Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:19](Cl)=[O:20])=[CH:4][CH:3]=1.Cl.[CH3:23][NH:24][O:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:26][O:25][N:24]([CH3:23])[C:19]([C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1)=[O:20]
Reactant: CNOC
Reactant: CSc1ncc2cc(C(=O)Cl)n(-c3ccc(F)cc3)c2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1cc2cnc(SC)nc2n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(4-fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonyl chloride, 25, (1.02 g, 3.15 mmol) in CH2Cl2 (20 mL) is added N,O-dimethylhydroxylamine hydrochloride salt (0.37 g, 3.80 mmol) and triethylamine (1.32 mL, 9.50 mmol). The mixture is allowed to stir at room temperature for 16 hours. The reaction is diluted with H2O and extracted three times with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (5% to 40% EtOAc/hexanes) to afford 660 mg of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.44 (dd, J=8.4, 5.9 Hz, 2H), 7.22 (dd, J=8.4, 5.9 Hz, 2H), 7.10 (s, 1H), 3.62 (s, 3H), 3.26 (s, 3H), 2.54 (s, 3H); ESI+ MS: m/z (rel intensity) 347.0 (100, M++H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O)=O.[CH:8]([C:10](=[N+:16]=[N-:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O>CO>[OH:2][CH2:1][CH2:3][N:4]1[CH:8]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:16]=[N:17]1
Reactant: NCCO
Reactant: CCOC(=O)C(C=O)=[N+]=[N-]
Solvent: CO
Solvent: O=CO
Product: CCOC(=O)c1cn(CCO)nn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
A solution of ethanolamine (60 ml, 1 mole) in methanol (320 ml) at 5° was treated with formic acid until a pH of 5 was obtained. A solution of ethyl α-formyldiazoacetate (crude, approximately 0.3 mole) in methanol (320 ml) was then added and the mixture stirred at room temperature for two days. The mixture was then evaporated, chloroform (1 liter), then water (200 ml) was added and the mixture was treated with sodium bicarbonate until a pH of 7 was reached. The phases were separated and the aqueous phase saturated with sodium chloride and extracted with chloroform (6×300 ml). The combined organic phases were dried (MgSO4), filtered and evaporated. The residue was then dissolved in toluene (approximately 100 ml). The resulting crystalline solid was filtered, washed with ether and dried to provide the title compound (41.6 g) as a solid; υmax (nujol) 3320, 3140, 1725 cm-1 ; δ (CDCl3), 1.38 (3H, t, J 7.5 Hz), 4.00-4.80 (7H, m, becomes 6H, m on D2O exch), 8.40 (1H, s). This material was pure enough for further synthetic progression.
Reaction SMILES: [F:1][C:2]1[C:13]([C:14]([OH:16])=O)=[CH:12][C:5]2[N:6]([CH3:11])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.CN1C2C=CC(C(Cl)=O)=CC=2OC1=O.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[C:34]([Cl:40])[CH:33]=1>[Zn].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>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:14]([C:13]2[C:2]([F:1])=[CH:3][C:4]3[O:9][CH2:8][C:7](=[O:10])[N:6]([CH3:11])[C:5]=3[CH:12]=2)=[O:16])=[C:34]([Cl:40])[CH:33]=1
Reactant: CN1C(=O)COc2cc(F)c(C(=O)O)cc21
Reactant: Clc1cc(Br)ccc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cn1c(=O)oc2cc(C(=O)Cl)ccc21
Agent: [Zn]
Product: CN1C(=O)COc2cc(F)c(C(=O)Cc3ccc(Br)cc3Cl)cc21

