Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.C(N(CC)CC)C.[C:32]([O:35][CH2:36]C)(=[O:34])C>CO.ClCCl.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:36][O:35][C:32]([C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1)=[O:34]
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(OC)n1
Reaction time: 20 h
Yield: 55 %

Procedure:
A solution of (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (0.35 g, 1.0 mmol) in a mixture of 7 ml methanol and 3.5 ml ethyl acetate was treated with triethylamine (0.21 ml, 1.5 mmol) and tris(dibenzylideneacetone) dipalladium dichloromethane-complex (70 mg, 0.09 mmol). The mixture was transferred to an autoclave, flushed with carbon monoxide and hold 20 hours at 80° C. under a pressure of 5 bar of carbon monoxide. After cooling and evacuating the carbon monoxide, the mixture was concentrated to about 2 ml and diluted again with a mixture of ethyl acetate/methanol 9:1 v/v. The title compound precipitated as an intensely yellow solid after cooling in the refrigerator for 17 hours. Yield=55%.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[CH2:19]([N:25]=[C:26]=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCOCC1.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:26]([NH:25][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:27])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: CCCCCCN=C=O
Solvent: CN1CCN(C)C1=O
Solvent: C1COCCO1
Product: CCCCCCNC(=O)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With the exclusion of moisture, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine are dissolved in 2.5 ml of dioxane and 1 ml of DMEU; 160 μl (1.1 mmol) of n-hexyl isocyanate are added and the reaction mixture is stirred overnight at RT. The dioxane is then evaporated off in a rotary evaporator and 30 ml of DIPE and 40 ml of hexane are added to the residue. Filtration with suction and washing with DIPE/hexane yield 4-(3chloro-phenylamino)-3-[(n-hexyl-amino)-carbonyl-amino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC:tRet(grad20-100)=10.3; FAB-MS: (M+H)+=388.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:4]=2[C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=O.[CH:22]1([C:25](=[O:30])[CH2:26][C:27](=O)[CH3:28])[CH2:24][CH2:23]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:22]1([C:25]([C:26]2[C:27]([CH3:28])=[N:1][C:2]3[S:6][C:5]4[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:4]=4[C:3]=3[C:12]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[O:30])[CH2:24][CH2:23]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)c(Cl)c1)CCCCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccc(Cl)c(Cl)c2)c1C(=O)C1CC1)CCCCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
To a stirred solution of 36 mg (0.11 mmol) (2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-3-yl)-(3,4-dichloro-phenyl)-methanone in 2 ml acetic acid was added 18 mg (0.11 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 10 mg (19%) cyclopropyl-[4-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-10-thia-1-aza-benzo[a]azulen-3-yl)-methanone as a light yellow oil. ES-MS m/e (%): 430 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][CH3:21])=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:22].C[OH:24].[OH-].[Na+]>O>[CH2:20]([C:16]1[CH:17]=[CH:18][C:19]([NH:11][C:3]2[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=2[F:10])=[C:14]([CH2:13][C:12]([OH:24])=[O:22])[CH:15]=1)[CH3:21]
Reactant: CO
Reactant: CCc1ccc2c(c1)CC(=O)N2c1c(F)c(F)cc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(2,3,5,6-tetrafluorophenyl)-5-ethyloxindole (72.67 g; 0.235 mol, is slurried in water containing a little methanol (10% v/v; 253 ml), and sodium hydroxide solution (50 wt %; 16.1 ml) is added. The mixture is stirred at 80-85° for 2-4 hours, then cooled to ambient temperature. The reaction solution is partially concentrated under reduced pressure (25-30 mm). After removal of 50 ml of the solvent, the mixture is diluted with water (150 ml) and t-butyl methyl ether (250 ml). The cooled mixture is acidified to pH 6.5-7.0 with aqueous HCI (12.1 N; 19.5 ml), keeping the temperature at 0-5°. The aqueous layer is discarded and the organic layer is washed with water (250 ml). The organic layer is concentrated under reduced pressure (20-100 mm) while exchanging the solvent to toluene. After the more volatile components have been removed, the batch volume is adjusted to 400-450 ml. This mixture is warmed to 700°, clarified, concentrated to one-half volume, and cooled to 0° After stirring at this temperature for 2 hours, the product is collected and is washed with toluene/heptane (10:90; 100 ml). The resulting solid is dried under reduced pressure at 50-60° for 4-8 hours to give 5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid of Example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]([C:24](=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:8]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:46])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:28]([O:27][C:25](=[O:26])[C:24]([N:7]([CH:8]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:46])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:32][CH:31]=1)=[O:30])[CH3:29]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(N)cc1)C(c1ccc(C(F)(F)F)cc1)C1CCCC1
Reactant: CCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCC(=O)Nc1ccc(CN(C(=O)C(=O)OCC)C(c2ccc(C(F)(F)F)cc2)C2CCCC2)cc1
Yield: 76 %

