[3,2-d]pyrimidin-4(3H)-one (1-7, 0.030 g, 0.081 mmol) was dissolved in DCE (1.0 mL) and treated successively with 4-bromo-benzoylchloride (0.026 g, 0.12 mmol) and TEA (0.03 mL, 0.24 mmol). The reaction was stirred at 25° C. for 1 h. The reaction was diluted with DCM (10 mL), washed with 5% NaHCO3 and dried over MgSO4. The organics were concentrated under reduced pressure and subjected to flash column chromatography (SiO2, 0-6% MeOH/CH2Cl2 gradient) to provide N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-8). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=5.2 Hz, 1H), 7.54 (m, 2H), 7.32 (m, 5H), 7.15 (m, 2H), 6.11 (d, J=16.0 Hz, 1H), 5.96 (t, J=7.0 Hz, 1H), 5.12 (d, J=16.0 Hz, 1H), 3.40 (m, 2H), 2.04 (m, 2H), 1.85 (m, 1H), 1.77 (s, 6H), 1.59 (m, 1H), 0.65 (t, J=6.9 Hz, 3H); MS 553.1 found, 553.5 required.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH2:48])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:49][C:50]#[N:51].[Na+].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][C:50]([NH2:51])=[O:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN)CCC3)cc1
Reactant: N#C[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCNC(N)=O)CCC3)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of 0.103 g (0.156 mmol) (3R,4R)-3-[1-(2-amino-ethyl)-1,2,3,4-tetrahydro -quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 15(b)] in 2 ml of tetrahydrofuran was added a solution of 0.101 g (1.56 mmol, 10.0 equiv.) of sodium cyanate in 1 ml of water. The resulting suspension was cooled to 0° C. and 0.156 ml (0.156 mmol, 1.0 equiv.) of 1 N HCl solution was added dropwise. The reaction flask was stoppered and the suspension was stirred for 2 h at 25° C. The reaction mixture was poured into 50 ml of an ice/water mixture, the pH was adjusted to 8 by addition of saturated sodium bicarbonate solution, and the aqueous phase was extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 25 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 100:10:1 v/v/v mixture of dichloromethane/methanol/28% ammonium hydroxide solution as eluent to yield 0.106 g (0.133 mmol, 85.3% of theory) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(2-ureido-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 799 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:19](=[O:20])[N:18]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:34])C=CC=CC=1>ClCCl.CO>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:19](=[O:20])[N:18]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:11]2[N:12]=[C:13]([S:16]([CH3:17])=[O:34])[N:14]=[CH:15][C:10]=2[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc2cc(NC(=O)OC(C)(C)C)c(=O)n(C3CCCC3)c2n1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)c1ncc2cc(NC(=O)OC(C)(C)C)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88.6 %

Procedure:
(8-Cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (1.3 g, 3.45 mmol, prepared according to Example 8) was added to 50:50 dichloromethane/methanol (12 ml) followed by 2-benzenesulfonyl-3-phenyl-oxaziridine (1.08 g, 4.14 mmol). The mixture was stirred at 25° C. for 3.5 hours, evaporated to an oil and eluted through silica gel with chloroform. Fractions containing the product were evaporated to yield (8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester as a solid (1.2 g, 89%). MS (APCI); M++1: Calc'd, 393.15. Found 393.1.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:11]S(O)(=O)=O>C(O)C>[CH2:1]([NH:7][CH2:8][C:9]([NH2:10])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNCC#N
Reactant: O=S(=O)(O)O
Solvent: CCO
Product: CCCCCCNCC(N)=O
Temperature: 100 °C

Procedure:
11.2 gr of hexylaminoacetonitrile (0.081 mol) were dropwise added to 31 ml of H2SO4 diluted in 30 ml of ice-cooled ethanol. After the addition was completed, ethanol was evaporated and 40 ml of H2SO4 were added to the white solid as obtained. This solution was heated for 1 hour at 100° C., then cooled and dropwise added to 200 ml of ice-cooled ethanol. The white precipitate which formed was filtered and washed with 50 ml of ethanol.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[C:15]([NH:33][C:34](=[O:37])[CH2:35]Br)=[CH:16][N:17]([CH2:19][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[C:23]2=[O:32])[CH:18]=1>CC#N>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[C:15]([NH:33][C:34](=[O:37])[CH2:35][N:2]([CH2:3][CH2:4][OH:5])[CH3:1])=[CH:16][N:17]([CH2:19][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[C:23]2=[O:32])[CH:18]=1
Reactant: O=C(CBr)Nc1cn(CCCN2C(=O)c3ccccc3C2=O)cc1-c1ccc(Cl)cc1Cl
Reactant: CNCCO
Solvent: CC#N
Product: CN(CCO)CC(=O)Nc1cn(CCCN2C(=O)c3ccccc3C2=O)cc1-c1ccc(Cl)cc1Cl
Reaction time: 12 h
Yield: 21 %

