Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16](Br)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21]SC>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:21][CH3:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Reactant: CSSC
Product: CSc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Yield: 78 %

Procedure:
Prepared in analogy to example 4 (b) from 4-(5-bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 4(a)) and dimethyl disulphide. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a yellow crystalline solid (yield 78%). MS (m/e): 316.3 (M+H+, 100%).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:19])[CH:9]([CH:10]=[CH:11][C:12]([O:14]C)=[O:13])[CH:8]1[C:16]([OH:18])=[O:17].[CH3:20][C:21]1(C)[CH:23](C=C(Br)Br)[CH:22]1C([O-])=O.O1CCCC1>C1CCCCC1>[CH3:6][C:7]1([CH3:19])[C@@H:9]([C:10]#[C:11][C:12]([OH:14])=[O:13])[C@H:8]1[C:16]([O:18][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:17]
Reactant: COC(=O)C=CC1C(C(=O)O)C1(C)C
Reactant: CC1(C)C(C=C(Br)Br)C1C(=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Temperature: -60 °C
Reaction time: 1 h

Procedure:
60 ml of a 20% solution of butyllithium in cyclohexane were added at -65° C. to a mixture of 26 g of tert.-butyl (1R, cis) 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-carboxylate and 175 ml of anhydrous tetrahydrofuran and the mixture was stirred at -60° C. for one hour. A current of carbon dioxide was bubbled through the mixture for 90 minutes and the mixture was poured into an ice-water mixture containing N sodium hydroxide. The alkaline aqueous phase was acidified to a pH of 4 and was extracted with ether. The organic phase was dried and evaporated to dryness under reduced pressure. The residue was crystallized from petroleum ether (b.p.=60°-80° C. to obtain 8.3 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(3-hydroxy-3-oxo-1-propynyl)-cyclopropane-1-carboxylate melting at 144° C.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25]O)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1nc[nH]n1
Product: C(=C/c1nc(COc2ccc(CCCCn3cncn3)cc2)co1)\c1ccccc1
Yield: 71 %

Procedure:
In substantially the same manner as in Working Example 1, 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butanol was allowed to react with 1,2,4-triazole to give 1-[4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole. The yield was 71%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 94-95° C.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:14]([O:18][CH3:19])(=[O:17])[C:15]#[CH:16].O>CC(N(C)C)=O>[CH3:19][O:18][C:14]([C:15]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=2[CH3:13])[CH:16]=1)=[O:17]
Reactant: C#CC(=O)OC
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cn(-c2cc(C(=O)O)ccc2C)nn1
Yield: 62.3 %

Procedure:
A mixture of 1.11 g (6.27 mmol) of 3-azido-4-methyl benzoic acid (Compound 2) and 1.12 mL (12.5 mmol) of methyl propiolate, was stirred in 4.2 mL of DMA at 110° C. in a sealed tube overnight. The resulting brown solution was poured into water, and the resulting precipitate was filtered, and then recrystallized from EtOH/water to provide 1.02 g (62.3%) of 1-(5-carboxy-2-methyl-phenyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester as tan crystals. ESI MS (m/z 262, 100, M+1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH2:5][C:6]1[C:7](=[S:12])[NH:8][CH:9]=[CH:10][CH:11]=1.[CH3:17]I>CO>[F:16][C:14]1[CH:13]=[C:4]([CH:3]=[C:2]([F:1])[CH:15]=1)[CH2:5][C:6]1[C:7]([S:12][CH3:17])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CI
Reactant: Fc1cc(F)cc(Cc2ccc[nH]c2=S)c1
Solvent: CO
Product: CSc1ncccc1Cc1cc(F)cc(F)c1