Procedure:
The same procedure as employed in the preparation of Example 15 (step d) but using ethyl ((4-aminobenzyl){cyclopentyl[4-(trifluoromethyl)phenyl]methyl}amino)(oxo)acetate and tridecanoyl chloride gave the title compound as a colorless oil (76%). 1H NMR (CDCl3, 300 MHz) δ 7.52-7.21 (m, 6H), 6.95 (d, 1H, J=8.5 Hz) 6.8 (d, 1H, J=8.5 Hz), 5.30 (m, 1H), 4.47-4.05 (m, 4H), 2.85-2.60 (m, 1H), 2.45-2.26 (m, 2H), 1.80-1.10 (m, 31H), 1.05-0.86 (m, 4H). M−(LC/MS(ESI)): 643.9; M+(LC/MS(ESI)): 645.2. HPLC (Condition A), Rt: 6.85 min (HPLC purity: 98.0%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:20]=[C:19](Br)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N:8][C:7]=1[CH3:22])=[O:5])[CH3:2].O.[CH3:24][N:25]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:20]=[C:19]([C:24]#[N:25])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N:8][C:7]=1[CH3:22])=[O:5])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)c1sc(-c2cc(Br)c3ccccc3c2)nc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1sc(-c2cc(C#N)c3ccccc3c2)nc1C
Temperature: 150 °C
Reaction time: 0.83 h

Procedure:
A suspension of 2-(4-bromonaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.050 g), zinc cyanide (0.031 g) and tetrakis(triphenylphosphine)palladium (0.015 g) in N-methylpyrrolidone (2 mL) was stirred at 150° C. for 50 minutes using microwave reactor (Biotage). To the reaction mixture was added water (15 mL), and the precipitated solid was collected by filtration, and washed with water and n-hexane to give 2-(4-cyanonaphthalene-2-yl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.042 g).
Reaction SMILES: C([O:3]C(C=NC1C=C(NC2N=C(NC3C=CC=C(O)C=3)C(F)=CN=2)C=CC=1)=O)C.[F:30][C:31]1[C:32]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([OH:60])[CH:55]=2)=[N:33][C:34]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([N:44]=[CH:45][C:46]([NH:48][CH2:49][CH2:50]NC)=[O:47])[CH:39]=2)=[N:35][CH:36]=1>>[F:30][C:31]1[C:32]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([OH:60])[CH:55]=2)=[N:33][C:34]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([N:44]=[CH:45][C:46]([NH:48][CH2:49][CH2:50][OH:3])=[O:47])[CH:39]=2)=[N:35][CH:36]=1
Reactant: CCOC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: CNCCNC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Product: O=C(C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1)NCCO

