Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K+].[N:2]1([CH2:8][CH2:9][C:10]([O-:12])=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(OC(=O)CCN1CCOCC1)C.FC(F)(F)C(O)=O.[C:33]1([C:39]2[CH:44]=[C:43]([CH:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[CH:42]=[CH:41][C:40]=2[NH:51][C:52]([C:54]2[NH:55][CH:56]=[C:57]([C:59]#[N:60])[N:58]=2)=[O:53])[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CCO)CC>O.CN(C=O)C>[C:33]1([C:39]2[CH:44]=[C:43]([CH:45]3[CH2:46][CH2:47][N:48]([C:10](=[O:12])[CH2:9][CH2:8][N:2]4[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)[CH2:49][CH2:50]3)[CH:42]=[CH:41][C:40]=2[NH:51][C:52]([C:54]2[NH:55][CH:56]=[C:57]([C:59]#[N:60])[N:58]=2)=[O:53])[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: O=C([O-])CCN1CCOCC1
Agent: CCN(CC)CCO
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)CCN1CCOCC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CCN4CCOCC4)CC3)cc2C2=CCCCC2)n1
Reaction time: 8 h
Yield: 6 %

Procedure:
To a flask containing 3-morpholin-4-yl-propionic acid potassium salt (94 mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl ester exactly as described in Example 7, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (179 mg, 0.36 mmol, as prepared in Example 14 (b)), EDCI (83 mg, 0.43 mmol), and HOBT (68 mg, 0.5 mmol) was added DMF (4 mL). To the stirred slurry was added DEEA (157 μL, 0.9 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the crude product was purified by silica gel preparative TLC to afford 10.4 mg (6%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.49-1.93 (m, 5H), 2.22-2.31 (m, 3H), 2.52 (br s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m, 4H), 3.10-3.17 (m, 2H), 3.72 (br s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81 (m, 2H), 5.81-5.82 (m, 1H), 6.81-6.82 (m, 1H), 6.99-7.00 (m, 1H), 7.09-7.13 (m, 1H), 7.70 (s, 1H), 8.26 (d, 1H, J=8.2 Hz), 9.51 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C29H36N6O3, 517.28 M+H), found 517.3.
Reaction SMILES: O.[C:2](Cl)([Cl:4])=[O:3].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>C(Cl)Cl>[Cl:4][C:2]([O:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Cl)Oc1ccccc1

Procedure:
Phenyl chloroform ate was prepared in a stirred reactor at a temperature which was kept below 10° C. by cooling. 1320 ml of methylene chloride were provided in the reactor together with 150 ml of water. 7.4 g/minute of phosgene were dosed for 10 minutes. 70.5 g of phenol in 333 ml of methylene chloride were then dosed in the course of 35 minutes. During this dosing of phenol, 3.7 g/min. of phosgene were added. The pH was kept at a value of 2-4 by dosing with sodium hydroxide solution. During the dosing of phenol 30 ml of water were added four times to the reactor. After termination of the phenol dosing, the phosgene dosing was continued for another 3 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:23])([CH3:22])[CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)=[C:4]([N+:24]([O-:26])=[O:25])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:23])([CH3:22])[CH2:10][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:4]([N+:24]([O-:26])=[O:25])[CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)Nc2ccc(Br)cc2[N+](=O)[O-])cc1
Product: CC(C)(CN1CCOCC1)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 105 °C