Procedure:
In analogy to Example 49, step 1, 7-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid was converted to the acid chloride and subsequently reacted with 4-bromo-1-bromomethyl-2-chloro-benzene in the presence of zinc and tetrakis(triphenylphosphine)palladium(0) to give the title compound as an off-white solid. MS (m/e)=412.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[C@@H:21]([OH:36])[C@@H:22]([NH:32][C:33](=[O:35])[CH3:34])[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C:38]1C=CC(S([O-])(=O)=O)=C[CH:39]=1.C1C=C[NH+]=CC=1.COC(C)C>ClCCl.CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][C@@H:9]1[C@H:21]1[O:36][C:38]([CH3:39])([CH3:37])[N:32]([C:33](=[O:35])[CH3:34])[C@H:22]1[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: COC(C)C
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)OC1(C)C
Yield: 734.4 %

Procedure:
Dissolve (2R,4R)-2-[(1S,2S)-2-Acetylamino-3-(3,5-difluoro-phenyl)-1-hydroxy-propyl]-4-benzyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.150 g, 0.3 mmol) in 1:1 dichloromethane/acetone (5 mL). Add PPTS (pyridine/p-toluene sulfonic acid) (0.03 mmol) and 2-methoxypropane (1.5 mmol). When the reaction is complete by TLC (15 minutes), concentrate the reaction mixture under reduced pressure. Dissolve the residue in ethyl acetate and wash with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. Dry over magnesium sulfate, concentrate under reduced pressure, and subject the residue to silica gel chromatography, eluting with ethyl acetate/hexane to provide the desired compound (0.120 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[Br:17]Br.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C(O)(=O)C>[Br:17][C:9]1[S:8][C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ncc2c(-c3ccccc3)csc2n1
Reactant: BrBr
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CC(=O)O
Product: Clc1ncc2c(-c3ccccc3)c(Br)sc2n1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
2-Chloro-5-phenyl-thieno[2,3-d]pyrimidine (0.5 g, 2.03 mmol) was stirred in acetic acid (10 mL). Bromine (0.65 g, 0.21 mL, 4.06 mmol) was added dropwise and the reaction allowed to stir at room temperature over the weekend. The reaction mixture was poured into saturated aqueous ascorbic acid solution. The resulting solid was filtered off and dried in vacuo at 40° C. to afford 6-bromo-2-chloro-5-phenyl-thieno[2,3-d]pyrimidine (567 mg).
Reaction SMILES: C(N[C:6]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])(=[O:11])=[O:10])=[O:7])CCC.C(Cl)(Cl)=O>>[CH3:23][CH:21]([S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([N:8]=[C:6]=[O:7])(=[O:10])=[O:11])(=[O:20])=[O:19])[CH3:22]
Reactant: CCCCNC(=O)NS(=O)(=O)c1ccccc1S(=O)(=O)C(C)C
Agent: O=C(Cl)Cl
Product: CC(C)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Temperature: 25 °C

Procedure:
A solution of N-[butylaminocarbonyl]-2-[(1-methylethyl)sulfonyl]benzenesulfonamide (17.4 g, 0.048 mol) and 1.4-diaza[2,2,2]bicyclooctane (0.1 g) in mixed xylenes (90 ml) was heated to 135°-140°. Liquid phosgene (3.6 ml, 0.050 mol) was added at a rate to maintain an internal temperature between 125°-135°. When the addition was complete, the solution was refluxed for 2 hours, cooled to room temperature and then filtered under a nitrogen atmosphere. Removal of solvent in vacuo gave 2-[(1-methylethyl)sulfonyl]benzenesulfonyl isocyanate, which was used immediately without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH2:35][CH2:36][CH3:37]>>[CH2:34]([N:38]1[CH2:43][CH2:42][N:41]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:40][CH2:39]1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 21 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.1 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:36]1([C:42]2[NH:46][C:45]3[CH:47]=[CH:48][CH:49]=[CH:50][C:44]=3[N:43]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1C2C(=CC=C3C=2N=NC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cu](I)I>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[C:5]1[C:4]2[C:13]([C:12]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[C:11]3[C:6]=1[CH:7]=[C:8]([N:46]1[C:45]4[CH:47]=[CH:48][CH:49]=[CH:50][C:44]=4[N:43]=[C:42]1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH:9]=[CH:10]3)=[CH:14][CH:15]=[CH:2][CH:3]=2
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: Brc1ccc2c(-c3ccc4ccccc4c3)c3ccccc3c(-c3ccc4ccccc4c3)c2c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3ccccc3n2-c2ccc3c(-c4ccc5ccccc5c4)c4ccccc4c(-c4ccc5ccccc5c4)c3c2)cc1
Yield: 35.3 %

