Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C(=O)CCC1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:28][CH2:29][CH3:30])=[C:24]([NH2:27])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:31]#[N:32])[CH:12]=[CH:13][C:14]=1[F:15].Cl.[CH3:34][N:35]([CH3:42])[CH2:36][CH:37]=[CH:38][C:39](Cl)=[O:40].C(=O)(O)[O-].[Na+]>CC#N.O>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:28][CH2:29][CH3:30])=[C:24]([NH:27][C:39](=[O:40])[CH:38]=[CH:37][CH2:36][N:35]([CH3:42])[CH3:34])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:31]#[N:32])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: CN(C)CC=CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC#N
Solvent: O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(C)C

Procedure:
A 3 L multi-neck flask equipped with agitator, thermometer, dip tube, and nitrogen protection is charged N-methyl pyrrolidinone (0.77 kg, 0.75 L, d=1.033 g/mL). At ambient temperature is added 4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline (0.0748 kg). The reaction mixture is heated to 40–45° C. and maintained for about (15 minutes). The reaction mixture is cooled to (0–10° C.) and the light suspension of 4-(dimethylamino)-2-butenoyl chloride hydrochloride in CH3CN added via dip tube and positive nitrogen pressure, over (30–45 minutes) while maintaining the temperature (0–10° C.) for at least (2 hours). Reaction completion is monitored by HPLC. The reaction is complete when there is ≦2% of the starting material (4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline) present. To a 12 L multi-neck flask equipped with agitator, thermometer, dip tube, and nitrogen protection is charged with water (2.61 kg, 2.61 L) and sodium bicarbonate (0.209 kg) with stirring until a solution is obtained followed by cooling to (20–24° C.) to which is transferred the reaction mixture above which contains ≦2% of the starting material (4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline), via dip tube and positive nitrogen pressure, to the 12 L flask over about (45–60 minutes) while maintaining the temperature at (20–24° C.). The temperature is maintained at (20–24° C.) for at least (1 hour). Filter the reaction mixture on a Buchner funnel, rinse with water (3×0.40 kg, 3×0.40 L), and maintain suction until dripping stops. Dry the product in a vacuum oven at about (50° C.) and about (10 mm Hg) for about (28–30 hours). The yield is 78.5 g (86%) at 79.7% strength and 12.3% total impurities.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[CH2:13][N:14]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[CH2:15][CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O1CCCC1>[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[CH2:13][N:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1)[CH2:15][CH3:16])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCN(Cc1ccccc1OCc1ccccc1)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1ccccc1OCc1ccccc1)c1ccc(C(=O)O)cc1

Procedure:
40% Aqueous sodium hydroxide (100 mL) was added to a solution of methyl 4-[N-(2-benzyloxybenzyl)-N-ethylamino]benzoate (44.0 g) in a mixture of methanol (200 mL) and tetrahydrofuran (100 mL) and the resulting mixture was heated under reflux for 6 hours. The reaction mixture was reduced to half its volume on a rotary evaporator and water (300 mL) was added. The mixture was acidified with acetic acid, the precipitate was filtered, washed three times with diethyl ether (50 mL each time) and dried in a vacuum oven at 60° C. to give 4-[N-(2-benzyloxybenzyl)-N-ethylamino]benzoic acid, melting point 165° C., yield 38.0 g (89%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[Cl:28][C:25]1[S:24][C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)=[CH:27][CH:26]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccc(Cl)s2)n1
Product: Clc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)s1
Yield: 68 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(5-chloro-2-thienyl)oxazole to give 2-(5-chloro-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 68%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 77-78° C.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH2:19][NH:20][S:21]([CH2:24][CH2:25][CH2:26]Cl)(=[O:23])=[O:22])[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[OH-].[K+]>CCO>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH2:19][N:20]5[CH2:26][CH2:25][CH2:24][S:21]5(=[O:23])=[O:22])[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(CCCCl)NCc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=S1(=O)CCCN1Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Yield: 70.2 %