Procedure:
In a 250 mL flask, mix toluene-4-sulfonic acid 2-(4-bromo-2-nitro-phenylamino)-2-methyl-propyl ester (19.5 g, 44 mmol) and morpholine (50 mL). Heat at 100-110° C. for 2 days. Follow the progress of the reaction by HPLC. Cool the reaction and partition between water and EtOAc. Wash the organic layer with water (2×), dry (MgSO4) and concentrate to give 14 g dark oil. Recrystallize from heptane (400 mL) to give 11 g that is 80% pure by HPLC. Recrystallize a second time to give 6.6 g (42%) orange crystals; MS (es) 358, 360 (M+1), HPLC (ISO80-10M) t=3.17 (94%).
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.N#N.[CH2:29]([N:32]1[CH2:45][CH2:44][C:35]2[NH:36][C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1)[CH:30]=[CH2:31]>CN(C=O)C>[CH2:29]([N:32]1[CH2:45][CH2:44][C:35]2[N:36](/[CH:2]=[C:3](/[C:5]3[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=3)\[CH3:4])[C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][C:42]=3[C:34]=2[CH2:33]1)[CH:30]=[CH2:31]
Reactant: CC(=CBr)c1ccncc1
Reactant: C=CCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: N#N
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C=CCN1CCc2c(c3cc(C)ccc3n2/C=C(\C)c2ccncc2)C1
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
4-(2-Bromo-1-methyl-vinyl)-pyridine (2.5 g, 13 mmol) and potassium phosphate (4.2 g, 20 mmol) were stirred for 5 min. DMF (20 mL) was added and the solution stirred for 5 min followed by addition of L-proline (230 mg, 2.0 mmol) and cuprous iodide (190 mg, 1.0 mmol). N2 gas was bubbled into the reaction mixture, and 2-Allyl-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.0 g, 10 mmol) was added. The reaction mixture was heated at 120° C. for 16 h. After completion of reaction (as monitored by TLC) the mixture was concentrated under vacuum and diluted with water. The compound was extracted with EtOAc (4×100 mL) and organic layer dried over sodium sulfate, concentrated under vacuum under vacuum. The crude product was purified by column chromatography [Eluent: 2% MeOH in DCM]. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.82 (d, 2H), 8.38 (d, 2H), 7.82 (s, 1H), 7.39 (s, 1H), 7.18 (s, 2H), 6.15 (m, 1H), 5.70 (m, 2H), 4.75 (m, 1H), 4.40 (m, 1H), 4.05 (d, 2H), 3.98 (m, 1H), 3.60 (m, 1H), 3.25 (m, 1H), 3.20 (m, 1H), 2.42 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][NH:1][CH2:2][CH2:3][NH:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=4[O:17][B:16]3[OH:28])=[O:13])[CH2:7][CH2:6]2)[CH2:31][CH2:30]1
Reactant: O=CC1CC1
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Product: O=C(C[C@H]1CC[C@H](NCCNCC2CC2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid and cyclopropanecarbaldehyde following the procedure described in Example 71. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 444 (MH)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4]Cl)[CH3:2].[NH:6]1[CH:10]=[CH:9][N:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][CH2:4][N:6]1[CH:10]=[CH:9][N:8]=[N:7]1)[CH3:2]
Reactant: CCOCCl
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCn1ccnn1
Temperature: 25 °C

Procedure:
Chloromethyl ethyl ether (125 g, 1.32 mole) was added dropwise over 1.5 hours to an ice-cooled, stirred suspension of 1,2,3-triazole (91.4 g, 1.32 mole) and anhydrous potassium carbonate (183 g, 1.32 mole) in acetone (1.5 l). The mixture was then allowed to warm to room temperature and stirred for a further 18 hours. The solvent was evaporated under reduced pressure, the residue dissolved in water (1 l) and the aqueous solution extracted with dichloromethane (3×300 ml). The combined extracts were washed with saturated brine (3×300 ml), dried (Na2SO4) and evaporated under reduced pressure to furnish a pale yellow oil.
Reaction SMILES: ClC1N=CC=CN=1.NCCN1CCC([NH:17][C:18]2[N:22](CC3C=CC(F)=CC=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)CC1.C(=O)([O-])O.[Na+]>C(O)C>[NH:19]1[C:20]2[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=2[N:22]=[C:18]1[NH2:17]
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: Clc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc2ccccc2[nH]1