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine, N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine and N-methyl-ethylen-1,2-diamine were reacted to prepare 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 12.31 min.; purity: 94.7%; MS (m/e): 426.01 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:14][C:15]3[S:16][C:17]4[C:18]([N:23]=3)=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=[CH:13][C:7]=2[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[S:16]1[C:17]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:23]=[C:15]1[O:14][C:11]1[CH:12]=[CH:13][C:7]2[CH:6]=[C:5]([CH2:3][OH:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1cc2ccc(Oc3nc4ncccc4s3)cc2s1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Product: OCc1cc2ccc(Oc3nc4ncccc4s3)cc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a cooled (0° C.) solution of 6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzo[b]thiophene-2-carboxylic acid methyl ester (0.18 g, 0.5 mmol) in DCM (5 mL) was added LAH (2 M in THF, 0.3 mL, 0.3 g, 0.5 mmol) and the reaction mixture was stirred (0° C., 1 h). The reaction mixture was treated with saturated aqueous Rochelle's salt (2 mL) and partitioned with EtOAc (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×15 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as an orange solid (0.13 mg, 82%). MS (ESI): mass calcd. for C15H10O2S2, 314.0; m/z found, 315.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (dd, J=4.8, 1.7, 1H), 8.02 (dd, J=7.9, 1.6, 1H), 7.95 (d, J=2.2, 1H), 7.76 (d, J=8.7, 1H), 7.38 (dd, J=8.6, 2.3, 1H), 7.21 (dd, J=7.9, 4.9, 2H), 4.94 (s, 2H), 2.14 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:12]3[O:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[I:27]Cl>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([I:27])=[CH:9][N:8]([C@@H:11]3[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:12]3[O:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CO[C@@H]1[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1n1ccc2c(Cl)ncnc21
Reactant: ClI
Solvent: ClCCl
Product: CO[C@@H]1[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1n1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a solution of compound 5.5 (1.25 g, 3.26 mmol) in CH2Cl2 (80 mL), a 1.0 M solution of ICl in CH2Cl2 (8.12 mmol) was added at room temperature and the resulting dark brown solution was stirred for 4 hr at room temperature. The solvents were evaporated in vacuo at 25° C.-35° C. and the residue was dried under high vacuum for 30 min. A light brown sticky material was obtained which was purified by flash column chromatography using gradient of pure CH2Cl2 to 1.5% MeOH in CH2Cl2 to afford the desired compound 5.6 (1.1 g, 66%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[NH2:5].Br[C:19]1[S:23][C:22]([C:24]([OH:35])([CH3:34])[CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[N:21][CH:20]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[NH2:5][C:4]1[CH:6]=[C:7]([C:19]2[S:23][C:22]([C:24]([OH:35])([CH3:34])[CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[N:21][CH:20]=2)[CH:8]=[C:2]([CH3:1])[CH:3]=1
Reactant: CC(O)(CO[Si](C)(C)C(C)(C)C)c1ncc(Br)s1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(N)cc(-c2cnc(C(C)(O)CO[Si](C)(C)C(C)(C)C)s2)c1
Temperature: 110 °C
Yield: 73.2 %

Procedure:
3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (69 mg, 0.296 mmol), the product of Step 2 (104 mg, 0.296 mmol), X-Phos (14.11 mg, 0.030 mmol), cesium carbonate (289 mg, 0.888 mmol), and Pd2(dba)3 (13.55 mg, 0.015 mmol) were placed in a flask flushed with Ar. Degassed Dioxane (1.2 ml) and Water (0.12 ml) were added and heated to 110° C. for 5.5 h. The reaction was allowed to cool to room temperature and then quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification via silica gel column chromatography (10-30% EtOAc:hexanes) afforded 2-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol (82 mg, 73%) as a brown oil. MS ESI: [M+H]+ m/z 379.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]=[C:9]=[S:10])=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:4][CH:3]=1.[NH3:17]>C(O)C>[CH3:1][C:2]1[C:7]([NH:8][C:9]([NH2:17])=[S:10])=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: Cc1cccc(N2CCCCC2)c1N=C=S
Solvent: CCO
Product: Cc1cccc(N2CCCCC2)c1NC(N)=S