Procedure:
A mixture of 3-chloropropane-1-sulfonic acid [2-(4-cyclopropylpiperazin-1-yl)benzothiazol-6-ylmethyl]amide (300 mg, 0.70 mmol) and potassium hydroxide (396 mg, 7.0 mmol) in EtOH (5 mL) was heated at reflux for 1 h. The volatiles were evaporated and the residue was extracted with CH2Cl2, washed with brine and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (elute: 5% CH2Cl2 in methanol) to give 2-(4-cyclopropylpiperazin-1-yl)-6-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzothiazole 193 mg (49%).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([O:14][CH3:15])=[N:6][CH:5]=1>Cl>[CH2:10]([C:8]1[C:7]([O:14][CH3:15])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([OH:16])=[O:2])[CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)c1cnc(OC)c(CC(C)C)c1
Agent: Cl
Product: COc1ncc(C(=O)O)cc1CC(C)C
Yield: 93.9 %

Procedure:
A solution of 5-isobutyl-6-methoxy-nicotinic acid methyl ester (260 mg, 1.17 mmol) in 25% aq. HCl (10 mL) is stirred at 60° C. for 6 h. The solvent is evaporated and the residue is dried under HV to give the title compound (230 mg) as a white solid; LC-MS: tR=0.95 min; [M+1]+=210.51; 1H NMR (D6-DMSO): δ 0.86 (d, J=6.5 Hz), 1.84-1.95 (m, 1H), 2.46 (d, J=7.0 Hz, 2H), 3.95 (s, 3H), 7.93 (d, J=2.3 Hz, 1H), 8.59 (d, J=2.3 Hz, 1H).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[C:11]([CH3:12])=[C:10]([C:13]#[N:14])[S:9][C:8]=1[NH2:15])=[O:6])C.[C:16](#[N:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[CH3:12][C:11]1[C:7]2[C:5](=[O:6])[NH:23][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][C:8]=2[S:9][C:10]=1[C:13]#[N:14]
Reactant: N#Cc1ccccc1
Reactant: CCOC(=O)c1c(N)sc(C#N)c1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C#N)sc2nc(-c3ccccc3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
A stream of dry hydrogen chloride was passed through a mixture of 2-amino-5-cyano-4-methylthiophene-3-carboxylic acid ethyl ester (0.003 mol) and benzonitrile (0.0045 mol) in 20 ml. of dioxane for 2 hours. Then, the reaction was stirred at room temperature for 12 hours, subsequently, the solvent was removed under reduced pressure and the residue was triturated with diethyl ether. A precipitate was obtained, filtered and dried to yield (92% yield) the title compound as a brown solid.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].C(O)CCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:5][CH2:6][CH2:1][CH3:7])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: Cc1ccccc1
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Product: CCCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 70 %

Procedure:
A toluene solution (1 L) containing pyruvic acid (440 g, 5.0 mol), n-butanol (371 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (40 mmHg, 93 to 100° C.) to give butyl pyruvate (505 g, yield: 70%).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]=[C:21]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:24]=[C:23]([C:36]([O:38][CH3:39])=[O:37])[CH2:22]1.CO.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C1C=CC=CC=1>[CH3:1][O:20][C:21]1[N:25]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=2)[N:24]=[C:23]([C:36]([O:38][CH3:39])=[O:37])[CH:22]=1
Reactant: COC(=O)C1=NN(c2ccc(C(F)(F)F)cc2)C(=O)C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1cc(OC)n(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A 500 mL round-bottomed flask was charged with triphenylphosphine (6.9 g, 26 mmol), methyl 5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylate 71 (5.0 g, 17 mmol), MeOH (0.88 mL, 22 mmol), and 200 mL of benzene. After cooling to 0° C., diisopropyl azodicarboxylate (DIAD) (5.2 mL, 26 mmol) was added dropwise. The mixture was stirred at room temperature for 18 h, then diluted with water and extracted with CH2Cl2. The combined extracts were dried and concentrated to give an oil that was purified by column chromatography on silica gel (5% to 40% EtOAc in hexanes) to give methyl 5-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate 72.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30]>>[O:30]=[C:25]1[NH:26][C:27](=[O:29])[C:28](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:10]=3)=[CH:7][CH:8]=2)[S:24]1
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(C=O)cc2)c1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 91.4 %

