Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15](O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][C:20]1[C:21]([NH2:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:18][N:19]1[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]=[C:15]1[CH:13]1[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: CNc1ccccc1N
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1c(C2CN(C(=O)OCc3ccccc3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
1-2 (3.0 g, 12.75 mmol) was dissolved in THF (64 mL) and N-methylbenzene-1,2-diamine (2.02 g, 16.58 mmol), EDC (2.93 g, 15.30 mmol), HOAt (2.08 g, 15.30 mmol), and Hunig's base (6.7 mL, 38.3 mmol) were added. After stirring for 18 hours at ambient temperature, the reaction solution was concentrated. The residue was then dissolved in acetic acid (30 mL). After stirring at ambient temperature for 2 hours, the solvent was removed. The residue was partitioned between ethyl acetate and 5% aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc/Hexanes) to provide 1-3 as a off-white solid (3.32 g, 81%). MS: m/z=322.4 (M+H).
Reaction SMILES: [CH:1](=[N:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[O:10]1[C:12]([CH3:14])([CH3:13])[CH2:11]1>O1CCCC1>[CH2:1]([N:5]1[CH2:11][C:12]([CH3:14])([CH3:13])[O:10][CH:6]1[CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=NCCCC
Reactant: CC1(C)CO1
Solvent: C1CCOC1
Product: CCCCN1CC(C)(C)OC1CCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
A mixture of 1 mmol of N-butylidenebutylamine, 2 mmol of 1,2-epoxy-2-methylpropane, 0.05 mmol of Cp*2Sm(THF)2, and 1 ml of tetrahydrofuran was stirred at room temperature for 5 hours. Products in a reaction mixture were isolated through column chromatography to yield 3-butyl-5,5-dimethyl-2-propyl-1,3-oxazolidine in yield of 53%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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].CCO>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:29]2[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)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
Solvent: CCO
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(S(C)(=O)=O)cc3)s2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.1 g, 0.320 mmol), 4-bromophenyl methyl sulfone (0.075 g, 0.320 mmol), Pd2 dba3 (0.029 g, 0.032 mmol), K2CO3 (0.049 g, 0.352 mmol) and X-Phos (0.076 g, 0.160 mmol) were added to a 5 mL microwave vial. Degassed EtOH (1 mL) was added and the vial evacuated and back-filled with N2 (×3). The resulting mixture was stirred at 100° C. overnight. Room temperature was attained, MeOH was added and the solvent removed in vacuo while loading onto silica. Purification of the residue by MPLC (0-10% MeOH—CHCl3) gave 5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[4-(methylsulfonyl)phenyl]amino}thiophene-3-carboxamide as a beige solid after triturating in DCM.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH:22][CH3:23])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1>[Pd]>[N:13]1[C:12]([C:14]2[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([NH:22][CH3:23])[N:15]=2)=[CH:11][N:7]2[C:6]=1[C:5]1[CH:24]=[CH:25][CH:2]=[CH:3][C:4]=1[O:10][CH2:9][CH2:8]2
Reactant: CNc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Product: CNc1nc(-c2cn3c(n2)-c2ccccc2OCC3)n(C(C)C)n1

Procedure:
5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-N-methyl-1H-1,2,4-triazol-3-amine was hydrogenated in the presence of 10% Pd on carbon to give 246 after reverse phase HPLC. LCMS: 325.2
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:20](=[O:23])[O:21][CH2:22][C:18]=4[C:17]([OH:24])=[C:16]4[C:11]=3[CH:12]=[C:13]([O:27][CH3:28])[C:14]([O:25][CH3:26])=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1.CI.[CH3:31]C(C)=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:20](=[O:23])[O:21][CH2:22][C:18]=4[C:17]([O:24][CH3:31])=[C:16]4[C:11]=3[CH:12]=[C:13]([O:27][CH3:28])[C:14]([O:25][CH3:26])=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc2c(O)c3c(c(-c4ccc5c(c4)OCO5)c2cc1OC)C(=O)OC3
Reactant: CC(C)=O
Solvent: CI
Product: COc1cc2c(OC)c3c(c(-c4ccc5c(c4)OCO5)c2cc1OC)C(=O)OC3

Procedure:
The product of step F, diphyllin, (10; 75 mg; 0.197 mmol), and 1 ml methyl iodide were dissolved in 5 ml acetone containing 82 mg potassium carbonate (0.6 mmol), and the resulting solution heated at about 60° for one hour. After removing acetone, a residue remained which was treated with methylene chloride and 10% aqueous hydrogen chloride. After separation of aqueous and organic layers, the organic layer was washed with saturated sodium chloride and dried over magnesium sulfate. Evaporation of solvent and purification on a preparative thin-layer chromatography plate provided ca. 67 mg of 9-(1,3-benzodioxol-5-yl)-4,6,7-trimethoxynaphtho[2,3-c]furan-1-(3H)-one, 11, mp 248°-250°. IR(CHCl3): 1770, 1620 cm-1 ; PMR (CDCl3): δ7.39 (s, 1H), 6.91 (s, 1H), 6.83-6.64 (m, 3H), 5.94 (2s, 2H), 5.42 (s, 2H), 4.05 (s, 3H), 3.98 (s, 3H), and 3.73 (s, 3H); MS: m/z 394.1006 (M+), calcd. for C22H18O7, 394.1049. A separate sample of product 11, prepared by substantially the foregoing procedure, was recrystallized from chloroform-ether, mp 256°-258°. This crystalline product was again recrystallized from chloroform-ether, mp 258°-260°.
Reaction SMILES: [NH:1](/[C:8](/NC(C)C)=[CH:9]\[C:10]([C:12]1[C:13](Cl)=[N:14][C:15](Cl)=[C:16](F)[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C.O>[C:2]1([N:1]2[C:13]3[C:12](=[CH:17][CH:16]=[CH:15][N:14]=3)[C:10](=[O:11])[CH:9]=[CH:8]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N/C(=C/C(=O)c1cc(F)c(Cl)nc1Cl)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn(-c2ccccc2)c2ncccc12
Temperature: 85 °C
Yield: 86.7 %

Procedure:
(2Z)-3-Anilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen-1-one (40.0 mg, 0.109 mmol) was dissolved in 4 mL of DMF. NaH (8.70 mg, 0.217 mmol, 60% dispersion in oil) was added and the reaction was heated to 85° C. under argon for 2 h. The reaction mixture was cooled to room temperature and diluted with water and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 100% EtOAc to 95:5 EtOAc:MeOH provided 7-chloro-6-fluoro-2-isopropylamino)-1-phenyl-1,8-naphthyridin-4(1H)-one (21 mg, 64%) as a white solid: LCMS RT: 2.57 min, MH+: 332.2.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[N:21]1([CH2:28][CH2:29][OH:30])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:24]2[CH2:25][CH2:26][CH2:27][N:21]([CH2:28][CH2:29][OH:30])[CH2:22][CH2:23]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: OCCN1CCCNCC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3CCCN(CCO)CC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
350 mg (1.2 mmol) of 8-Chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (for preparation see: DE 3420743) are dissolved according to DE 3635218 in 3 ml of dry pyridine and heated at reflux with 202 mg (1.4 mmol) of hexahydro-1H-1,4-diazepine-1-ethanol for 4 hours. After standing overnight the mixture is concentrated, taken up with water and brought to pH 6 using dilute hydrochloric acid. The solution is saturated with sodium chloride at boiling heat. After it has cooled to room temperature, it is extracted a number of times with dichloromethane. The organic extracts are filtered over a little silica gel and concentrated. 288 mg of the target compound are obtained this way. The compound is used as a crude product in the subsequent reaction stages.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:14]1[CH:26]=[CH:25][C:17]([C:18]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[O:19]=[C:18]([C:17]1[CH:25]=[CH:26][C:14]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[CH:15][CH:16]=1)[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCC(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 120 °C
Yield: 53.5 %

Procedure:
A stirred mixture of 4-phenyl-piperidine (10.4 g, 0.064 mol), 3-(4-fluorobenzoyl)-propionic acid (12.1 g, 0.062 mol), and potassium carbonate (17.5 g, 0.13 mol) in DMSO (15 mL) was heated under an atmosphere of nitrogen at 120° C. for 18 hours. The mixture was allowed to cool, diluted with water (100 mL), and brought to pH 2 dropwise with 1 M HCl. The resulting solid was filtered, washed with water, and dried in vacuo to yield a pale orange solid as the title compound (11.2 g, %C,H,N found: 74.54, 6.98, 4.07).