Procedure:
Reaction of 6-methyl-2-piperidinophenyl isothiocyanate (6.8 g) with 25% aqueous ammonia solution (65 ml) in ethanol (20 ml) for 8 hours at room temperature gave 1-(6-methyl-2-piperidinophenyl) thiourea as a pale yellow solid (m.p. 197°-198° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:7][C:6]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:5]=2[C:4](=O)[CH2:3]1.[CH2:17]([NH2:19])[CH3:18].[BH4-].[Na+]>O1CCCC1.C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:17]([NH:19][CH:4]1[CH2:3][C:2]([CH3:16])([CH3:1])[S:7][C:6]2[S:8][C:9]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:10][C:5]1=2)[CH3:18]
Reactant: CCN
Reactant: CC1(C)CC(=O)c2cc(S(N)(=O)=O)sc2S1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCNC1CC(C)(C)Sc2sc(S(N)(=O)=O)cc21
Yield: 77.1 %

Procedure:
A solution of 5,6-dihydro-6,6-dimethyl-4H-thieno[2,3-b]thiopyran-4-one-2-sulfonamide (3.00 g, 0.011 mol) in dry tetrahydrofuran (40 ml) and benzene (40 ml) was cooled to -10° C. and condensed ethylamine (15 ml, 10.8 g, 0.24 mol) was added rapidly with stirring. Titanium tetrachloride 1.14 g, 0.006 mol) was added over 20 minutes while maintaining the temperature below 0° C. The mixture was stirred at ambient temperature for 2.5 hours, filtered, and the solid was washed with tetrahydrofuran. The combined filtrate and washings were evaporated in vacuo and the residue was suspended in absolute methanol (105 ml). With stirring under nitrogen, sodium borohydride (0.53 g, 0.014 mol) was added portionwise over 15 minutes and the mixture was stirred at ambient temperature for 21 hours. After acidification with concentrated hydrochloric acid, the mixture was concentrated in vacuo. The residue was distributed between water (100 ml) and ethyl acetate (100 ml), and the aqueous layer was separated and extracted with ethyl acetate (2×50 ml). The water layer then was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×250 ml). The combined extracts were washed with water (3×), dried over sodium sulfate, and evaporated in vacuo. The residue was crystallized as the hydrochloride salt from ethanolic hydrogen chloride to afford 2.60 g (69%) of pure product.
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.C(OCC)C.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>CCCCCC>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]([C:7]1[S:6][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=1)[OH:24]
Reactant: O=Cc1ccccc1Cl
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(c1nc2ccccc2s1)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
47 mL of 1.6M-butyllithium in hexane was added dropwise to a solution of benzothiazole (10 g, from Aldrich) and diethyl ether (200 mL) at -78° C. under nitrogen. The red brown solution was stirred at -78° C. for 30 min., followed by the addition of a solution of o-chlorobenzaldehyde (10.8 g) and diethyl ether (100 mL) at -78° C. The mixture was then stirred at -78° C. for 2 hours before it was allowed to warm to room temperature and stirred at room temperature overnight.
Reaction SMILES: C1(=O)C2C(C3C(C=2)=CC=CC=3)=CC=C1.[Na].[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[N:27]=[CH:26][CH:25]=[C:24]([C@H:28]([OH:39])[C@@H:29]3[N:34]4[CH2:35][C@H:36]([CH:37]=[CH2:38])[CH:31]([CH2:32][CH2:33]4)[CH2:30]3)[C:22]=2[CH:23]=1>C1(C)C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[N:27]=[CH:26][CH:25]=[C:24]([C:28]([C@@H:29]3[N:34]4[CH2:35][C@H:36]([CH:37]=[CH2:38])[C@@H:31]([CH2:32][CH2:33]4)[CH2:30]3)=[O:39])[C:22]=2[CH:23]=1
Reactant: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Agent: O=C1C=CC=C2C1=Cc1ccccc12
Agent: [Na]
Solvent: Cc1ccccc1
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2C(=O)c1ccnc2ccc(OC)cc12