Procedure:
In a manner similar to that of Example 1(f) by reacting 7.4 g (24 mmol) of tert-butyl (4′-formyl-biphenyl-3-ylmethyl)carbamate (prepared as in Example 1(e) from tert-butyl (3-bromo benzyl)carbamate)with 2.8 g (24 mmol) of 2,4-thiazolidine dione, 9 g (95%) of the expected product are obtained.
Reaction SMILES: [CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:4]2[C:3]=1[CH3:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:35]1[CH2:39]OC[CH2:36]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[S:23][C:5]2=[N:6][C:7]([CH3:22])=[C:8]([CH:17]([CH2:36][CH2:35][CH3:39])[C:18]([O:20][CH3:21])=[O:19])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:4]2[C:3]=1[CH3:24]
Reactant: COC(=O)Cc1c(C)nc2sc(C)c(C)c2c1-c1ccc(C)cc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc(C)c(C)c2c1-c1ccc(C)cc1
Yield: 58.2 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(2,3,6-trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.113 g; 0.333 mmol), LHMDS 1N in THF (0.367 mL; 0.367 mmol), 1-iodopropane (0.049 mL; 0.502 mmol) in DMF (5 mL) for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-10%) in heptane furnished 0.074 g (58%) of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:15][C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O.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]>[CH3:15][C:16]1[N:17]=[C:18]([NH:21][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[S:19][CH:20]=1
Reactant: Clc1cc(Oc2ccccc2)ccn1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1csc(Nc2cc(Oc3ccccc3)ccn2)n1
Yield: 23.6 %

Procedure:
Using the method of Example 3, Step B, 2-chloro-4-phenoxypyridine (0.575 g, 2.79 mmol), 4-methylthiazol-2-amine (6.35 mL, 2.54 mmol), potassium phosphate (0.593 g, 2.79 mmol), Pd2(dba)3 (0.0582 g, 0.0635 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0404 g, 0.0699 mmol) in toluene (8 mL) and water (2 mL) afforded N-(4-methylthiazol-2-yl)-4-phenoxypyridin-2-amine (170 mg, 23% yield) as yellow solid. 1H NMR (CDCl3) δ 9.72 (bs, 1H), 8.17 (d, 1H), 7.41 (m, 2H), 7.25 (m, 1H), 7.08 (m, 2H), 6.48 (dd, 1H), 6.30 (s, 1H), 6.28 (d, 1H), 2.19 (d, 3H); Mass spectrum (esi) m/z=284 (100) (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][C:7]([C:8](O[C@H]2CC3C(=CC=CC=3)[C@@H]2NC2C(CC)=NC(C3C=CC(Cl)=CC=3Cl)=C(CC)N=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:41]([C:43]1[C:44]([NH:60][C@@H:61]2[CH2:65][O:64][CH2:63][C@H:62]2[OH:66])=[N:45][C:46]([CH2:58][CH3:59])=[C:47]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=2[CH3:57])[N:48]=1)[CH3:42]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:66][C@H:62]2[C@@H:61]([NH:60][C:44]3[C:43]([CH2:41][CH3:42])=[N:48][C:47]([C:49]4[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=4[CH3:57])=[C:46]([CH2:58][CH3:59])[N:45]=3)[CH2:65][O:64][CH2:63]2)=[O:9])=[CH:39][CH:40]=1)([O-:3])=[O:2]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1COC[C@H]1O
Product: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@H]1COC[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure for the preparation of (1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl 4-nitrobenzoate but substituting trans-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow semi-solid. MS (ESI+) for m/z 507.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]([SH:10])=[C:5]([NH:11][CH3:12])[N:4]=1)[CH3:2].Cl[CH2:14][C:15]([OH:17])=O.O.[OH-].[Na+].Cl>>[CH2:1]([C:3]1[NH:8][C:7](=[O:9])[C:6]2[S:10][CH2:14][C:15](=[O:17])[N:11]([CH3:12])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc(NC)c(S)c(=O)[nH]1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1nc2c(c(=O)[nH]1)SCC(=O)N2C
Yield: 77.2 %

