Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:25][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:30][CH:31]=1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([NH:25][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[C:15]([C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:31]=[CH:30][CH:29]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1
Reactant: Nc1cccc(NC(=O)c2ccccc2)c1
Product: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Nc4cccc(NC(=O)c5ccccc5)c4)c3c2c1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 267 using 296 (40 mg, 0.12 mmol) and N-(3-amino-phenyl)-benzamide to provide 301. LC-MS (M+H=521, obsd.=521).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)c2ccc(C)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.1 %

Procedure:
A mixture of 4-methyl-1-[(4-methylphenyl)sulfinyl]benzene (1.15 g, 5.00 mmol), N-bromosuccinimide (1.08 g, 6.00 mmol), 2,2′-azobis-(2-methylpropionitrile) (100 mg, 0.600 mmol), and CCl4 (25.0 mL) as solvent was stirred for 5 min at room temperature and then heated to reflux for 12 h. The reaction mixture was cooled to room temperature and filtered and the solvent was removed in vacuo, affording a crude product which was used in the next step without any further purification (1.21 g, 78.1% yield). 1H NMR (CDCl3) δ 7.71-7.57 (m, 2H), 7.57-7.40 (m, 4H), 7.36-7.16 (m, 2H), 4.46 (s, 2H), 2.37 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:5]=[C:6]([Cl:22])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15](OCC)[O:16]CC.C(O)(=O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:5]=[C:6]([Cl:22])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]=[O:16]
Reactant: CCOC(COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
Then, 1.81 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene was added to a mixture of 10 ml of acetic acid and 1 ml of concentrated hydrochloric acid with stirring under ice cooling, and the stirring was further continued for 15 minutes. The reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, saturated aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and concentrated, which afforded 1.51 g (yield, 94%) of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(O)C>[Cl:10][CH2:11][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: ClCc1csc(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
A solution of thiobenzamide (1.37 g, 10 mmol) and 1,3-dichloro-acetone (1.27 g, 10 mmol) in ethanol (25 mL) is warmed to 75° C. and stirred at this temperature for 1 h. The resulting solution is cooled, poured into ice then brought to pH 8 with K2CO3 solution (sat.). This mixture is extracted with ethyl acetate, dried over MgSO4 and concentrated to give the title compound. This product is used without further purification. MS (ESI) 210 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.[I:10]Cl>CN(C)C=O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=1[I:10]
Reactant: ClI
Reactant: Nc1cc(Br)c(Cl)cn1
Solvent: CN(C)C=O
Product: Nc1ncc(Cl)c(Br)c1I
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of Example 52A (3 g, 14.46 mmol) in N,N-dimethylformamide (60 mL) was heated to 40° C. and iodine chloride (2.82 g, 17.35 mmol) was added. After stirring at 40° C. for 3 hours, a second lot of iodine chloride (2.82 g, 17.35 mmol) was added and the mixture was stirred overnight at 40° C. The mixture was cooled to room temperature and quenched with ice cold water. The mixture was extracted with ethyl acetate (100 mL×2) and the organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 20% ethyl acetate in hexane) afforded the title compound. LCMS: 334.6 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH2:12][C:7]2[C:8]3[C:3](=[C:2]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:11]=[CH:10][CH:9]=3)[CH:4]=[CH:5][CH:6]=2)=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: COc1ccc(NC(=O)Cc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Reactant: OB(O)c1ccccc1
Product: COc1ccc(NC(=O)Cc2cccc3c(-c4ccccc4)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 5-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-ylacetamide (E20) and phenylboronic acid using a similar procedure to Example 4 (39%).
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:24][CH:25]1[O:30][CH:29]([CH3:31])[CH2:28][NH:27][CH2:26]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:27]3[CH2:26][CH:25]([CH3:24])[O:30][CH:29]([CH3:31])[CH2:28]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC1CNCC(C)O1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Solvent: CCCCO
Product: CC1CN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)CC(C)O1