Procedure:
A solution of fluorenone ketyl was prepared by mixing 9 g. of fluorenone and 6.5 g. of sodium in anhydrous toluene. To this solution was added a hot solution of 37 g. of anhydrous quinidine base in 150 ml. of anhydrous toluene. After 15 minutes at reflux, the reaction was complete. After extraction and neutralization treatments as in Example I, 36 g. of pure quinidinone (TLC) was obtained (97% of theory).
Reaction SMILES: CC(C)(C)C[OH:4].[CH:7]([C:9]1[CH:55]=[CH:54][C:12]([O:13][C:14]2[CH:53]=[CH:52][C:17]([C:18]([N:20]3[CH2:24][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C@@H:22]([CH2:31][N:32]([C@@H:40]([C:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH:45]=[CH:44][CH:43]=4)[CH3:41])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:21]3)=[O:19])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)=[O:8].P([O-])(O)(O)=O.[K+].CC(=CC)C.Cl([O-])=O.[Na+]>>[C:35]([O:34][C:33]([N:32]([CH2:31][C@@H:22]1[C@@H:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:24][N:20]([C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:54]=[CH:55][C:9]([C:7]([OH:4])=[O:8])=[CH:10][CH:11]=3)=[CH:53][CH:52]=2)=[O:19])[CH2:21]1)[C@@H:40]([C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1)[CH3:41])=[O:39])([CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(Oc3ccc(C=O)cc3)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)CO
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(Oc3ccc(C(=O)O)cc3)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 4 ml 2,2-dimethylpropanol/1 ml water mixed solution of 286 mg of tert-butyl ({(3R,4S)-1-[4-(4-formylphenoxy)benzoyl]-4-phenylpyrrolidin-3-yl}methyl)[(1R)-1-(1-naphthyl)ethyl]carbamate was mixed with 892 mg of potassium dihydrogenphosphate, 1 ml of 2-methyl-2-butene and 394 mg of sodium chlorite and stirred at room temperature for 3 hours. By carrying out its work-up and purification in the standard method, 293 mg of 4-(4-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}phenoxy)benzoic acid was obtained as a pale yellow oily substance. EP: 671. (3) By carrying out the Boc-elimination reaction in the same manner as in Example 5,4-(4-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}phenoxy)benzoic acid hydrochloride was produced from 4-(4-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}phenoxy)benzoic acid.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:20]4[CH2:23][CH:22]([OH:24])[CH2:21]4)[C:17]=3[F:19])[C:12](=[O:26])[C:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10]2)[CH2:8][CH2:7]1.O>N1C=CC=CC=1>[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:20]4[CH2:21][CH:22]([O:24][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:23]4)[C:17]=3[F:19])[C:12](=[O:26])[C:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(O)C3)c(F)cc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(OS(C)(=O)=O)C3)c(F)cc2c1=O
Temperature: 0 °C
Yield: 74 %

Procedure:
6.3 g (55.0 mmoles) of mesyl chloride are slowly added to a solution of 1.0 g (2.75 mmoles) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 50 ml of pyridine cooled to 0° C., and the reaction is maintained at 0° C. for 3 hours. The solution is added to a mixture of ice and water giving a precipitate which is filtered and washed with water. The solid is dried under vacuum yielding 0.9 g (73%) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-mesyloxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate melting at 191°-193° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11]2[C:6](=[C:7]([CH2:12][CH2:13]O)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.C1C(=O)N([Br:47])C(=O)C1>>[Br:47][CH2:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][CH:4]([CH3:15])[CH:3]2[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC1c2cccc(CCO)c2CC1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1c2cccc(CCBr)c2CC1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 41.3 g (0.2 mol) of 2-(1-methoxy-2-methyl-2,3-dihydro-1H-inden-4-yl)ethanol and 52.5 g (0.2 mol) PPh3 in 800 ml of THF 35.6 g (0.2 mol) of NBS was added at vigorous stirring for 5 min at 0° C. This mixture was stirred for 2 h at room temperature and then evaporated to dryness. A solution of the residue in 500 ml of hexanes was filtered through glass frit (G3), and the precipitate was additionally washed by 3×300 ml hexanes. The combined organic extract was evaporated to dryness. The product was isolated from the residue using flash chromatography on Silica Gel 60 (40-63 um, d 80 mm, l 250 mm; eluent: hexanes/ether=20/1, vol.). Yield 39.3 g (73%) of ca. 1 to 1 mixture of the diastereomers A and B.