Procedure:
N-Methyl ethanolamine (2 eq) was added to a stirred solution of N-{4-(2,4-dichlorophenyl)-1-[3-(1,3-dioxobenzo[c]azolin-2-yl)propyl]pyrrol-3-yl}-2-bromoacetamide (6) (8.65 eq) in CH3CN at RT. The reaction was monitored by LC/MS and was determined to be complete after 12 hours. The reaction was concentrated and purified by silica column chromatography eluting with MeOH in CH2Cl2 (5:95, v/v). After collecting the purified fractions and concentrating, N-{4-(2,4-dichlorophenyl)-1-[3-(1,3-dioxobenzo[c]azolin-2-yl)propyl]pyrrol-3-yl}-2-[(2-hydroxyethyl)methylamino]acetamide (7) was obtained as a light yellow glass (21% yield, LC/MS m/z 530.4 MH+) in 95% purity.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([CH3:16])=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[C:1]1([CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=C(C)CCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)CCc1ccccc1

Procedure:
(1.00 g, 4.58 mmol) obtained in the above item (a) was dissolved in ethyl acetate (10 ml), and the resulting solution was subjected to hydrogen catalytic reduction by using 10% palladium-carbon (0.2 g) as a catalyst. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30) to obtain 0.82 g of ethyl 5-phenyl-3-methylpentanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH:14]=[N:15][OH:16])[N:4]=1.[CH2:21](Br)[C:22]#[CH:23].O>CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[CH2:23]([O:16][N:15]=[CH:14][C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[O:11][C:5]1[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=1)[C:22]#[CH:21]
Reactant: C#CCBr
Reactant: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCON=Cc1ccccc1Oc1nc(OC)cc(OC)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
5.5 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime and 7.1 g of propargyl bromide were dissolved in 100 ml of N,N-dimethylformamide containing 1.4 g of potassium carbonate, and the solution was stirred at 100° C. for 4 hours. After the reaction mixture was allowed to cool down, it was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate=10:1) to obtain 4.8 g of O-(2-propynyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime as an oily substance.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1.C1COCC1>CN(C1C=CN=CC=1)C.C(O)C>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(Sc2cc(-c3ccccc3)c3ccccc3n2)cc1
Yield: 451.6 %

Procedure:
2-Chloro-4-phenylquinoline (4.18 mmoles, 10.0 g), 4-aminothiophenol (41.8 mmoles, 5.2 g) and DMAP (41.8 mmoles, 5.0 g) were stirred in 200 ml ethanol and 50 ml THF for 3 days. The solution was concentrated, ethyl acetate added, washed with water, dried over sodium sulfate and the solvent removed. The product was purified by HPLC over silica gel eluted with 30% ethyl acetate in hexane to yield 2-(4-aminophenylthio)-4-phenylquinoline 6.2 g, 45%. Mass Spec (FD) 328. Calculated for C21H16N2S: C, 76.80; H, 4.91 N, 8.53. Found: C, 77.04; H, 5.00; N, 8.55.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4].O.CC[O:16]CC>C1COCC1.[Cl-].[Na+].O>[OH:16][CH2:4][CH2:3][CH2:2][CH2:1][C:5]1[CH:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=1
Reactant: CCOCC
Reactant: C=CCCc1ccc(C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CCCCO)cc1
Temperature: 0 °C

Procedure:
4-(3-Butenyl)benzonitrile (from step (i) above, 10.8 g, 69 mmol) was dissolved in dry THF (140 mL) and was cooled to 0° C. BH3—Me2S complex (20 mL, 2 M) was added dropwise over 45 minutes at 0° C. and, after 7 hours, water (70 mL) and NaBO3—4H2O (25 g) were added and the mixture was stirred overnight before dilution with ether (700 mL) and brine (satd., 250 mL). After separation, the aqueous phase was extracted with ether (2×200 mL) and the combined extracts were dried, filtered and evaporated to give crude sub-title compound. Purification by flash chromatography on SiO2 (300 g) with heptane:EtOAc (3:1 to 1:1) gave the sub-title compound (6.99 g).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]#[N:9].[CH2:10]([NH:12][NH2:13])C>C(O)C>[CH3:10][N:12]1[C:8]([NH2:9])=[C:3]2[C:2]([CH2:7][CH2:6][CH2:5][CH2:4]2)=[N:13]1
Reactant: N#CC1CCCCC1=O
Reactant: CCNN
Solvent: CCO
Product: Cn1nc2c(c1N)CCCC2

Procedure:
A solution of 2-oxocyclohexanecarbonitrile 120 (10 g, 81.2 mmol) and ethyl hydrazine 119 (3 equiv, 14.6 g) in 150 mL of absolute ethanol was refluxed for 20 hrs and was concentrated on rotavapor to dryness. The crude product was recrystallized from methanol to afford the desired product 124. (Reference for the preparation of compound 124: J. Am. Chem. Soc. 1959, 81, 2448-2452)