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[NH2:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH3:14][S:15][C:16]1[S:20][C:19]([C:21]#[N:22])=[CH:18][C:17]=1[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:27]=1)(=[O:25])=[O:24]>C1COCC1>[C:1]([O:5][C:6](=[O:8])[NH:7][C:21](=[NH:22])[C:19]1[S:20][C:16]([S:15][CH3:14])=[C:17]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:27]=2)(=[O:25])=[O:24])[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C#N)cc1S(=O)(=O)c1cccc(N2CCCCC2)c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(N2CCCCC2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
To a solution of carbamic acid tert-butyl ester (8 mg, 0.069 mmol, Aldrich Chemical Company) in 1 mL of THF at −78° C. was added 35 uL of n-BuLi under Ar. The mixture was stirred at −78° C. for 15 min. A solution of 5-methylsulfanyl-4-(3-piperidin-1-yl-benzenesulfonyl)-thiophene-2-carbonitrile (20 mg, 0.053 mmol, Example 286: step g) in 1 mL of THF was added. The resulting mixture was stirred at RT for 5 h, then at 50° C. overnight. Cooled to RT, the mixture was purified directly by PTLC (20% EtOAc/hexane) to give 10 mg (38%) of product as colorless oil: 1H-NMR (CDCl3; 400 MHz) δ 8.42 (s, 1H), 7.74 (dd, 1H, J=1.6, 1.6 Hz), 7.67 (s, 1H), 7.62 (ddd, 1H, J=7.5, 1.6, 1.6 Hz), 7.57 (d, 1H, J=7.5, 1.6, 1.6 Hz), 7.52 (dd, 1H, J=7.5, 7.5), 3.42–3.40 (m, 4H), 2.54 (s, 3H), 1.64 (br s, 6H), 1.61 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C22H29N3O4S3, 496.1 (M+H), found 495.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[NH:13][C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[NH:13][C:14](=[O:29])[C:15]1[CH:16]=[C:17]([C:25]([F:27])([F:28])[F:26])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-nitro-benzoic acid methyl ester (1.85 g, 4.24 mmol) in ethyl acetate (250 mL) in a Parr flask was added 10% palladium on carbon (0.20 g). The flask was attached to a Parr shaker and purged with nitrogen gas. The flask was then charged to 50 psi with hydrogen gas and the shaker was activated. After 2 hours the apparatus was recharged to 50 psi with hydrogen gas and the mixture was allowed to agitate. After an additional 2 hours the apparatus was recharged to 50 psi with hydrogen gas and the mixture was allowed to agitate for 4 additional hours (8 hours total time). The mixture was removed from the apparatus and filtered through a plug of Celite. The Celite was rinsed with ethyl acetate until no more color came through and the filtrate was concentrated under reduced pressure. The crude material was dissolved in ethyl acetate, dried over MgSO4, filtered and concentrated under reduced pressure to give 4-amino-2-(3,5-bis-trifluoromethyl-benzoylamino)-benzoic acid methyl ester (1.70 g, 99%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6); δ 13.52 (s, 1H), 8.49 (s, 2H), 8.44 (s, 1H), 7.83 (d, 1H), 7.73 (d, 1H), 6.40-6.36 (m, 2H), 6.37 (s, 2H), 6.36 (dd, 1H), 3.80 (s, 3H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[Si:24]([O:31][CH2:32][C:33]1[NH:34][CH:35]=[CH:36][N:37]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:34]1[CH:35]=[CH:36][N:37]=[C:33]1[CH2:32][O:31][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Reactant: CC(C)(C)[Si](C)(C)OCc1ncc[nH]1
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1CO[Si](C)(C)C(C)(C)C
Yield: 91.2 %

Procedure:
(2R,4R)-1-Allyloxycarbonyl-4-methylsulfonyloxy-2-(2-methylsulfonyloxyethyl) pyrrolidine (28.8 g) and 2-(t-butyldimethylsilyloxymethyl)imidazole (18.1 g) were reacted in substantially the same manner as that of Preparation 10-3) to give (2R,4R)-1-allyloxycarbonyl-2-[2-(2-(t-butyldimethylsilyloxymethyl) imidazol-1-yl)ethyl]-4-methylsulfonyloxypyrrolidine (34.5 g) as a yellow paste.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15](=[S:18])[NH:16][NH2:17])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][CH2:24][C:25](Cl)=O>>[C:1]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:18][C:25]([CH2:24][Cl:23])=[N:17][N:16]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1NC(=S)NN
Reactant: O=C(Cl)CCl
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nnc(CCl)s1

Procedure:
Example 473a was synthetized following the procedure for Example 1 using 4-(2-(2-tert-butylphenoxy)pyridin-3-yl)thiosemicarbazide (Example 1b) with chloroacetyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]([N:14]1[CH2:18][CH2:17][CH:16]2[N:19]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:20][CH:21]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH:15]12)=[O:13])[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH:9]([CH3:11])[CH3:10])[C:12]([N:14]1[CH2:18][CH2:17][CH:16]2[N:19]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:20][CH:21]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH:15]12)=[O:13]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
To a solution containing 72 (210 mg, 0.40 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. After 90 min, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 148 mg (87%) of 73 which was used without further purification. Mass spectrum, m/z [423] (M+H)+.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23](=[O:28])(=[O:27])[N:24]([CH3:26])[CH3:25])[CH:17]=3)=[CH:12][S:11]2)=[CH:5][C:4]=1C.[CH2:30](N(CC)CC)C>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[N:14]([CH3:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([S:23](=[O:28])(=[O:27])[N:24]([CH3:25])[CH3:26])[CH:17]=3)=[CH:12][S:11]2)=[C:5]([CH3:30])[CH:4]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)ccc1Cl
Agent: Br
Product: Cc1cc(Cl)ccc1N=c1scc(-c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)n1C

Procedure:
Obtained by a procedure analogous to that indicated in Example 2 (a), from 2-(4-chloro-3-methylphenyl-imino)-4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-4-thiazoline hydrobromide and triethylamine. Melting point 137°-141° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.Cl[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][N:15]=1.CCOC(C)=O>C1COCC1.CCOCC.[Cl-].[Zn+2].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]=2)[CH:19]=1
Reactant: Cc1csc(Br)n1
Reactant: Fc1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1csc(-c2cc(F)ccn2)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 24.4 %

Procedure:
To a dry 10 mL Schlenk flask equipped with a stir bar and placed under N2 atmosphere was added 2-bromo-4-methylthiazole (244 mg, 1.37 mmol) in THF (5 mL). The flask was cooled to −78° C. To the solution was added n-butyllithium in hexanes (0.55 mL, 1.37 mmol). The solution was stirred for 5 minutes. To the solution was added zinc(II) chloride in THF (2.74 mL, 1.37 mmol). A thick ppt. immediately formed which hindered stirring. The flask was immediately transfered to a r.t. water bath and the solution was allowed to warm to r.t. with stirring for 30 min. To the solution was added 2-chloro-4-fluoropyridine (150 mg, 1.14 mmol), then Pd(dppf)Cl2 (42 mg, 0.057 mmol). The vial was placed in a 60° C. heating block with stirring (t=0). The reaction mixture was transfered to a 125 mL separatory funnel and was diluted with Et2O:EtOAc (25 mL:25 mL). The solution was washed with water:brine (25 mL:25 mL). The aq. phase was extracted with EtOAc (25 mL). The combined organics were washed with brine (25 mL); dried over MgSO4; filtered; then concentrated in vacuo. The residue was subjected to silica gel chromatography to afford 2-(4-fluoropyridin-2-yl)-4-methylthiazole as an orange solid (54 mg, 24%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].OS(O)(=O)=O.O>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:17])[C:12](=[CH:15][CH:16]=1)[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the benzaldehyde G3a (127.5 g, 0.52 mol) in MeOH (1 L) at 0 ° C., NaBH4 (16 g, 0.42 mol) was added. The reaction mixture was stirred for 18 h at rt. Reaction progress was monitored by TLC. Upon completion, the reaction mixture was reduced to one-fourth volume and was treated with 0.5 N aq H2SO4 to adjust pH to about 6-7 followed by addition of H2O (1 L). Upon vigorous stirring white precipitate formed. After filtration, the precipitate was lyophilized, washed using chilled toluene (ca. −50° C.) and dried under vacuum to obtain G3 (89 g, 0.38 mol, 73%) as an off-white solid: mp 86-88° C. (Lit.8 88-90° C.); 1H NMR (DMSO, 400 MHz) δ 9.33 (1H, s), 7.35 (5H, m,) 7.08 (1H, d, J=8.4 Hz), 6.42 (2H, m), 5.01 (2H, s), 4.80 (1H, m), 4.39 (2H, s).
