Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[CH3:17][S-:18].[Na+].O>CN(C)C=O>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([S:18][CH3:17])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(NC2CC2)n2ncc(C=O)c2n1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (4.0 g, 16.87 mmol) in dimethylformamide was added sodium thiomethoxide (3.54 g, 50.5 mmol) and the reaction mixture was heated to 80° C. for 2 hrs. Cooled the reaction mixture, added water, stirred for 15 minutes and filtered white precipitate, dried to yield 7-(cyclopropylamino)-5-(methylthio)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (3.60 g, 86% yield). LCMS (M+1=249)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)[C:18](Cl)=[O:19]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([CH:18]=[O:19])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Solvent: CN(C)C=O
Product: O=Cc1cc2ccc(-c3ccc(F)cc3)cc2[nH]1

Procedure:
The desired compound was prepared by Vilsmeier formylation of 6-(4-fluorophenyl)indole using DMF and oxalyl chloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH3:16].Cl.[CH2:19]([O:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([O:26][N:27]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[C:13]1[CH2:14][CH2:15][CH3:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCC(=O)Nc1cnc2ccccc2c1Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCc1nc2cnc3ccccc3c2n1OCc1ccccc1
Yield: 29.1 %

Procedure:
A solution of N-(4-chloroquinolin-3-yl)butyramide (3.3 g, 13 mmol, 1.0 eq) and O-benzylhydroxylamine hydrochloride (4.23 g, 26.5 mmol, 2.0 eq) in ethanol (150 mL) was heated at reflux for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 3% methanol in dichloromethane) to provide 1.20 g of 1-benzyloxy-2-propyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[N:16]=[CH:15][NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:11][C:12]1[N:16]=[CH:15][N:14]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[N:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 70 °C

Procedure:
A mixture of 4-fluoro-1-nitrobenzene (0.28 g, 2.0 mmol), 3-methyl-1H-1,2,4-triazole (0.18 g, 2.2 mmol), K2CO3 (0.55 g, 4.0 mmol) and DMF (2 mL) was heated at 70° C. overnight. The reaction mixture was cooled down to room temperature, diluted with water, extracted with EtOAc (3×). The organic solution was dried over anhydrous MgSO4 and concentrated in vacuo to provide a solid. Purification of this material by column chromatography on silica gel (40% EtOAc/hexane) provided 3-methyl-1-(4 nitrophenyl)-1H-1,2,4-triazole as the major product. 1H NMR (CDCl3, 400 MHz) δ 8.59 (s, 1H), 8.39 (d, 2H), 7.88 (d, 2H), 2.53 (s, 3H). Further elution with 65% EtOAc/hexane provided 5-methyl-1-(4-nitrophenyl)-1H-1,2,4-triazole as the minor product. 1H NMR (CDCl3, 400 MHz) δ 8.34 (d, 2H), 7.93 (s, 1H), 7.66 (d, 2H), 2.59 (s, 3H).
Reaction SMILES: [CH:1]1([Tl])[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:7]1([P:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[C:15]1([P:13]([C:2]2[CH2:1][CH:5]=[CH:4][CH:3]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: [Tl]C1C=CC=C1
Solvent: CCOCC
Product: C1=CCC(P(c2ccccc2)c2ccccc2)=C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50 g (0.186 moles) of cyclopentadienylthallium (obtained from Fluka) were placed in a 500 ml flask together with 300 ml of diethyl ether. The suspension was cooled to 0° C. and 34.2 ml (0.186 moles) of diphenylchlorophosphine were added dropwise over 10 minutes. The suspension was then heated to room temperature, stirred for one hour and finally filtered through a frit. The solvent was then stripped off under vacuum to leave 39.5 g (85% of the theoretical yield) of the intermediate diphenylphosphinocyclopentadiene, compound 2. An 18.6 g portion (0.074 moles) of compound 2 was then diluted with toluene and cooled to 0° C. 33.2 ml of a 2.24 molar solution of butyllithium in hexane (0.074 moles) were added to this solution over 10 minutes. After being heated to room temperature and stirred for 2 hours, the yellow solution produced a precipitate, which was filtered off and washed with toluene and then with hexane. After drying under vacuum, 13.2 g of compound 3 (70% of the theoretical yield) were obtained in the form of a brownish powder (cf. J. Am. Chem. Soc. 105, (1983), 3882; Organometallics 1, (1982), 1591). 1H NMR (400 MHz, THF-d8): δ=7.3 (m, 4H); 7.15 (m, 6H); 5.96 (m, 2H); 5.92 (m, 2H); 31P NMR (161.9 MHz, THF-d8): δ=−20.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[C:12]([O:15][CH2:16][C:17]1[CH2:24][S:23][CH:22]2[N:19]([C:20](=[O:26])[CH:21]2[NH2:25])[C:18]=1[C:27]([OH:29])=[O:28])(=[O:14])[CH3:13]>C(OCC)(=O)C>[C:12]([O:15][CH2:16][C:17]1[CH2:24][S:23][CH:22]2[N:19]([C:20](=[O:26])[CH:21]2[NH:25][C:9](=[O:10])[CH2:8][C:6]2[S:7][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=2)[C:18]=1[C:27]([OH:29])=[O:28])(=[O:14])[CH3:13]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: O=C(Cl)Cc1ccc(CCl)s1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CCl)s3)C2SC1

