Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[CH2:8]=[CH:9][CH2:10][CH2:11]CC.ClC(Cl)C1C=CC=CC=1.C(OCC)=C.C(OCCCCC=CCCCC)(=O)C>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=CCCCC
Reactant: C=CCCCCCl
Agent: C=COCC
Agent: CCCCC=CCCCCOC(C)=O
Solvent: ClC(Cl)c1ccccc1
Product: CCCCC=CCCCCCl
Reaction time: 3 h

Procedure:
1-Chloro-5-decene was synthesized as follows: 200.1 g (1.61 mol 95% pure) of 1-chloro-5-hexene, 282 g (416 mL, 3.35 mol) of 1-hexene and 2.0 mL of α,α-dichlorotoluene (metal hydride inhibitor) were added to a dry 1-L 2-necked round-bottomed flask containing a reflux condenser and a stir bar. This mixture was sparged sub-surface with Argon. After 10 minutes 5.5 g (6.67 mol) of the metathesis catalyst of Example 1 was added. The mixture was placed in a 62° C. oil bath and stirred. Samples were taken periodically and analyzed by gas chromatography (GC) to determine the extent of conversion. After 3 hours, the reaction stopped and the catalyst was inactivated by the addition of 3 mL of ethyl vinyl ether. The catalyst was removed by filtering the mixture through 200 g of silica gel. The silica gel was rinsed with 500 mL of hexane and combined with the post-filtered reaction solution. 1-chloro-5-decene was purified by vacuum distillation to yield 105.9 g. This was converted to 5-decenyl acetate as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([S:42](Cl)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34][N:33]=1>C1COCC1.CC(C)=O>[Cl:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([S:42]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:11][N:10]=[CH:9][N:8]=3)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34][N:33]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)nccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reaction time: 0.08 h
Yield: 36.3 %

Procedure:
A 250 mL round bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (2.291 g, 9.12 mmol) and THF (45.6 mL). The resulting mixture was cooled in a dry ice and acetone bath for 10 min. To this solution was added lithium bis(trimethylsilyl)amide (13.68 mL, 13.68 mmol) dropwise over 30 seconds. The ice bath was removed for 10 minutes and then the flask was returned to the bath for an additional 5 minutes. A solution of 1-chloroisoquinoline-6-sulfonyl chloride (2.39 g, 9.12 mmol) in 7 mL of THF was then added dropwise over 5 minutes. The ice bath was removed and the resulting mixture stirred for 30 minutes. LC/MS indicated that the desired product was generated. The reaction mixture was concentrated, taken up in minimal DCM, loaded onto a cartridge and purified by silica gel chromatography (330 g), using 0 to 30% Heptane: EtOAc. Fractions containing the product were combined and concentrated to afford (1-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (1.58 g, 3.31 mmol) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([S:4]Cl)[CH3:3].[O:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].CN(C)CC1C=CC=CC=1>ClC1C=CC=CC=1.CN(C)C=O>[CH3:1][CH:2]([S:4][N:8]1[CH2:9][CH2:10][O:6][C:7]1=[O:11])[CH3:3]
Reactant: CC(C)SCl
Reactant: O=C1NCCO1
Agent: CN(C)Cc1ccccc1
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)SN1CCOC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
A solution of 0.6 mol of 2-propylsulphenyl chloride in 200 ml of chlorobenzene was added dropwise at 0° to 10° C. to 52.2 g (0.6 mol) of oxazolidin-2-one and 85 g (0.62 mol) of dimethylbenzylamine in 200 ml of chlorobenzene and 50 ml of dimethylformamide. After stirring for 1.5 hours at room temperature, the mother liquor was filtered from precipitated amine hydrochloride, washed with water and dried over sodium sulphate and the solvent was subsequently removed in vacuo at 40° C. 58 g of 3-(2-propylthio)oxazolidin-2-one were obtained as a brown oil.
Reaction SMILES: C1OC1CO.C(N(CC)CC)C.[CH2:13]([O:20][CH2:21][CH:22]1[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]C1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C1C=CC=CC=1>[CH2:13]([O:20][CH2:21][CH:22]1[CH2:27][O:26][C:25]([CH3:28])([CH3:29])[O:24]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(C)OCC(COCc2ccccc2)CO1
Agent: OCC1CO1
Solvent: OCc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)OCC(COCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Boron trifluoride-diethyl ether complex (0,9 ml,0.007 ml) was dropped in benzyl alcohol (92 ml) of glycidol (22.01 g, 0.3 mol) on ice bath. After dropping the mixture was stirred for 8 hours at 25° C. After the reaction was over, triethylamine was added thereto and benzyl alcohol was removed in vacuo. The desidue was dissolved in acetone and thereto p-toluenesulfonic acid was added. The mixture was reacted for 8 hours at 25° C. After the completion of the reaction triethylamine was added thereto and acetone was removed in vacuo. The crude product was distilled to give a mixture (43.8 g, yield 81%) of 4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane and 5-benzyloxymethyl-2,2-dimethyl-1,3-dioxane. The ratio of the dioxolane and the dioxane was 8 to 1 by analysis with gas chromatography.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25](OCC)=[O:26])[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:21]2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][OH:26])[C:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[N:21]2)=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 267.7 %