Reaction SMILES: [C:1]([CH:3]([C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2[C:11]([CH3:18])([CH3:17])[CH2:10][CH2:9][C:8]([CH3:20])([CH3:19])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[OH:21][C:22]1[CH:31]=[C:30](I)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>>[OH:21][C:22]1[CH:31]=[C:30]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[C:14]([O:15][CH3:16])=[CH:13][C:12]3[C:11]([CH3:18])([CH3:17])[CH2:10][CH2:9][C:8]([CH3:20])([CH3:19])[C:7]=3[CH:6]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CC(O)c1cc2c(cc1OC)C(C)(C)CCC2(C)C
Product: COC(=O)c1ccc(C#CC(O)c2cc3c(cc2OC)C(C)(C)CCC3(C)C)cc1O
Yield: 76.6 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.15 g (4.2 mmol) of α-ethynyl-3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.21 g (4.64 mmol) of methyl 2-hydroxy-4-iodobenzoate, 1.36 g (76%) of the expected product, with a melting point of 125°-126° C., were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[CH2:13][C:14]#[N:15].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[C:24](O)(=[O:28])[CH2:25][CH:26]=[CH2:27].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CCOCC.C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[CH2:13][CH2:14][NH:15][C:24](=[O:28])[CH2:25][CH:26]=[CH2:27]
Reactant: C=CCC(=O)O
Reactant: COc1ccc2c(c1)C(CC#N)CCO2
Agent: On1nnc2ccccc21
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: C=CCC(=O)NCCC1CCOc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an anhydrous medium, the nitrile obtained in Step E of Example 12 (740 mg; 3.64 mmol) is solubilised in 30 ml of ether; LiAlH4 (1.5 eq; 5.46 mmol; 207 mg) is then added in portions. The mixture is heated at reflux for 3 hours, under argon. After returning to ambient temperature, 210 μl of water, 210 μl of a 15% solution of NaOH, and then 620 μl of water are added in succession. The solution is stirred for 30 minutes at ambient temperature. The salts are filtered off on a frit; the filtrate is dried over MgSO4 and evaporated under reduced pressure. The yellow oil obtained is used immediately in the following Step: in an anhydrous medium, at −10° C., 3-butenoic acid (1.5 eq; 5.43 mmol; 467 mg) and HOBT (1.5 eq; 5.43 mmol; 733 mg). The mixture is stirred, under argon, at −10° C. for 30 minutes. In parallel, the amine is dissolved in 10 ml of distilled CH2Cl2 and placed in the presence of triethylamine (1 eq; 3.62 mmol; 504 μl). The “activated” 3-butenoic acid is then added to the solution of free amine. The reaction medium is left for 2 hours at −10° C., and then for 60 hours at ambient temperature. The mixture is then washed in succession with 1N HCl, with water, with 1N NaOH and with water and dried over MgSO4; the solvent is evaporated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (eluant: PE/AcOEt (3/7)). The product is obtained in the form of white crystals after washing with ether.