Procedure:
The reaction of 3-(3,5-difluorobenzyl)pyridine-2-thione, prepared in Example 10, with methyl iodide in methanol in the presence of base by standard techniques yields 3-(3,5-difluorobenzyl)-2-methylmercaptopyridine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C(OC(CO)CO)N=1.[C@@H:49]1(O)[CH2:53][CH2:52][CH2:51][C@H:50]1[OH:54].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([C@@H:49]2[CH2:53][CH2:52][CH2:51][C@H:50]2[OH:54])[CH:7]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: O[C@@H]1CCC[C@H]1O
Agent: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O[C@@H]1CCC[C@H]1c1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step 2.3 g) and (trans)-cyclopentane-1,2-diol (1 g) in THF (50 ml) was added NaH (0.30 g) slowly and the reaction was then allowed to stir for 18 h at RT. The reaction mixture was then partitioned between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting clear oil was purified by column chromatography on silica gel EtOAc/iso-Hexane (2:8) to give the subtitle compound as a clear colourless oil. Yield 0.94 g
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH3:36][NH2:37].O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:37][CH3:36])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: CN
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 3.0 g (5.56 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 11.12 ml (22.24 mmol) of methylamine were stirred in 75 ml of THF overnight. About 300 ml of water were added to the reaction mixture, and the precipitate formed was filtered off and washed with water and dried under high vacuum. This gave 2.69 g (91% of theory) of the desired target compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:28]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1)(=[O:30])[CH3:29]>CC(C)=O>[C:28]([N:31]1[CH2:32][CH2:33][CH:34]([C:37]([O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=3)(=[O:9])=[O:10])=[CH:4][CH:3]=2)=[O:38])[CH2:35][CH2:36]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)N1CCC(C(=O)Oc2ccc(S(=O)(=O)c3ccc(S(N)(=O)=O)s3)cc2)CC1
Reaction time: 0.25 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (3.19 g; 0.01 mole) in acetone (60 ml) at -15° was treated with triethylamine (1.11 g; 0.011 mole). Then 1-acetylpiperidine-4-carbonyl chloride hydrochloride (2.41 g; 0.011 mole) was added, portionwise, during 15 minutes at -15°. The cooling bath was removed and stirring was continued. After 20 hours at room temperature, the reaction mixture was treated with triethylamine (1.11 g; 0.011 mole). Then after stirring one hour longer, the reaction mixture was treated with 1-acetylpiperidine-4-carbonyl chloride hydrochloride (2.41 g; 0.011 mole) and triethylamine (2.22 g; 0.022 mole) and stirred at room temperature.
Reaction SMILES: C(Cl)Cl.[SH:4][C:5]1[NH:14][C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.Br[CH:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18]([OH:20])=[O:19]>C(N(CC)CC)C>[O:15]=[C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([S:4][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([OH:20])=[O:19])[NH:14]1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: O=c1[nH]c(S)nc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(Sc1nc2ccccc2c(=O)[nH]1)c1ccccc1
Yield: 31 %