Procedure:
5.1 g (10 mmol) of 2-bromo-9,10-di(2-naphthyl)anthracene, 2.3 g (12 mmol) of 2-phenyl-1H-benzimidazole, 0.19 g (11.0 mmol) of copper iodide, and 3.6 g (2.0 mmol) of 9,10-phenanthroline were dissolved into a 2 M solution of cesium carbonate in dimethylformamide (DMF), and the whole was refluxed under heating for 48 hours in an argon atmosphere. After the completion of the reaction, the resultant was filtered. The filtrate was poured into 1 L of 10-mass % hydrochloric acid, and the whole was extracted with methylene chloride. An organic layer was taken out and dried with magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resultant solid was purified by means of silica gel column chromatography to obtain 2.2 g of a pale yellow solid (35% yield). Mass spectral analysis confirmed that the solid was a target product. The solid had an m/e of 622 with respect to a molecular weight of 622.24.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.S(=O)(=O)(O)O.[CH3:28]O>>[F:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)=[CH:4][CH:5]=[C:6]([CH:8]([CH3:12])[C:9]([O:11][CH3:28])=[O:10])[CH:7]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc(-c2ccc(C(F)(F)F)cc2)c(F)c1
Yield: 95 %

Procedure:
A solution of 2-(2-fluoro-4′-trifluoromethylbiphenyl-4-yl)propionic acid (0.2 g, 0.64 mmoles) in methanol (3 ml) is added with 98% sulfuric acid (0.5 g) and refluxed for 2.5 hours. The solvent is removed under vacuum, the residue is taken up with ethyl acetate (5 ml) and washed with a 5% NaHCO3 solution (5 ml), then with water. The solution is dried over Na2SO4 and concentrated under vacuum to afford an oil (0.2 g, 95%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CCOCC.Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1)[CH3:2]
Reactant: CC[Mg]Br
Reactant: Brc1ccc(Br)nc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of ethylmagnesium bromide in ether (100 ml, 3M, 0.3 mol) was added dropwise to a cold (5° C.) solution of anhydrous zinc chloride (40.9 g, 0.3 mol) in THF (500 ml) under nitrogen. After stirring for one hour at 0° C., tetrakis(triphenylphosphine)-palladium (0) (1.0 g, 0.87 mmol) was added followed by a solution of 2,5-dibromopyridine (50 g, 0.21 mol) in THF (200 ml). The resulting yellow suspension was stirred at room temperature overnight, quenched by the addition of water (200 ml) and then evaporated in vacuo. The residue was treated with a suspension of ethylenediaminetetraacetic acid (200 g) in water (1000 ml) and dichloromethane (500 ml). The organic layer was separated and the aqueous layer again extracted with dichloromethane (500 ml). The combined extracts were dried (MgSO4), solvent evaporated in vacuo, and the residue distilled (123-124° C., 60 mmHg) to give the required product as a colourless oil (28.8 g, 76%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].[NH2:10][C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][SH:13].O>C(O)C>[CH3:2][C:1]1([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][S:13]1
Reactant: CC(=O)c1cccnc1
Reactant: N[C@@H](CS)C(=O)O
Solvent: CCO
Solvent: O
Product: CC1(c2cccnc2)NC(C(=O)O)CS1
Yield: 37.8 %