Procedure:
Lithium aluminium hydride (884 mg) was added to a solution of ethyl 1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylate (9.61 g) in tetrahydrofuran (50 ml) at 0° C., and the mixture was stirred at 0° C. for one hour. After adding water, the reaction mixture was stirred at room temperature for one hour. After the precipitate was removed by filtration, the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The crystals obtained were collected by filtration to yield [1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazol-4-yl]methanol (23.10 g, yield: 97%). This was recrystallized from ethyl acetate-hexane. Melting point: 88–89° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][NH2:21].Cl.N>O>[CH3:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=[C:2]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=2)[CH:7]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Agent: Cl
Agent: N
Solvent: O
Product: Cc1cc(NCc2cccc(C(F)(F)F)c2)nc(-c2ccccn2)n1
Yield: 24.7 %

Procedure:
A mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol), 3-trifluoromethylbenzylamine (70.1 mg, 0.4 mmol), water (5 ml) and 2N HCl (300 μl) was refluxed for two days. The resulting solution was basified to pH ˜11 with ammonia and extracted with ethyl acetate (10 ml×3). The combined ethyl acetate extracts were dried with sodium sulfate, and evaporated under vacuum. The residue was purified by column chromatography (hexane/ethyl acetate: 1/1) to give the title compound as a solid (34 mg, 25%). 1H NMR (CD3OD): 8.59 (d, J=4.2 Hz, 1H), 8.27 (m, 2H), 7.86 (m, 2H), 7.43 (m, 2H), 6.18 (s, 2H), 4.76 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:17])=[C:13]([CH2:15]I)[N:14]=2)=[CH:6][CH:5]=1.[OH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([O:25][CH2:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:28]=2[C:29]([O:31][CH3:32])=[O:30])[CH2:20]1.C(OC)(C)(C)C>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:17])=[C:13]([CH2:15][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH:21]([O:25][CH2:26][C:27]4[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:28]=4[C:29]([O:31][CH3:32])=[O:30])[CH2:20]3)[N:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CI
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cccc1COC1CCCC(OCc2nc(-c3ccc(Br)cc3)oc2C)C1
Reaction time: 1 h

Procedure:
At room temperature, 50 mg of a 60% sodium hydride suspension and then 408 mg of 2-(4-bromophenyl)-4-iodomethyl-5-methyloxazole were added to a solution of 200 mg of methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate in 5 ml of dimethylformamide. After one hour, methyl tert-butyl ether was added, and the mixture was extracted with water. The organic phase was dried over magnesium sulfate, the solvents were removed under reduced pressure and the residue was purified by RP-HPLC. This gave 49 as a light-yellow oil. C27H30BrNO5 (528.45), MS(ESI): 528.2, 530.2 (M+H+). 2-{3-[2-(4-Bromophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexyloxymethyl}-6-methylbenzoic acid 50
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:20][C:21](N)=[O:22])=[O:19].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:21]([NH:20][C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)=[O:19])=[O:22])[CH2:5]2
Reactant: NC(=O)NC(=O)c1ccccn1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(=O)c1ccccn1)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 14b, from 3-aminoquinuclidine dihydrochloride(1.0 g, 5 mmol), 2-pyridoylurea (0.82 g, 5 mmol) and di-isopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml) by refluxing for 4 days. The pyridine was evaporated and the residue partitioned between ether and 10% aqueous w/v citric acid. The mixture was filtered, the aqueous phase washed with ether, then basified with potassium carbonate to precipitate the title compound (0.60 g) which was converted to the 1:1 fumarate, mp 202°-203° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([NH2:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH:4]([NH:12][S:28]([C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)(=[O:30])=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C(N)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-3-phenyl-propionic acid methyl ester is dissolved in 25 mL of methylene chloride and the reaction charged with triethylamine (0.97 mL, 7 mmol) and 4-chlorobenzenesulfonylchloride at 0° C. The reaction is allowed to warm to room temperature (rt) and stirred overnight. The reaction is quenched with sodium bicarbonate, extracted with methylene chloride, dried over sodium sulfate, and concentrated in vacuo. The resultant solid is triturated with 20% ethylacetate/hexanes to provide the title compound. 13C NMR (100 MHz, CDCl3) 39.5, 52.8, 57.1, 127.5, 128.8, 128.9, 129.5, 129.6, 135.1, 138.4, 139.4, 171.5. MS 354.1 m/z (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10]C)=O.[CH3:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].Cl>CCCCCC.O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:8](=[O:10])[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(=O)C(C)(C)C)cc1OC
Reaction time: 7 h
Yield: 66 %

