Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Cl.N1C=CC=CC=1.Cl[N:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]2[S:30][CH:31]([I:33])[CH:32]=[C:23]12.C(=O)(O)[O-].[Na+]>C(OCCO)C>[I:33][C:31]1[S:30][C:24]2[C:23](=[N:22][CH:27]=[C:26]([C:28]#[N:29])[C:25]=2[NH:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:32]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: N#CC1=CN(Cl)C2=CC(I)SC2=C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)cc(OC)c1OC
Yield: 85.7 %

Procedure:
A mixture of 3,4,5-trimethoxyaniline (964 mg, 5.26 mmol), pyridine hydrochloride (100 mg, 0.76 mmol) and 4-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (937 mg, 2.92 mmol) in 50 mL of 2-ethoxyethanol is heated at reflux overnight. The solution is poured into saturated aqueous sodium bicarbonate and the resulting solid is collected by filtration, washed with water and dried under reduced pressure. The resultant solid is purified by flash column chromatography eluting with 2% methanol in dichloromethane. The fractions containing product are combined and concentrated to provide 1.17 g of 2-iodo-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 254-256° C.; 1H NMR (DMSO-d6) δ 3.70-3.78 (m, 9H), 6.66 (s, 2H), 7.72 (s, 1H), 8.53 (s, 1H), 9.56 (s, 1H); MS 468.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[CH:24]=O)[CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])[N:6]=1.[NH2:29][CH2:30][C@@H:31]([C:40]1[CH:49]=[CH:48][C:47]([OH:50])=[C:46]2[C:41]=1[CH:42]=[CH:43][C:44](=[O:51])[NH:45]2)[O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Si:33]([O:32][C@H:31]([C:40]1[CH:49]=[CH:48][C:47]([OH:50])=[C:46]2[C:41]=1[CH:42]=[CH:43][C:44](=[O:51])[NH:45]2)[CH2:30][NH:29][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([CH2:20][N:17]2[CH2:16][CH2:15][C:13]3([O:12][CH2:11][CH2:10][N:9]([C:7]([C:5]4[N:6]=[C:2]([CH3:1])[S:3][CH:4]=4)=[O:8])[CH2:14]3)[CH2:19][CH2:18]2)[CH:22]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C=O)c4)CC3)C2)cs1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)CC3)C2)cs1
Temperature: 0 °C

Procedure:
A solution of 3-((4-(2-methylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)benzaldehyde (example 96, step a) (0.303 g), (R)-5-(2-amino-1-(tert-butyldimethylsilyloxy)ethyl)-8-hydroxyquinolin-2(1H)-one (WO2004106333) (0.330 g) and acetic acid (0.043 mL) in methanol (5 mL) was stirred at room temperature for 30 minutes, then cooled in an ice-water bath under nitrogen and treated with sodium triacetoxyborohydride (0.243 g) in one portion. The mixture was stirred in ice-water for 2 hours, then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution, the phases were separated, and the aqueous phase was extracted twice more with ethyl acetate. Any insoluble gummy residues were dissolved in methanol. The combined ethyl acetate phases were washed with brine, dried over magnesium sulphate and combined with the methanol solution. The whole was purified by flash chromatography on silica eluted with 1:7:92 triethylamine:methanol:dichloromethane to afford the slightly impure subtitled product as a yellow foam. Yield 0.324 g.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH2:8]([Li])CCC.[CH3:13][O:14][C:15](=[O:42])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH:36]([CH3:38])[CH3:37])=[C:27]([CH:39]=O)[C:26]=2[CH3:41])=[CH:19][CH:18]=1>O1CCCC1>[CH3:13][O:14][C:15](=[O:42])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]([CH3:32])([CH3:34])[CH3:33])[C:28]([O:35][CH:36]([CH3:38])[CH3:37])=[C:27]([C:39]#[CH:8])[C:26]=2[CH3:41])=[CH:21][CH:22]=1
Reactant: [Li]CCCC
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(C=O)c2C)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Product: C#Cc1c(C)c(C#Cc2ccc(CC(=O)OC)cc2)cc(C(C)(C)C)c1OC(C)C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 11.6 %