Procedure:
A mixture of 1.2 equivalents of 5-chloromethyl-2-thienylacetyl chloride and 1 equivalent of 3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is refluxed for 50 minutes in ethyl acetate after which the solvent is removed and the remaining product is purified by column chromatography on silica gel to give 3-[(acetyloxy)methyl]-7-[[2-[5-(chloromethyl)-2-thienyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([O:25][CH3:26])[N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>>[CH3:26][O:25][C:23]1[CH:22]=[C:4]([CH:3]=[C:2]([NH:1][C:27](=[O:30])[CH2:28][CH3:29])[N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:14][CH:15]=1)[CH3:9])=[O:6]
Reactant: CCC(=O)Cl
Reactant: COc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(N)n1
Product: CCC(=O)Nc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(OC)n1
Yield: 39 %

Procedure:
The title compound is prepared in 39% yield (11.2 mg) from 2-amino-6-methoxy-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (25 mg, 0.068 mmol, single enantiomer, Step-1) and propionyl chloride (19 mg, 0.20 mmol) by the similar manner in Step-2 of Example-8.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:11]1(N=C=NC2CCCCC2)CCCC[CH2:12]1.CCO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:11]([O:9][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)=[O:10])[CH3:12]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccnc(Cl)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.8 %

Procedure:
After 2-chloropyrimidin-4-carboxylic acid (0.223 g, 1.4 mmol) was dissolved in DCM (7 mL), dicyclohexylcarbodiimide (0.29 g, 1.4 mmol), DMAP (0.017 g, 0.14 mmol) and EtOH (0.1 mL, 1.4 mmol) were added thereto, and the mixture was stirred at room temperature for 24 hours. After the termination of the reaction, the reactant was filtered and separated by column chromatography to obtain the title compound (0.13 g, 50%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[H-].[Na+].[NH:10]1[C:21](=[O:22])[C:20]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12].O>CS(C)=O>[CH2:2]([N:10]1[C:21](=[O:22])[C:20]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 43 h
Yield: 98.2 %

Procedure:
1-(5,6-Oxidohexyl)-3,7-dimethylxanthine (CT1541) was synthesized and used as an intermediate for synthesizing CT1517 and CT1595 as described in examples 2 and 3 below. A mixture of 1-bromo-5-hexene (10.7 g, 66 mmol), sodium hydride (1.58 g, 66 mmol), and theobromine (11.9 g, 66 mmol) in dimethylsulfoxide (100 ml) was stirred for 43 hr. The solution was treated with water (200 ml) and then extracted with dichloromethane (3×80 ml). The combined extracts were washed with water (3×100 ml), dried over magnesium sulfate, and then the solvent was evaporated under vacuum to give 1-(5-hexenyl)-3,7-dimethylxanthine (CT1539) (17 g, 98% yield) as a white powder.
Reaction SMILES: Cl.Cl.[OH:3][CH2:4][C@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][C@@H:8]2[CH2:7][CH2:6]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:3][CH2:4][C@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][N:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)[CH2:13][C@@H:8]2[CH2:7][CH2:6]1
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Reactant: Clc1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OC[C@@H]1CC[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Yield: 65.1 %