Procedure:
In a 200 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 2.45 gm (61 mmol) of 60% sodium hydride, 10 gm (51 mmol) of methyl 3,4-dimethoxybenzoate, and 100 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and refluxed with heating while 6.1 gm (61 mmol) of pinacolone was added dropwise. The refluxing under heat was continued for 7 hours. After cooling the reaction mixture, 30 ml of 2N hydrochloric acid was added and the mixture was extracted twice with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Hexane was added to the crude product and insoluble substances were filtered off. The filtrate was concentrated by evaporation, and recrystallization afforded 8.9 gm of the target compound as colorless needles (yield: 65%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[CH2:17]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[CH2:31][CH2:30]2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]1=[O:16])[CH3:18]
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(C)cc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCN2CCN(c3ccc(F)cc3)CC2)C(=O)Nc2ccc(C)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 3-(4-chlorobutyl)-3-ethyl-5-methyl-1,3-dihydro-2H-indol-2-one and 1-(4-fluorophenyl-)-piperazine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](=O)=O.C(O[C:13]([C:15]1[C:16]([NH:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=N[C:18]([S:21][CH3:22])=[N:19][CH:20]=1)=[O:14])C>C1COCC1>[CH:24]1([NH:23][C:16]2[C:15]([CH2:13][OH:14])=[CH:20][N:19]=[C:18]([S:21][CH3:22])[CH:7]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)c1cnc(SC)nc1NC1CCCC1
Reactant: O=C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1cc(NC2CCCC2)c(CO)cn1
Reaction time: 5 h

Procedure:
Lithium aluminum hydride (10 g, 35.5 mmol) was suspended in THF under a nitrogen atmosphere and cooled with dry ice. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (7), (2.02 g, 53.3 mmol) was dissolved in THF and added dropwise to the cooled LAH solution, keeping the reaction temperature below −20° C. for the duration of the addition. The reaction was subsequently brought to room temperature and stirred for 5 h. After stirring, the reaction was quenched by the addition of water (5 ml), 15% NaOH (10 ml) and then water (15 ml) again. A white solid that precipitated was filtered away and the filtrate evaporated in vacuo to provide product (8) as a yellow solid (7.2 g). Product (8) was used without further purification or characterization.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21](COCC[Si](C)(C)C)[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.[CH:72]1([O:77][C:78]2[CH:83]=[CH:82][N:81]=[C:80]([Sn](CCCC)(CCCC)CCCC)[CH:79]=2)[CH2:76][CH2:75][CH2:74][CH2:73]1.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:4][CH2:5][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:80]4[CH:79]=[C:78]([O:77][CH:72]5[CH2:76][CH2:75][CH2:74][CH2:73]5)[CH:83]=[CH:82][N:81]=4)[N:26]=3)[NH:21][CH:20]=2)=[O:18])[C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(OC2CCCC2)ccn1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: CC(C)(C)[C@@H](NC(=O)c1c[nH]c2ncc(-c3cc(OC4CCCC4)ccn3)nc12)C(=O)N1CCC(C#N)CC1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 4-cyclopentyloxy-2-tributylstannanyl-pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=530.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]([C:17]([OH:19])=O)=[CH:9][CH:8]=1>>[CH3:5][O:6][C:7]1[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]([C:17]([Cl:3])=[O:19])=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)c2c1OCCO2
Product: COc1ccc(C(=O)Cl)c2c1OCCO2
Yield: 100.6 %