Procedure:
Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 90 μL of 2,6-dimethylmorpholine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2,6-dimethylmorpholino)nicotinamide. MS (Q1) 423.4 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][CH:6]=[CH:5]2.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: COc1cc2ncccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4cccnc4cc3OC)c2cc1OC
Temperature: 155 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
6-Hydroxy-7-methoxyquinoline (65 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (148 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 155° C. overnight. The reaction solution was cooled to room temperature. Water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (134 mg, yield 100%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:10]([O:12][CH2:13][CH2:14]Br)[CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:10]([O:12][CH2:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])[CH3:11]
Reactant: OCc1ccccc1O
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1ccccc1CO
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of 2-hydroxybenzyl alcohol (2.00 g), 2-bromoethyl ethyl ether (2.7 ml), potassium carbonate (4.45 g) and DMF (20 ml) was stirred at 90° C. for 3 days. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to purification using column chromatography (ethyl acetate:hexane 1:2) to obtain 2-(2-ethoxyethoxy)benzyl alcohol (2.30 g) as a light yellow oily substance.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)C)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][NH:8][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: [H][H]
Reactant: CN(CCn1ccnc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNCCn1ccnc1

Procedure:
The title compound of Step 11 (5.70 g, 26.5 mmol) was reacted with Pd(OH)2 /C in methanol at 60° with 60 psi of hydrogen for 4 hours. Filtration through Celite gave the title compound as a clear, colorless oil (3.46 g). The proton spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][P:2]([CH2:14][C:15]([N:17]1[C@H:25]([C:26]([O:28]C)=[O:27])[CH2:24][C:19]2([S:23][CH2:22][CH2:21][S:20]2)[CH2:18]1)=[O:16])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:3].[OH-].[Na+]>>[OH:3][P:2]([CH2:14][C:15]([N:17]1[C@H:25]([C:26]([OH:28])=[O:27])[CH2:24][C:19]2([S:20][CH2:21][CH2:22][S:23]2)[CH2:18]1)=[O:16])([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:1]
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)CP(=O)(O)CCCCc1ccccc1)SCCS2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CC2(CN1C(=O)CP(=O)(O)CCCCc1ccccc1)SCCS2

Procedure:
(S)-7-[[Hydroxy(4-phenylbutyl)phosphinyl]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, methyl ester (2.99 g) and 1 N sodium hydroxide (15 ml) is stirred for 30 minutes at room temperature. The reaction mixture is extracted with ether (50 ml) and the aqueous phase is acidified with concentrated hydrochloric acid to pH 1.0. A solid precipitates out of solution along with an oil. This is extracted into ethyl acetate, passed through sodium sulfate, and the solvent is stripped yielding 2.74 of the title compound, melting point 105.5°-107° C.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[C:8]=2[F:15])[CH:6]=1.C([Mg]Cl)(C)C.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24].[NH4+].[Cl-]>C1COCC1>[CH2:30]([Sn:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[C:8]=2[F:15])[CH:6]=1)[CH2:31][CH2:32][CH3:33]
Reactant: Fc1cc(F)c(F)c(-n2cnc(I)c2)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(F)cc(F)c2F)cn1
Reaction time: 1.5 h