Procedure:
A mixture of 3.63 g of 3-acetylpyridine, 3.63 g of L-cysteine, 25 ml of water and 25 ml of ethanol was refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure, isopropanol was added to the residue, and the resultant powder was collected by filtration. Ethanol was added to the powder, the insoluble matter was filtered off, and the filtrate was concentrated to dryness. The residue was dissolved in water and adjusted to pH 6 by addition of diluted hydrochloric acid under ice colling and stirring, and the resultant powder was collected by filtration, washed with ethanol and dried to give 2.54 g of 2-methyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([C:14](OC)=[O:15])[C:11]([CH:18]([CH3:20])[CH3:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH:18]([CH3:20])[CH3:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cn(-c2cccc(OC)c2)nc1C(C)C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc(-n2cc(C=O)c(C(C)C)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A solution (15 mL) of methyl 1-(3-methoxyphenyl)-3-(propan-2-yl)-1H-pyrazole-4-carboxylate (3.4 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (35 mL) of lithium aluminum hydride (0.48 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr, ice-cooled again, and water (1.25 mL), 1N aqueous sodium hydroxide solution (6.3 mL), water (1.25 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (2.7 g) of 1-(3-methoxyphenyl)-3-(propan-2-yl)-1H-pyrazole-4-methanol as a pale-yellow oil. This was dissolved in toluene (50 mL), manganese dioxide (3.0 g) was added, and the mixture was heated under reflux with a Dean-Stark trap for 1 hr. The reaction mixture was allowed to cool to room temperature, and manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title object compound (2.6 g, 84%) as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(C2CNc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N1CC(c2ccccc2)c2ccccc21
Reaction time: 0.17 h

Procedure:
1.0 G of 3-phenylindoline was dissolved in 10 ml of acetic anhydride at room temperature. After 10 minutes, the reaction mixture was poured into 100 ml of water, slightly basified with aqueous sodium hydroxide and extracted with methylene chloride. After removal of the methylenechloride, the residue was recrystallized from cyclohexane to give 1.15 g of the desired N-acetyl-3-phenylindoline which was found to have a 106°-7° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[C:4]=2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:25]=[C:24]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])[CH:23]=[C:22]([Cl:32])[C:18]=1[C:19](O)=[O:20]>>[Cl:16][C:17]1[CH:25]=[C:24]([CH:23]=[C:22]([Cl:32])[C:18]=1[C:19]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[C:4]=2[CH:3]=[CH:2]1)=[O:20])[C:26]([NH:27][CH:28]([CH3:30])[CH3:29])=[O:31]
Reactant: CC(C)NC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: O=C(Nc1nccc2[nH]ccc12)C1CC1
Product: CC(C)NC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1

Procedure:
3,5-Dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)-N-(propan-2-yl)benzamide (Compound No. 106) was prepared using N-(1H-pyrrolo[3,2-c]pyridin-4-yl)cyclopropane carboxamide and 2,6-dichloro-4-[(propan-2-yl)carbamoyl]benzoic acid.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH:4]1([Zr+3:9])[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH3:10][Sn:11]([C:14]1[CH:15]([Sn](C)(C)C)[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:1].[CH3:10][Sn:11]([C:14]1[CH:15]([Zr+2:9][CH:4]2[CH:8]=[CH:7][CH:6]=[CH:5]2)[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:13])[CH3:12]
Reactant: [Zr+3]C1C=CC=C1
Reactant: C[Sn](C)(C)C1=Cc2ccccc2C1[Sn](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C[Sn](C)(C)C1=Cc2ccccc2C1[Zr+2]C1C=CC=C1
Yield: 177.1 %