Procedure:
391 g of thionyl chloride and 138 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with a condenser. The mixture was heated to 50°-55° C. and the excess thionyl chloride was distilled off under vacuum. 151 g of 8-methoxy-1,4-benzodioxane-5-carbonyl chloride were obtained (yield: 100%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[NH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1.[BH4-].[Na+]>CO>[CH2:1]([CH:8]1[CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:11]=2)[CH:7]1[CH2:6][NH2:5])[CH2:2][CH3:3]
Reactant: CCC=O
Reactant: NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC1Cc2cc(C3=NNC(=O)CC3)ccc2C1CN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
Propanal (1.51 g) dissolved in 5 ml of methanol was added dropwise to 6.15 g of 2-aminomethyl-5-[4,5-dihydro-pyridazin-3(2H)-on-6-yl]indane dissolved in 60 ml of methanol. The mixture was stirred at room temperature for 30 minutes. Then, under ice cooling, 1.03 g of sodium borohydride was added to the mixture. The resulting mixture was stirred at the same temperature for 20 minutes and then stirred at room temperature for 1 hour. After methanol was removed, water was added to the residue, and the residue was extracted with ethyl acetate. The organic layer was collected by filtration, washed with water and dried, and the solvent was removed. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol (15:1)) to obtain 5.22 g of 2-propyl-aminomethyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[N:5]([C:17]1[CH:22]=[C:21]([Br:23])[N:20]=[C:19](Br)[C:18]=1[N+:25]([O-:27])=[O:26])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[NH3:29]>>[CH2:1]([O:3][C:4](=[O:28])[N:5]([C:17]1[CH:22]=[C:21]([Br:23])[N:20]=[C:19]([NH2:29])[C:18]=1[N+:25]([O-:27])=[O:26])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1cc(Br)nc(Br)c1[N+](=O)[O-]
Reactant: N
Product: CCOC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 69 using (2,6-dibromo-3-nitro-pyridin-4-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (2.75 g), aqueous ammonia (11 ml), and 2-methyl-THF (11 ml). This gave the product (1.92 g) as a yellow oil.
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][CH2:13][C:14]1[CH:43]=[CH:42][C:17]([CH2:18][N:19]([CH:32]2[CH2:41][C:40]3[N:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:34][CH2:33]2)[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[Cl:44][C:45]1[CH:53]=[N:52][CH:51]=[C:50]([Cl:54])[C:46]=1[C:47](O)=[O:48].ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:44][C:45]1[CH:53]=[N:52][CH:51]=[C:50]([Cl:54])[C:46]=1[C:47]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])(=[O:21])=[O:22])[CH:32]2[CH2:41][C:40]3[N:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:34][CH2:33]2)=[CH:42][CH:43]=1)=[O:48]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: NCc1ccc(CN(C2CCc3cccnc3C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: O=C(NCc1ccc(CN(C2CCc3cccnc3C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1)c1c(Cl)cncc1Cl
Yield: 39.4 %

Procedure:
Using the EDCI coupling general procedure F: Reaction of N-(4-Aminomethyl-benzyl)-2-nitro-N-(5,6,7,8-tetrahydro-quinolin-7-yl)-benzenesulfonamide (75 mg, 0.17 mmol), 3,5-dichloroisonicotinic acid (75%, 55 mg, 0.22 mmol), 1-hydroxybenzotriazole (23 mg, 0.17 mmol), 4-methyl morpholine (100 μL, 0.89 mmol), and EDCI (32 mg, 0.17 mmol) for two days at 50° C. followed by column chromatography on silica gel (1:1:98 MeOH—NH4OH—CH2Cl2) gave the title compound (42 mg, 40%) as a yellow foam.
Reaction SMILES: [CH:1]1([N:4]([CH:41]2[CH2:43][CH2:42]2)[C:5]([C:7]2[N:38]([CH2:39][CH3:40])[C:10]3=[N:11][C:12]([N:19](CC4C=CC(OC)=CC=4OC)C(=O)OC(C)(C)C)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:19][C:12]1[N:11]=[C:10]2[N:38]([CH2:39][CH3:40])[C:7]([C:5]([N:4]([CH:41]3[CH2:43][CH2:42]3)[CH:1]3[CH2:3][CH2:2]3)=[O:6])=[CH:8][C:9]2=[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=12
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N(Cc3ccc(OC)cc3OC)C(=O)OC(C)(C)C)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
To a solution of tert-butyl 7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (example 1I, 2.66 g, 4.51 mmol) in dichloromethane (33.8 mL) was added TFA (11.28 mL). The reaction mixture was stirred at rt 45 min and was concentrated in vacuo. The crude residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (2 x) and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by flash chromatography using an Isco 40 g column eluting with 4-10% MeOH/CH2Cl2 to yield 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (1.2 g, 3.55 mmol, 79% yield) as a pale yellow solid.