Procedure:
2-Ethyl-5-mercapto-6-methylamino-3H-pyrimidin4-one (6.6g, 0.036 mole) from Example 112 and 3.37g (0.036 mole) of chloroacetic acid were added to approximately 120ml of water containing 4.27g (0.107 mole) of sodium hydroxide. The resultant solution was refluxed for approximately 4 hours, allowed to cool and acidified to about pH 2 with concentrated hydrochloric acid. The white solid was separated by filtration and dried (7.4g), then refluxed in approximately 100ml of acetic anhydride for about 2 hours and allowed to cool. The precipitate was removed by suction filtration, washed with diethyl ether and dried, providing 6.26g (78%) of 6,7 dihydro-2-ethyl-8-methyl-3H-pyrimido[5,4-b][1,4]thiazine-4,7-dione. The structural assignment was confirmed by infrared spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18]C)=[CH:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][S:7][C:6]=2[C:16]=1[Cl:17].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][S:7][C:6]=2[C:16]=1[Cl:17]
Reactant: COc1cc2c(-c3ccccc3)csc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cc2c(-c3ccccc3)csc2c(Cl)c1Cl
Yield: 84.7 %

Procedure:
A mixture of 1.6 mmoles of 6,7-dichloro-5-methoxy-3-phenylbenzo[b]thiophene and 5 g of pyridine hydrochloride is heated at 195° for 30 min. with stirring. The mixture is cooled and triturated with 50 ml of water. The solid material is collected on a filter, air dried and recrystallized from acetone-hexane to give 0.4 g of 6,7-dichloro-5-hydroxy-3-phenylbenzo[b]thiophene as white prisms, mp 157°-159°.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1([F:55])[C:53](=O)[NH:52][C:26]2([C:39]3[CH:38]=[C:37]([O:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=[CH:35][C:34]=3[O:33][C:32]3[C:27]2=[CH:28][C:29]([C:46]2[CH:47]=[N:48][CH:49]=[N:50][CH:51]=2)=[CH:30][CH:31]=3)[CH2:25]1>C1(C)C=CC=CC=1>[F:23][C:24]1([F:55])[C:53](=[S:10])[NH:52][C:26]2([C:39]3[CH:38]=[C:37]([O:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=[CH:35][C:34]=3[O:33][C:32]3[C:27]2=[CH:28][C:29]([C:46]2[CH:47]=[N:48][CH:49]=[N:50][CH:51]=2)=[CH:30][CH:31]=3)[CH2:25]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)COc1ccc2c(c1)C1(CC(F)(F)C(=O)N1)c1cc(-c3cncnc3)ccc1O2
Solvent: Cc1ccccc1
Product: CC(C)(C)COc1ccc2c(c1)C1(CC(F)(F)C(=S)N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 90 °C