Procedure:
A mixture of 34.5 parts of 2-chloropyrimidine, 110 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 25 parts of sodium hydrogen carbonate and 1200 parts of ethanol was stirred and refluxed overnight. The reaction mixture was cooled and filtered over Hyflo. The filtrate was evaporated. The residue was purified by HPLC over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 82 parts (61%) of 1-[(4-fluorophenyl)methyl]-N-[1-[(2-pyrimidinyl)amino]-ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 168.4° C. (compound 1).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][CH:16]3[N:19]([CH3:34])[C:20]3[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=3)[O:23][CH2:24][C:25]([O:27]C(C)C)=[O:26])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][CH:16]3[N:19]([CH3:34])[C:20]3[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)OC(=O)COc1cccc(N(C)C2CCc3ccc(-c4cccc(F)c4)cc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(c1cccc(OCC(=O)O)c1)C1CCc2ccc(-c3cccc(F)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Aqueous lithium hydroxide (1 N, 1 mL, 1 mmol) was added to a solution of isopropyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)phenoxy)acetate (12 mg, 0.028 mmol) in THF (1 mL) in a scintillation vial. The vial was sealed and stirred overnight at room temperature. After 24 h, the reaction mixture was allowed to cool and the volatiles were concentrated. The residue was acidified with hydrochloric acid (1 N, 1 mL) and extracted with ethyl acetate (3×2 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by preparative TLC (1000 mm thickness, 10% methanol/dichloromethane) to afford 7 mg (65%) of the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[CH:6]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([I:21])[CH:20]=1.CO>O1CCCC1>[Cl:22][C:18]1[N:17]=[CH:16][C:15]([CH2:14][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[CH2:9][O:8][C:7](=[O:10])[CH:6]=2)=[CH:20][C:19]=1[I:21]
Reactant: Clc1ncc(CBr)cc1I
Reactant: O=C1C=C(NC2CC2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C=C(N(Cc2cnc(Cl)c(I)c2)C2CC2)CO1
Temperature: 25 °C
Yield: 26.5 %

Procedure:
200 mg (1.44 mmol) of 4-(cyclopropylamino)furan-2(5H)-one (VI-1) and 86 mg (2.17 mmol) of a 60% strength dispersion of sodium hydride in mineral oil in 100 ml of tetrahydrofuran are heated under reflux for 1 hour. After cooling to room temperature, 478 mg (1.44 mmol) of 3-bromomethyl-6-chloro-5-iodopyridine (VII-3) are added, and the mixture is heated under reflux for a further 6 hours. After cooling of the reaction mixture to room temperature and addition of methanol, the mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (3:1) gives 149 mg (26% of theory) of 4-[[(6-chloro-5-iodopyridin-3-yl)methyl](cyclopropyl)amino]furan-2(5H)-one.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=C[O:11][C@H:10]1[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=[O:25].[Na+].O=[O+][O-].[BH4-].[Na+].CC([O-])=O.[Na+]>CO.C(Cl)Cl.O.CCOC(C)=O>[CH2:16]([O:15][C@H:14]([C@@H:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:10]([OH:11])[CH3:23])[CH2:13][OH:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C([O-])O
Reactant: C[C@@H]1OC=C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: O=[O+][O-]
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: C[C@H](O)[C@H](OCc1ccccc1)[C@H](CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 932.4 %