Procedure:
A methylene chloride solution of 8.9 g (0.05M) of 2-mercapto-4(3H)-quinazolinone, α-bromophenylacetic acid and triethylamine is heated to gentle reflux for 48 hours. A small amount of insoluble material is filtered off and then the solvent is removed. The oily residue is dissolved in water and insoluble material filtered off. The aqueous filtrate is acidified with a dilute HCl solution and the gummy solid is extracted with methylene chloride. The methylene chloride solution is dried over anhydrous magnesium sulfate. After the solvent is removed the residual solid is dissolved in 500 ml hot acetonitrile, and upon cooling the solid is filtered. The filtrate, upon standing, gives 5.0 g (31% yield) of product which has a melting point of 184°-5° C. dec.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH3:31])=[CH:25][C:23]=1[NH2:24].Cl.N1C=CC=CC=1>C(OCCO)C.C(=O)(O)[O-].[Na+]>[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH3:31])=[CH:25][C:23]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1O
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2cc3c(Nc4cc(OC)c(Cl)cc4Cl)c(C#N)cnc3cc2cc1O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
A mixture of 0.7 g (2.46 mmol) of 4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.57 g (2.95 mmol) of 2,4-dichloro-5-methoxyaniline and 0.28 g (2.46 mmol) of pyridine hydrochloride in 7 mL of 2-ethoxyethanol is heated at 120° C. for 2 hours, then cooled to room temperature. The product mixture is diluted with saturated solution of sodium bicarbonate and stirred for 15 minutes. The resulting solid is collected by filtration, washed with water and dried. The crude product is purified by silica gel chromatography, utilizing a 98:2 to 90:10 gradient of methylene chloride/methanol to give 0.71 g of 4-(2,4-dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid, mp, 238–240° C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]2[S:22][C:23]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[C:24]([C:26]([NH2:28])=[O:27])[N:25]=2)[CH2:16]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[S:22][C:23]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[C:24]([C:26]([NH2:28])=[O:27])[N:25]=3)[CH2:16]2)=[O:11])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)c1nc(N2CCC[C@@H](N)C2)sc1Nc1ccccn1
Reactant: CC(C)(C)c1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(=O)N[C@@H]2CCCN(c3nc(C(N)=O)c(Nc4ccccn4)s3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 6-tert-butylnicotinic acid (23.5 mg, 131 μmol) and 2-((R)-3-amino-piperidin-1-yl)-5-(pyridin-2-ylamino)-thiazole-4-carboxylic acid amide (38 mg, 119 μmol) in N,N-dimethylformamide (1 mL) was added diisopropylethylamine (35 μL, 200 μmol) followed by 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 161 μmol). After stirring at ambient temperature overnight under an atmosphere of argon the reaction was quenched by the addition of saturated aqueous ammonium chloride (2 mL), the mixture poured into water (5 mL) and extracted with ethyl acetate (3×3 mL). The combined organic extracts were washed with brine (2×2 mL), dried over sodium sulfate, filtered and concentrated in vacuo to a yellow solid. The crude product was purified by chromatography using a 13 g C-18 column gradient eluted from 10% acetonitrile in water up to 100% acetonitrile. The product containing fractions were combined and concentrated in vacuo and the residue lyophilized from acetonitrile/water to give (R)-2-(3-(6-tert-butylnicotinamido)piperidin-1-yl)-5-(pyridin-2-ylamino)thiazole-4-carboxamide as a pale yellow solid (37.8 mg, 66%).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1>O.[OH-].[Na+]>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[O:2])=[CH:10][CH:9]=1
Reactant: O=C(O)Cc1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(S(=O)c2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4.49 g of sodium metaperiodate in 80 ml of water is added a solution of 5.57 g of [p-(p-chlorophenylthio)phenyl]acetic acid in 75 ml of 1.75% NaOH. A white solid precipitates immediately. After stirring overnight the mixture is filtered and the filtrate is acidified with concentrated HCl to give a white solid. This product, which contains some starting material, is reworked, as above, to yield the pure product. Recrystallization from chloroform-hexane affords white crystals, mp 139°-141° C. and 144°-148.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](/[CH:10]=C/N(C)C)[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][CH:5]=1)[CH3:2].I([O-])(=O)(=O)=[O:19].[Na+]>O1CCCC1.O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH:10]=[O:19])[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOc1ccc([N+](=O)[O-])c(/C=C/N(C)C)n1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc([N+](=O)[O-])c(C=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred solution of the compound prepared in Example 422 (2.2 g) in tetrahydrofuran (40 mL) was added sodium periodate (5.95 g) in water (40 mL). The mixture was stirred at room temperature overnight. The suspended inorganic solids were filtered out, washed with tetrahydrofuran and the filtrate evaporated in vacuo. The residue was taken in small amount of water and extracted with chloroform, dried, evaporated in vacuo to a brown oil and further dried under high vacuum to afford the title compound (1.6 g) with the following physical data.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Br:33][C:34]1[CH:39]=[C:38]([CH2:40][NH:41][CH:42]([CH3:44])[CH3:43])[CH:37]=[CH:36][N:35]=1>C(#N)C>[Br:33][C:34]1[CH:39]=[C:38]([CH2:40][N:41]([CH:42]([CH3:44])[CH3:43])[C:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)=[O:9])[CH:37]=[CH:36][N:35]=1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: CC(C)NCc1ccnc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)N(Cc1ccnc(Br)c1)C(=O)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 23 h
Yield: 97.6 %