Procedure:
Anhydrous tetrahydrofuran (3 mL) was added to a 2M solution of trimethylsilyl diazomethane in hexanes (0.37 mL, 0.74 mmol) and the resulting reaction mixture was cooled to −78° C. A solution of 1.6M n-butyl lithium in hexanes (0.5 mL, 0.8 mmol) was added followed, after 30 minutes, by a solution of [4-(5-tert-butyl-3-formyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 144, 0.2 g, 0.49 mmol) in anhydrous tetrahydrofuran and the resulting reaction mixture was stirred at −78° C. for 1 h and at 0° C. for 40 minutes. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 2.5-4% ethyl acetate in hexane as the eluent followed by preparative normal phase HPLC using 5% ethyl acetate in hexane as the mobile phase to afford the title product as a colorless oil (0.023 g, 11.6%). 1H NMR (300 MHz, CDCl3): δ 7.49 (d, 2H, J=8.0 Hz), 7.44 (s, 1H), 7.26 (d, 2H, J=8.0 Hz), 5.76 (heptet, 1H, J=6.1 Hz), 3.70 (s, 3H), 3.64 (s, 2H), 3.58 (s, 1H), 2.58 (s, 3H), 1.39 (s, 9H), 1.31 (d, 6H, J=6.1 Hz).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[C:15]([OH:20])=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([O:31][CH3:32])=[O:30].[I-].[K+]>CN(C)C=O>[C:1]([NH:9][CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[C:15]([O:20][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCl
Reactant: O=C(NC1CCCc2c(O)cccc21)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1CCCC2NC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
50 mmol of 5-benzoylamino-1-hyroxy-5,6,7,8-tetrahydro-naphthalene and 100 ml of anhydrous potassium potassium carbonate are stirred at 50° C. in 100 ml of absolute dimethylformamide for 20 minutes. A solution of 60 mmol of methyl chloroacetate and 25 mmol of potassium iodide in 25 ml dimethylformamide is added dropwise and the mixture is stirred at 50° C. for 6 to 8 hours. It is filtered under the influence of heat, the residue is rinsed thoroughly with ethyl acetate and the filtrate is evaporated. The residue is stirred in a mixture of 10% strength NaOH and ethyl acetate or tetrahydrofuran for 10 minutes. The ethyl acetate phase is extracted by shaking once with 10% strength NaOH, dried over Na2SO4 and evaporated. The residue is recrystallized from ethyl acetate.
Reaction SMILES: [N:1]1[CH:6]=[N:5][CH:4]=[N:3][CH:2]=1.Cl.N([C:10]1[CH:11]=[C:12]([CH:17]=C[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])N.C(Cl)(Cl)Cl>C(O)C>[N:5]1([C:6]2[CH:17]=[C:12]([CH:11]=[CH:10][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:4]=[N:3][CH:2]=[N:1]1
Reactant: c1ncncn1
Reactant: COC(=O)c1cccc(NN)c1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(-n2cncn2)c1
Yield: 76.7 %

Procedure:
1.04 g of 1,3,5-triazine was added to a solution of 3.7 g of methyl 3-hydrazinobenzoate hydrochloride in 20 ml of ethanol. The mixture was refluxed by heating, for 3 hours. The reaction mixture was allowed to cool and mixed with chloroform. The resulting insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: methylene chloride/methanol=100/0 to 100/1) and then subjected to crystallization from diisopropyl ether. The crystals were collected by filtration to obtain 2.0 g of methyl 3-(1,2,4-triazol-1-yl)benzoate as colorless needle-like crystals.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1.C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[O:34]>ClCCl>[CH3:39][O:38][CH2:37][CH2:36][O:35][C:33]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1)=[O:34]
Reactant: N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Reactant: COCCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCCOC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Reaction time: 4 h
Yield: 78.1 %

Procedure:
(5R)-3-(4-((3R)-3-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (200 mg, 0.52 mM) was suspended by stirring in dichloromethane (10 ml) at 0° and sodium bicarbonate solution (5 ml) added. 2-Methoxyethyl chloroformate (340 mg, 2.46 mM) was added, and the mixture stirred 4 hours, allowing the temperature to rise to ambient. The organic layer was separated, washed with sodium dihydrogen phosphate (2%, 2×15 ml), water (15 ml) and dried (magnesium sulfate). Filtration and evaporation gave the desired product (183 mg).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[N:16][C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:14]2[OH:26].CCOCC>N1C=CC=CC=1>[OH:26][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[CH:12]=2)[N:17]=[N:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2ccc(NS(C)(=O)=O)cc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulphonic anhydride (1.392 g.) was added to a solution of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (0.932 g.) in dry pyridine (20 ml.), and the mixture was stirred at room temperature overnight. The resulting solution was poured into ether (500 ml.) and the amorphous solid which precipitated was filtered off and applied to a silica column (100 g. Kieselgel 60). Elution with a mixture of 15% v/v ethanol and 85% v/v chloroform, and evaporation of the appropriate fractions gave ethyl 4-hydroxy-6-(methanesulphonylamino)cinnolin-3-yl carboxylate, m.p. 274°-5° C.
Reaction SMILES: NC1C(OC)=CC=CC=1[C:4](OC)=[O:5].[CH:14]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][CH:23]([N:27]([C:43](=[O:45])[CH3:44])[CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:22]2[CH:46]=[CH:47][CH:48]=[CH:49][C:21]1=2)=[O:19])([CH3:16])[CH3:15]>>[C:43]([N:27]([CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:30]=1)[CH:23]1[CH2:24][CH2:25][CH2:26][N:20]([C:18]([O:17][CH:14]([CH3:16])[CH3:15])=[O:19])[C:21]2[C:49]([O:5][CH3:4])=[CH:48][CH:47]=[CH:46][C:22]1=2)(=[O:45])[CH3:44]
Reactant: COC(=O)c1cccc(OC)c1N
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Product: COc1cccc2c1N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O