Procedure:
A mixture of (2S,3S,4S)-3,4-bis(benzyloxy)-2-methyl-3,4-dihydro-2H-pyran (0.621 g, 2.00 mmol) and NaHCO3 (17.0 mg, 0.200 mmol) in MeOH (0.22 ml) and DCM (7 mL) was treated with ozone at −78° C. until the solution became light blue in color. The mixture was purged with nitrogen until colorless, diluted with MeOH (7 mL), and treated with a solution of NaBH4 (0.454 g, 12.0 mmol) and NaOAc (0.335 g, 4.08 mmol) in H2O (7 mL). The mixture was slowly warmed to room temperature and stirred for 12 h. The mixture was diluted with EtOAc and washed with H2O. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered, and the filtrate concentrated. The crude residue was purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to yield the title compound as a colorless oil (0.590 g, 93%): IR (neat) 3389, 2876, 1453, 1064, 733, 696 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.39-7.27 (m, 10H), 4.64 (s, 2H), 4.63 (s, 2H), 4.06-3.97 (m, 1H), 3.92-3.83 (m, 1H), 3.80-3.73 (m, 2H), 3.47 (dd, J=6.2, 4.3 Hz, 1H), 2.92 (d, J=4.9 Hz, 1H), 2.23 (dd, J=6.9, 4.9 Hz, 1H), 1.24 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 137.91, 137.71, 128.69, 128.62, 128.23, 128.19, 128.09, 81.72, 79.53, 73.63, 72.78, 67.66, 61.45, 19.74; ESIMS m/z 339.2 ([M+Na]+).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([F:15])[C@@H:13]([CH2:16][CH:17]([P:25]([O:30]CC)([O:27]CC)=[O:26])[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:12][C@H:11]1[N:33]1[CH:41]=[N:40][C:39]2[C:38](=[O:42])[NH:37][C:36]([NH:43][C:44](=[O:46])[CH3:45])=[N:35][C:34]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1NC(=O)C2N=CN(C3OC(C=CP(O)(O)=O)C(OC(=O)C4C=CC=CC=4)C3OC)C=2N=1)(=O)C(C)C>>[C:44]([NH:43][C:36]1[NH:37][C:38](=[O:42])[C:39]2[N:40]=[CH:41][N:33]([C@@H:11]3[O:12][C@H:13]([CH2:16][CH:17]([P:25](=[O:26])([OH:27])[OH:30])[S:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C@@H:14]([F:15])[C@H:10]3[O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:34]=2[N:35]=1)(=[O:46])[CH3:45]
Reactant: CCOP(=O)(OCC)C(C[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NC(C)=O)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1F)Sc1ccccc1
Agent: COC1C(OC(=O)c2ccccc2)C(C=CP(=O)(O)O)OC1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Product: CC(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CC(Sc3ccccc3)P(=O)(O)O)[C@@H](F)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]1
Yield: 66.2 %

Procedure:
Compound 35.16 (45 mg, 66% yield) was synthesized from compound 35.15 (77 mg, 0.11 mmol) using the procedure described for the preparation of compound 16.8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.C(OCC)(OCC)OCC.[CH:35]([NH2:38])([CH3:37])[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C=O)C.CC(O)=O>[CH:35]([NH:38][CH2:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:8][CH:9]=3)[C:13](=[O:24])[NH:14]2)=[CH:19][CH:18]=1)([CH3:37])[CH3:36]
Reactant: CC(C)N
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: CC(C)NCc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde (step (a), 100 mg, 0.3 mmol), 1.5 mL AcOH, 1.5 mL of triethyl orthoformate, isopropylamine (0.5 mL), and 30 mL of DMF was stirred for 3 h. Gentle heating was be used to bring about a homogenous solution. After 3 h, NaBH(OAc)3 (0.5 g, Aldrich) was added and the reaction was stirred for 3 days at RT. The solution was concentrated in genevac overnight to remove DMF. The resulting solid was dissolved in a minimal amount of DMSO and purified by mass triggered HPLC to give a yellow solid after drying in genevac (TFA salt). MS m/z: 377.3 (M+1).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH2:47][CH3:48])[CH3:46])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH2:47][CH3:48])[CH3:46])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCN(C)C(=O)CCl
Product: CCN(C)CCOc1ccc(CN(CC)c2cc(OC)c(OC)cc2C2CCc3cc(O)ccc3C2)cc1F
Yield: 11.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-ethyl-N-methylacetamide (9.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.2 mg) was obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH3:12])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>O.CO>[OH:1][CH:2]([CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH3:12])[C:3]([OH:5])=[O:4]
Reactant: CCCC=CCC(O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC=CCC(O)C(=O)O
Temperature: 25 °C