Procedure:
A solution of 4-iodo-1-(2,3,5-trifluorophenyl)-1H-imidazole (0.140 g, 0.43 mmol) in 2 mL of THF under Ar was chilled in an ice/water bath 5 min. Isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.225 mL, 0.45 mmol) was added, the bath was removed, and the pale yellow solution was stirred for 1.5 h. Tributyltin chloride (0.055 mL, 0.20 mmol) was added all at once, and the pale yellow solution was stirred 1 h. A sat. aq. NH4Cl solution (10 mL) was added, and the mixture was extracted with two 10 mL portions of EtOAc. The combined organic layers were washed with 10 mL of a sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated to give 4-tributylstannanyl-1-(2,3,5-trifluoro-phenyl)-1H-imidazole as a yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]3[CH2:24][O:23]C(C)(C)[O:21]3)[N:15]=2)=[O:12])[C:7](=[O:34])[CH:6]=1.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]([OH:21])[CH2:24][OH:23])[N:15]=2)=[O:12])[C:7](=[O:34])[CH:6]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)[C@H](CC3CCCCC3)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
A solution of ((S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-propionamide (prepared in Example 62, 201 mg, 0.37 mmol) in tetrahydrofuran (6 mL) was treated with 1N aqueous hydrochloric acid (3 mL). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with ethyl acetate (60 mL), washed with saturated sodium bicarbonate, a saturated sodium chloride solution and dried over magnesium sulfate. Upon concentration afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-((R)-2,3-dihydroxy-propyl)-1-H-pyrazol-3-yl]-propionamide (153 mg, 83%) as a white powder: HR-ES-MS m/z calculated for C25H31ClN4O5, [M+H]+ 503.2056 observed 503.2056; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81-1.02 (m, 2H), 1.02-1.29 (m, 4H), 1.52-1.83 (m, 7H), 3.18-3.32 (m, 2H), 3.70-3.93 (m, 2H), 4.09 (dd, J=13.6, 3.6 Hz, 1H), 4.19 (d, J=18.4 Hz, 1H), 4.59 (d, J=18.4 Hz, 1H), 4.71 (t, J=5.4 Hz, 1H), 4.80 (s, 1H), 4.85-4.92 (m, 1H), 4.94 (d, J=5.4 Hz, 1H), 6.40 (d, J=1.8 Hz, 1H), 7.37 (td, J=7.8, 1.5 Hz, 1H), 7.46 (t, J=7.2 Hz, 1H), 7.50-7.56 (m, 2H), 7.65 (d, J=7.8 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:12][OH:13].O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=[C:3]1[CH2:12][O:13][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1
Reactant: Cc1ccnc2c1nc(CO)n2C
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1nc(COc1ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc1)n2C

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.50 g of 3,7-dimethyl-2-hydroxymethylimidazo[5,4-b]pyridine (prepared as described in Preparation 40), 3.94 g of 5-(4-hydroxy-benzyl)-3-triphenylmethylthiazolidine-2,4-dione, 2.11 ml of tributylphosphine, 2.14 g of 1,1'-(azodicarbonyl)di-piperidine and 30 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 1:2 by volume as the eluent, to give 1.11 g of the title compound, melting at 92°-105° C. (softening).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:20]([CH3:21])=[N:19][NH:18][C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:20]([CH3:21])=[N:19][N:18]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][O:22]3)[C:7]=2[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)nc2[nH]nc(C)c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(O)cc2)nc2c1c(C)nn2C1CCCCO1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 6-(4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methyl ester (15 g), 3,4-dihydro-2H-pyran (24 mL) and p-toluenesulfonic acid monohydrate (3.0 g) in THF (400 mL) was stirred at r.t. until the reaction was complete. Water was added and the mixture was extracted with ethyl acetate, the combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed over a short path column (heptane/ethyl acetate gradient). The product containing fractions were combined, concentrated, and the resulting residue was triturated with ether to give 11 g (57%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].OO.[OH:28]S(O)(=O)=O>C(Cl)CCl.O>[CH:11]1[C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]([Cl:18])=[C:7]([N:6]2[N:5]=[C:4]([C:19]#[N:20])[C:3]([S+:21]([O-:28])[C:22]([F:25])([F:24])[F:23])=[C:2]2[NH2:1])[C:12]=1[Cl:13]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Agent: OO
Solvent: ClCCCl
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Temperature: 13.5 °C
Yield: 74.4 %