Procedure:
This compound was prepared utilizing the same methodology described in Example 1 wherein replacement of 2-amino-benzoic acid methyl ester with methyl 2-amino-3-methoxybenzoate following the procedure of Example 1, Steps 1-8 for the synthesis of 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester. CI MS 547 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:13]1([O:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([O:19][C:20]([N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[NH:10][C:9]2=[O:12])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cccc2[nH]c(=O)[nH]c12
Solvent: c1ccncc1
Product: COc1cccc2c1[nH]c(=O)n2C(=O)Oc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 4-methoxy-2-oxo-2,3-dihydrobenzimidazole (24 g; 0.146 mol) in pyridine (200 ml), phenylchloroformate (18.4 ml; 0.146 mol) was added dropwise. The reaction mixture was refluxed for 14 hours then was poured into ice-water. The precipitated solid was collected and dried to give the title compound. 30 g; m.p. 204-205° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15]>ClCCl>[CH3:15][CH:14]([CH3:16])[C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[CH3:12])=[O:17]
Reactant: Cc1cccc(C)c1
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)C(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (28.0 g, 0.21 mole) was suspended in 200 ml of anhydrous dichloromethane and cooled to 0° C. A solution of m-xylene (21.2 g, 0.2 mole) and isobutyryl chloride (21.3 g, 0.20 mole) in 50 ml of anhydrous dichloromethane was slowly added to this suspension. After the addition was completed, the reaction mixture was stirred at 0° C. for 1 h.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:35]=[C:34]([CH3:36])[O:33][N:32]=2)[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.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.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[N:35]=[C:34]([CH3:36])[O:33][N:32]=5)[CH:28]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reactant: Cc1nc(-c2cccc(I)c2)no1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4noc(C)n4)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 79.7 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.125 g, 0.4 mmol) and 1-iodo-3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzene (0.09 g, 0.32 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, followed by trituration from hexanes/ethyl acetate, provided the title compound as colorless crystals (0.12 g, 67%), m.p. 116-118° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1(O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH:13]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(OC2CCCCC2)cc1
Reaction time: 22 h

Procedure:
822 mg (4.95 mmol) of ethyl 4-hydroxybenzoate was dissolved in 20 ml of tetrahydrofuran. 545 mg (5.45 mmol) of cyclohexanol, 1.56 g (5.94 mmol) of triphenylphosphine and 202 mg (1.50 mmol) of diethyl azodicarboxylate were added to the solution, and they were stirred for 22 hours. The reaction liquid was diluted with water. After the extraction with ethyl acetate, the organic layer was washed with 1 N sodium hydroxide and then with saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH3:10])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:22]1([NH:27][C:28]2[C:33]([CH:34]=O)=[CH:32][N:31]=[C:30]([S:36][CH3:37])[N:29]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([N:27]2[C:28]3[N:29]=[C:30]([S:36][CH3:37])[N:31]=[CH:32][C:33]=3[CH:34]=[C:5]([CH2:6][CH2:7][O:8][CH2:9][CH3:10])[C:4]2=[O:11])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOCCCC(=O)OCC
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOCCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of 4-ethoxy-butyric acid ethyl ester (9.85 g, 61.47 mmol) in THF (25 ml) was added lithium bis(trimethylsilyl)amide (77.0 ml, 76.85 mmol, 1 M solution in THF). The reaction mixture was stirred for 10 minutes to form the anion. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was then added and the reaction allowed to warm to RT and stirred overnight. The reaction mixture was quenched with 10% aqueous HCl (100 ml). The aqueous layer was extracted with ethylacetate (150 ml total) and the organic layers were combined and concentrated to give a yellow oil. Chromatographic purification on silica gel (chloroform/ethyl acetate gradient) gave 8-cyclopentyl-6-(2-ethoxy-ethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3.22 g, 9.65 mmol). MS (APCI+) 334 (M+1, 100); 1H NMR δ (400 MHz, DMSO-d6) 8.54 (s, 1H), 7.47-7.46 (m, 1H), 5.99-5.90 (m, 1H), 3.69 (t, J=6.25 Hz, 2H), 3.49 (q, J=7.03 Hz, 2H), 2.84 (t, J=6.25 Hz, 2H), 2.59 (s, 3H), 2.34-2.29 (m, 2H), 2.08-2.02 (m, 2H), 1.88-1.83 (m, 2H), 1.69-1.65 (m, 3H), 1.17 (t, J=7.04 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[S:17][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][CH:14]=1>N1C=CC=CC=1>[Cl:12][C:13]1[S:17][C:16]([S:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8](=[O:9])(=[O:10])[NH2:11])(=[O:20])=[O:19])=[CH:15][CH:14]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1ccc(Cl)s1
Temperature: 60 °C
Yield: 57 %