Procedure:
Cyclopentadienylzirconium trichloride (CpZrCl3, 3.94 g, 15.0 mmol) which was slurrified by adding toluene of 70 ml was added into the mixed solution including bis(trimethylstannyl)indene (6.75 g, 15.28 mmol) and toluene of 100 ml, and then reacted for 21 hours at 85° C. Yellowish (trimethylstannyl-indenyl)(cyclopentadienyl)zirconium dichloride compound (6.71 g, yield: 86%) was obtained by a series of processes, such as removing toluene from reactant, slurrifying the obtained solid by adding hexane (100 ml) and filtering the slurry.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Solvent: ClCCl
Product: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2NC(=S)N2CCN(C)CC2)CC1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a stirred solution of 90 g of 2-tert-butyl-6-isothiocyanato-5-(4-methylpiperidin-1-yl)benzothiazole in 900 ml of methylene chloride is added dropwise 26 g of N-methylpiperazine. The solution is stirred for 1 hour, washed with water, dried over anhydrous sodium sulphate and evaporated to give 110 g of 2-tert-butyl-6-[(4-methylpiperazin-1-yl)thiocarbonylamino]-5-(4-methylpiperidin-1-yl)benzothiazole, melting at 192°-195° C.
Reaction SMILES: CN1CCOCC1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2([C:21]([OH:23])=O)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1.Cl.Cl.[F:26][C:27]1[C:32]2[C:33](=[O:40])[O:34][C:35]3([CH2:39][CH2:38][NH:37][CH2:36]3)[C:31]=2[CH:30]=[CH:29][N:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN(C)C=O>>[F:26][C:27]1[C:32]2[C:33](=[O:40])[O:34][C:35]3([CH2:39][CH2:38][N:37]([C:21]([C:18]4([C:11]5[C:12]6[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=6)[N:8]=[CH:9][CH:10]=5)[CH2:19][CH2:20]4)=[O:23])[CH2:36]3)[C:31]=2[CH:30]=[CH:29][N:28]=1
Reactant: O=C1OC2(CCNC2)c2ccnc(F)c21
Reactant: O=C(O)C1(c2ccnc3ccccc23)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C1OC2(CCN(C(=O)C3(c4ccnc5ccccc45)CC3)C2)c2ccnc(F)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl in dioxane (4.0 M, 1 mL) was added to tert-butyl 4-fluoro-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidine]-1′-carboxylate (25.8 mg, 0.0000837 mol). The reaction mixture was stirred at room temperature for 30 minutes before the volatiles was removed to afford the free amine (hydrochloric acid salt), which was subsequently used in the coupling reaction. 4-Methylmorpholine (50 μL, 0.0004 mol) was added to a mixture of 1-quinolin-4-ylcyclopropanecarboxylic acid (17.8 mg, 0.0000837 mol), 4-fluoro-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride (23.5 mg, 0.0000837 mol), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (45.7 mg, 0.0000879 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol). The reaction mixture was stirred at room temperature for 2 hours. The crude product was purified by prep-LCMS. LC/MS: 402.1 (M+H+).
Reaction SMILES: O[C:2]1([C:14]([CH:15](O)[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=[CH:11][CH2:10]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:36]([O-:40])(=[O:39])(=[O:38])=[O:37].[Na+]>C1C=CC=CC=1>[Cl:36]([O-:40])(=[O:39])(=[O:38])=[O:37].[CH2:16]([C:15]1[N+:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=12)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC(O)C1=CC=CCC1(O)Cc1ccccn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: c1ccccc1
Product: CCCCc1c2ccccc2cc2cccc[n+]12
Yield: 11 %

Procedure:
To a refluxing solution of 11.1 g (0.04 mol) of 2-[1-hydroxy-6'-(1-hydroxypentyl)-benzyl]pyridine in 250 mL of benzene was added 23.9 mL (0.14 mol) of triflic anhydride in 5 min, the mixture was heated for 65 min and then cooled. The reaction mixture was concentrated in vacuo, the residual oil was triturated in ether and decanted. The oil was chromatographed on silica (ethyl acetate/methylene chloride, 1:1 ) to afford an oil, which was treated with sodium perchlorate solution. The salt was triturated in hot water, decanted, and the residue crystallized on cooling. The above solid was crystallized (2×) from ethyl acetate/methylene chloride to afford 1.5 g (11%) of 6-butylbenzo[b]quinolizinium perchlorate (Formula II: R1 =R7 =H; R2 =n-butyl; X- =ClO4-), as a pale solid, m.p. 174°-177° C.