Procedure:
Lawesson's reagent (6.72 mg, 0.017 mmol) was added to a solution of 4,4-difluoro-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)spiro[pyrrolidine-2,9′-xanthen]-5-one (0.015 g, 0.033 mmol) in toluene (0.665 mL) and the reaction was heated at 90° C. for 2.5 hours before being concentrated. The crude material was purified by dissolving in a minimal amount of CH2Cl2 and filtering through a pad of silica gel eluting with 1:4 EtOAc in hexane followed by 1:1 EtOAc in hexane, to provide 4,4-difluoro-2′-(neopentyloxy)-7′-(pyrimidin-5-yl)spiro[pyrrolidine-2,9′-xanthene]-5-thione. M=468.1 [M+H].
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[Li]CCCC.[C:13]([NH:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26](I)[CH:27]=2)[CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C1COCC1.C(Cl)Cl.[Cl-].[Zn+2].[Cl-].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>[C:16]([O:15][C:13]([NH:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:3]#[C:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:27]=2)[CH2:22]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(I)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
A mixture of ethyl propiolate (0.85 mL, 8.36 mmol) in THF (20 mL) was treated with a 2.5 M solution of n-BuLi in THF (3.3 mL, 8.3 mmol) at −78° C., stirred for 10 min, followed by addition of a 1.0 M solution of zinc chloride in THF (8.4 mL, 8.4 mmol). Warmed reaction to RT, added a solution of N-Boc-2-amino-5-iodo-2,3-dihydro-1H-indene (0.800 g, 2.22 mmol) in THF (1 mL) followed by Pd(PPh3)4 (0.30 g, 0.26 mmol). Warmed reaction mixture to 60° C., stirred for 2 hours, then cooled. Diluted with DCM, washed with 1 N HCl, water, dried (Na2SO4), conc. Chromatography on SiO2 (0-50% EtOAc/hexanes) gave the intermediate ethyl 3-{2-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl}prop-2-ynoate (392 mg, 54% yield): 1H NMR (600 MHz, CDCl3) δ 7.41 (s, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 4.71 (br s, 1H), 4.45 (br s, 1H), 4.27 (q, J=7.0 Hz, 2H), 3.23-3.28 (m, 2H), 2.75-2.81 (m, 2H), 1.42 (s, 9H), 1.33 (t, J=Hz, 3H); MS cal'd for C19H23NO4Na [M+Na]+352.2. found 352.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][C:12](N)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:22]([O:21][C:17](=[O:20])[CH:18]=[CH:19][C:12]1[CH:11]=[N:10][C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:16])=[CH:14][CH:13]=1)[CH3:23]
Reactant: C=CC(=O)OCC
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C=Cc1ccc(N(C)C(=O)OC(C)(C)C)nc1
Temperature: 110 °C

Procedure:
A mixture of 12-3 (6.0 g, 20.9 mmol), ethyl acrylate (6.3 mL, 62.7 mmol), triethylamine (17 mL, 125.5 mmol), tri-o-tolylphosphine (1.3 g, 6.2 mmol) and Pd(OAc)2 (0.5 g, 2.1 mmol) in 50 mL CH3CN was purged with argon for 5 min and subsequently refluxed at 110° C. for 20 hr. The mixture was cooled and concentrated. The residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:3) to afford the desired product 12-4 as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Li]CCCC.[Si:16](OS(C(F)(F)F)(=O)=O)([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Clc1ccnc2[nH]ccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (3.21 g, 21 mmol) in THF (60 mL), cooled at −78° C., is added slowly n-BuLi (1.6 M in hexane, 13.8 mL, 22 mmol). After stirring for 30 minutes, the TIPSOTf (5.77 mL, 21.4 mmol) is added. The mixture is allowed to rise to room temperature and quenched with water. The mixture is partitioned between hexanes (200 mL) and brine. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography (silica gel, eluting with hexanes) to afford the title compound: 1H NMR 600 MHz (Acetone-d6) δ 8.19 (d, 1H, J=5.4 Hz), 7.57 (d, 1H, J=3.0 Hz), 7.18 (d, 1H, J=5.4 Hz), 6.69 (d, 1H, J=3.0 Hz), 1.92 (sept, 3H, J=7.2 Hz), 1.12 (d, 18H, J=7.2 Hz); MS m/z 309.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1cccc([N+](=O)[O-])c1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
3.5 g (0.01 mol) of (Z)-3-[1-(3-nitrophenylamino)-1-phenyl-methylidene}-2-indolinone are dissolved in 200 ml of THF and after the addition of 0.5 g of palladium/charcoal hydrogenated with hydrogen. Then the catalyst is filtered off and concentrated by evaporation.