Procedure:
1.5 liter of ethylene dichloride & 421.0 gms of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluromethylphenyl)-4-trifluromethylthio pyrazole was charged in a reactor flask with overhead stirring & condenser system. This mass was then cooled to 12-15° C. and 68.0 gms of H2O2 (50.0% w/w) & 500.0 gms of H2SO4 (90.0% w/w) were simultaneously added over a period of 3.0 to 4.0 hours. The reaction temperature was then raised to 28-30° C. & maintained for about 2.0 hours. The reaction mass obtained thereafter was slowly added into 1700 ml of chilled water at 10-20° C. over a period of 2.0 hours. To this mass, 1500 ml of ethylene dichloride was added and the mixture was heated to 60° C. in order to separate the aqueous and organic layers. The obtained organic phase was washed with water & then with 5% NaHCO3 solution followed by water wash, till a neutral pH was obtained. The crude yield of fipronil after removal of solvent was 425.0 gms. The crude fipronil was crystallized from same solvent after partial evaporation to yield 325 gms of crystalline fipronil with 94.0% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[N:33]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[N:36][N:35]=[N:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:41]5[CH2:42][CH2:43][CH:38]([N:33]6[CH:37]=[N:36][N:35]=[N:34]6)[CH2:39][CH2:40]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:31])([F:30])[F:32])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: c1nnnn1C1CCNCC1
Product: O=C1N=C(N2CCC(n3cnnn3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-tetrazol-1-yl-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-tetrazol-1-yl-piperidine following General Procedure B.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9][C:4]21[O:8][CH2:7][CH2:6][O:5]2.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:21][S:22]([O:1][CH2:2][CH:3]1[CH2:11][CH:10]([CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9][C:4]21[O:5][CH2:6][CH2:7][O:8]2)(=[O:24])=[O:23]
Reactant: OCC1CC(CO)C2(C1)OCCO2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CC(COS(C)(=O)=O)C2(C1)OCCO2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
6,8-Bis(hydroxymethyl)-1,4-dioxaspiro[4.4]nonane (8.18 g, 43.5 mmol) was dissolved in dichloromethane (200 ml) and chilled to 0° C. To the chilled solution was added 4-dimethylaminopyridine (0.53 g, 4.4 mmol) and distilled triethylamine (18.2 ml, 131 mmol). Then methanesulfonyl chloride (7.41 ml, 11.0 g, 95.7 mmol) was added drop-wise via syringe over 10 min and the reaction was allowed to come to ambient temperature and stir for 18 h under nitrogen. The reaction was quenched with saturated sodium bicarbonate (25 ml) and stirred for 30 min. After stirring, the layers were separated and the aqueous phase extracted with dichloromethane (2×50 ml). The organics were combined, dried over sodium sulfate, filtered and concentrated to yield a reddish brown oil (14.9, 99.4%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][CH2:9][CH2:10][C:11]#[N:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:12][CH2:11][CH2:10][C:9]#[N:8]
Reactant: N#CCCN
Reactant: O=Cc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N#CCCNCc1cccs1

Procedure:
3-[(Thiophen-2-ylmethyl)-amino]-propionitrile was prepared following general procedure D using thiophene-2-carboxaldehyde (477 μL, 98%, 5 mmol), 3-amino-propionitrile (373 μL, 99%, 5 mmol), 1 M acetic acid solution in DCE (6 mL), DCE (9 mL) and sodium triacetoxyborohydride (1.31 g, 97%, 6 mmol). The crude product was used without further purification. LCMS m/z: 167 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([C:6]1([OH:21])[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1)([CH3:5])[CH:3]=[CH2:4]>CO.[Pd]>[CH3:5][C:2]([C:6]1([OH:21])[CH2:10][CH2:9][NH:8][CH2:7]1)([CH3:1])[CH2:3][CH3:4]
Reactant: C=CC(C)(C)C1(O)CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCC(C)(C)C1(O)CCNC1
Reaction time: 3 h

Procedure:
Benzyl 3-(1,1-dimethylprop-2-en-1-yl)-3-hydroxypyrrolidine-1-carboxylate (56 mg, 0.00019 mol) was dissolved in methanol and to this solution was added Pd/C (10% dry, 10 mg). The reaction vessel was purged with hydrogen and allowed to stir for 3 h with a hydrogen balloon. The catalyst was filtered off and the filtrate was concentrated in-vacuo to afford the desired product. LCMS (M+H)=158.