Procedure:
Methyl 2-hydroxy-4-octenoate (23)(7.04 g, 0.041 mol, 1.0 eq) is heated under reflux with a large excess of sodium hydroxide (13.5 g, 0.34 mol, 8.3 eq) in water (30 ml) and methanol (30 ml) for 1 hour. After cooling down to room temperature, the mixture is washed with hexane (50 ml) and the organic phase separated. The clear aqueous layer is acidified to pH 1 with concentrated hydrochloric acid and the resultant mixture is extracted with diethylether (3×50 ml), the combined organic layers being washed with brine (50 ml) thence dried over anhydrous magnesium sulphate and evaporated to give a colourless oil which slowly crystallised to furnish the product acid (21) as a white waxy solid, 5.72 g (88%), m p 37-38° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH2:23][N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]4)[CH:20]=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1ccc(Cl)cc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4ccc(Cl)cc4)c(C(N)=O)s3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
To a mixture of 0.16 g (0.40 mmole) of 4-(4-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.19b), 0.51 g (2.38 mmole) of sodium triacetoxy-borohydride and 15 mL of dichloromethane was added 0.07 mL (0.60 mmole) of 1-methylpiperazine. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-15:85) to give 0.16 g of 4-(4-chloro-phenyl)-2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.19c).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].Cl.CN.[CH2:18]([N:20](CC)CC)C.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH:20][CH3:18])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
A solution of 2-fluoro-5-nitrobenzenesulfonyl chloride (3.2 g, 12.6 mmol) in THF (30 mL) at −45° C. was treated with methylamine hydrochloride (1.0 g, 15.1 mmol) and triethylamine (2.1 mL, 15.1 mmol) and stirred for 30 minutes. The mixture was then treated with 6M aqueous HCl to adjust the pH to 3 and warmed to room temperature before being diluted with water and extracted with EtOAc. The organic extract was dried (sodium sulfate), concentrated, and subjected to flash chromatography (5-20% EtOAc-petroleum ether) to give 2-fluoro-N-methyl-5-nitrobenzenesulfonamide as a yellow solid (3.0 g, 93%). MS (m/z) 235.1 (M+H+).
Reaction SMILES: CS(C)=O.C[O:6][C:7]1[CH:16]=[C:15]2[C:10](C(Cl)=CC=N2)=[CH:9][C:8]=1C(N)=O.[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](NC1CC1)=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](=[O:31])[O:6][C:7]1[CH:16]=[CH:15][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Reactant: O=C(Nc1ccc(O)cc1Cl)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(O)cc1Cl)Oc1ccccc1
Temperature: 70 °C
Reaction time: 23 h
Yield: 142.4 %

Procedure:
To dimethyl sulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was heated and stirred at 70° C. for 23 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added, and the resultant crystals were then filtered off to give 1.56 g of the titled compound (yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[CH2:9][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C(O)(=O)/C=C\C(O)=O.[Cl:33]C1C=C2N(C3C=CC=CC=3[N+]([O-])=O)CC3(CCNCC3)C2=CC=1.C(O)C.Cl>[Fe].O>[ClH:1].[ClH:33].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1
Reactant: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21
Agent: [Fe]
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: O
Solvent: CCO
Product: Nc1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21

Procedure:
A mixture of 2.1 g of 6-chloro-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine], free base of Example 33, 95 ml of 95% ethyl alcohol, 7.5 ml of water and 4.4 g of iron powder is acidified with 0.2 ml of concentrated hydrochloric acid and then refluxed under nitrogen for 10 minutes. Thereafter, the mixture is permitted to cool before being filtered through celite. The filtrate is concentrated under vacuum leaving an oily residue which is basified. The alkaline mixture is extracted with ether and then dried. The product is converted to a solid dihydrochloric acid salt which is recrystallized from a methyl alcohol-ether mixture to provide off-white prisms, mp 270°-273° C. (after darkening) of 1-(2-aminophenyl)-6-chlorospiro[indoline-3,4'-piperidine] dihydrochloride.