Procedure:
After a solution of methyl-1H-imidazole-4-carboxylic acid (1.45 g), 1-hydroxybenzotriazole hydrate (HOBT.H2O) (2.08 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (2.60 g) in acetonitrile (35 mL) was stirred at room temperature for 10 min, a solution of N-[(2-bromopyridin-4-yl)methyl]propan-2-amine (2.59 g) in acetonitrile (15 mL) was added thereto, and the resulting solution was then stirred at room temperature for 23 hr. The solvent was distilled off under reduced pressure, and the residue was then diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution. After extracting with chloroform, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=98:2-82:18) and (the same column, chloroform:methanol=98:2-85:15) to afford the title compound (3.72 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:13])[CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c15) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: C(NC(=O)[O-])C.[OH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1
Reactant: Fc1ccccc1CBr
Reactant: CC1c2ccc(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Product: CC1c2ccc(OCc3ccccc3F)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 2-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24FNO3+H: 370, observed: 370.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[CH3:21][N:22]([CH3:25])C=O>C(O)C.CNCC1C=CC=CC=1>[CH2:21]([N:22]([CH3:25])[CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:7]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Agent: CNCc1ccccc1
Solvent: CCO
Product: CN(Cc1ccccc1)C[C@@H](O)COc1cccc(-c2noc3ncccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and N-methylbenzylamine in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=390.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N+:21]([O-])=[CH:22]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:22]1[C:23]2[C:18](=[C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=4)[O:16][N:15]=3)[CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][N:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c[n+]([O-])ccc34)no2)cc1Cl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Temperature: 65 °C
Yield: 92.2 %

Procedure:
5-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline 2-oxide (D6; 1.18 g, 3.09 mmol) and phosphorus oxychloride (5.76 ml, 61.8 mmol) was stirred under an atmosphere of argon at room temperature for 4 hours. The mixture was then heated to 65° C. for 15 minutes, the phosphorus oxychloride evaporated under reduced pressure, and the residue, azeotroped with toluene and dried under vacuum overnight. The pale yellow solid residue was dissolved in dichloromethane (50 ml) and stirred with 2M NaOH (10 ml). The organic layer was separated, dried with MgSO4 and evaporated to dryness under reduced pressure to give a pale yellow solid (1.14 g) which was chromatographed over silica eluting with dichloromethane to give the title compound as a white solid (0.85 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2([CH3:20])OCC[O:16]2)[C:8]1=[O:21])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:16])[CH3:20])[C:8]1=[O:21])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cnc2ccccc2c1)N1CCC(CCCC2(C)OCCO2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C[C@@H](c1cnc2ccccc2c1)N1CCC(CCCC(C)=O)C1=O

Procedure:
A solution of 6-1 (380 mg, 1.0 mmol), p-TSA (20 mg) and acetone (50 mL) was heated at reflux for 4 hr. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 6-2 as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.1 %

Procedure:
To a solution of Intermediate 62A (0.843 g, 4.08 mmol) in THF (20.41 mL) was added triethylamine (5.69 mL, 40.8 mmol) followed by methanesulfonyl chloride (0.414 mL, 5.31 mmol). The reaction mixture was allowed to stir at room temperature for 3 days, then quenched with a saturated aqueous solution of NaHCO3 and diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (2×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound (245 mg, 0.861 mmol, 21.09% yield) as a white solid. HPLC Ret timej: 1.32 min. MS (ES): m/z=284.2 [M+H]−. Intermediate 62 was used in the synthesis of Example 212.