Procedure:
To a solution of 2-aminobenzenesulfonamide (172 mg) in pyridine (3 ml) was added 5-chlorothiophene-2-sulfonyl chloride (217 mg) and the resulting mixture was heated at 60° C. for 18 h. The mixture was concentrated and then partitioned between DCM (20 ml) and 2N HCl (10 ml). The organics were separated, dried (MgSO4) and evaporated to a gum which was purified by silica chromatography eluting with a gradient of ethyl acetate/hexane to give the title compound as a solid (201 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]=1[CH2:24]O>C1C=CC=CC=1>[Cl:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]=1[CH2:24][Cl:3]
Reactant: OCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
47.6 g of thionyl chloride are added to a suspension of 45 g of 5-chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenyl-pyrazole in 45 ml of benzene, there being a considerable evolution of gas and solution occurs. Following this heating is carried out for 30 minutes at boiling point for completion of the reaction. The solvent is distilled off in vacuo and this operation is carried out with the addition of benzene. The residue is caused to crystallise with the help of petroleum ether. 5-Chloro-4-chloromethyl-3-p-chlorophenyl-1-phenyl-pyrazole is obtained with a 98.5 % yield; F 96.5°-97°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:4][C:3]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.[C:25]([C:27]1[O:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1)#[N:26].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd].CCOC(C)=O>[F:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[C:6]([NH:8][C:32]([C:30]2[O:31][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)=[O:33])[CH:7]=1
Reactant: CC1CCN(c2cc(N3CCN(C)CC3)c(F)cc2[N+](=O)[O-])CC1
Reactant: N#Cc1ccc(C(=O)O)o1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2cc(N3CCN(C)CC3)c(F)cc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 82.1 %

Procedure:
The procedure of Example 4, step (c) was followed using 58.5 mg (0.174 mmol) of 1-[2-fluoro-5-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-4-methyl-piperazine (as prepared in the previous step), 29 mg of 10% palladium on carbon (50% by weight water), 28.6 mg (0.209 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 27.3 μL (0.314 mmol) of oxalyl chloride, and 72.8 μL (0.418 mmol) of DIEA except the isolated impure product was dissolved in 10 mL of EtOAc, washed with 1M K2CO3 (2×5 mL), dried (Na2SO4) and then concentrated in vacuo. Chromatography on a 5-g silica SPE column with 1-3% MeOH-dichloromethane afforded 60.8 mg (82%) of the title compound as a crystalline yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.76 (br s, 1H), 8.19 (d, 1H, J=14.1 Hz), 7.22, 7.26 (AB q, 2H, J=3.7 Hz), 6.80 (d, 1H, J=8.5 Hz), 3.11-3.19 (m, 4H), 2.92-2.95 (m, 2H), 2.69-2.76 (m, 2H), 2.55-2.65 (br m, 4H), 2.37 (s, 3H), 1.82-1.86 (m, 2H), 1.5-1.7 (br m, 1H) and 1.42-1.53 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C23H28FN5O2, 426.2 (M+H), found 426.3.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[C:3]1=[O:16].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH:26][C:27](O)=[O:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([F:30])([F:31])[F:17])[CH2:6][CH2:5]2)[C:3]1=[O:16]
Reactant: CN1C(=O)C2(CCNCC2)c2ccccc21
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A solution of 1-methylspiro[indoline-3,4′-piperidin]-2-one (100 mg, 0.46 mmol) in CH2Cl2 (5 mL) was added 3-(2-trifluoromethyl-phenyl)-acrylic acid (120 mg, 0.56 mmol), HOBt (124 mg, 0.92 mmol), EDCI (181 mg, 0.92 mmol) and DIEA (297 mg, 2.30 mmol). The reaction mixture was stirred at rt overnight. The above mixture was concentrated and the residue was purified by preparative HPLC to give (E)-1-methyl-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidin]-2-one (50 mg, 26%). 1H NMR (CDCl3): 1.85-2.00 (m, 4H), 3.72 (s, 3H), 3.90-4.00 (m, 2H), 4.15-4.30 (m, 1H), 4.40-4.50 (m, 1H), 6.80-6.90 (m, 2H), 7.10-7.15 (m, 1H), 7.25-7.35 (m, 2H), 7.45-7.60 (m, 2H), 7.68-7.72 (m, 2H), 7.91-8.00 (m, 1H).