Procedure:
A mixture of 1.35 g (5.56 mmol) of (7R,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine dihyrochloride (Preparation 1), 4.11 g (27.8 mmol) of 2,5-dichloropyridine, 2.94 g (27.8 mmol) of sodium carbonate and 60 mL of isoamyl alcohol was heated at reflux for 48 h. The mixture was cooled and the solvent removed in vacuo. Purification by flash silica gel chromatography with 95:5 chloroform: methanol gave 1.02 g (65%) of the title compound. mp (base) 139.0–140.5° C. 13C NMR (CDCl3): δ 26.8, 29.1, 39.1, 45.3, 50.8, 54.6, 58.6, 60.6, 66.2, 107.7, 120.1, 137.1, 146.2, 157.6.
Reaction SMILES: [CH3:1][C:2]([S:9][S:10][CH3:11])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[N:32]1([CH2:38][CH2:39][O:40][C:41]2[CH:46]=[C:45]([CH2:47][OH:48])[N:44]=[C:43]([CH2:49][OH:50])[CH:42]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN(C=O)C>[CH3:8][C:2]([S:9][S:10][CH3:11])([CH3:1])[CH2:3][CH2:4][C:5]([N:35]1[CH2:36][CH2:37][N:32]([CH2:38][CH2:39][O:40][C:41]2[CH:46]=[C:45]([CH2:47][OH:48])[N:44]=[C:43]([CH2:49][OH:50])[CH:42]=2)[CH2:33][CH2:34]1)=[O:7]
Reactant: CSSC(C)(C)CCC(=O)O
Reactant: OCc1cc(OCCN2CCNCC2)cc(CO)n1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CSSC(C)(C)CCC(=O)N1CCN(CCOc2cc(CO)nc(CO)c2)CC1
Reaction time: 15 h
Yield: 39.2 %

Procedure:
344 μL of TEA and then, after stirring for 10 min, 748 mg of 4-methyl-4-(methyldisulphanyl)pentanoic acid, 417 μl of diisopropylcarbodiimide and 69 mg of 1-hydroxybenzotriazole hydrate are added to 600 mg of 4-[2-(piperazin-1-yl)ethoxy]-2,6-bis(hydroxymethyl)pyridine in solution in 12 ml of DMF. After 15 h at AT, the mixture is concentrated under RP, 15 ml of water are added and extraction is carried out 2× with AcOEt. The combined organic phases are dried over MgSO4 and concentrated under RP, and the residue is purified by flash chromatography on silica (Analogix Super Flash SiO2 SF25-80 g) using a gradient from 2 to 10% of MeOH in DCM. 390 mg of 4-(2-[4-(4-methyl-4-(methyldisulphanyl)pentanoyl)piperazin-1-yl]ethoxy)-2,6-bis(hydroxymethyl)pyridine are thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[NH:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:16][CH:15]=1.CN(C)C=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:10][CH2:9][N:34]2[CH2:35][CH2:36][CH:31]([NH:30][C:22]3[N:21]([CH2:20][C:17]4[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:32][CH2:33]2)=[O:7])=[CH:11][CH:12]=1
Reactant: O=C(c1ccc(F)cc1)N1CC1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ccc(F)cc1
Yield: 19 %

Procedure:
To 3.96 parts of 1-(4-fluorobenzoyl)aziridine, dissolved in 16 parts of benzene, are added 3.25 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 90 parts of benzene and 45 parts of N,N-dimethylformamide. The whole is stirred and refluxed for 5 hours. The reaction mixture is cooled and poured onto water. The layers are separated and the aqueous phase is extracted with methylbenzene. The combined organic phases are dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 1part (19%) of 4-fluoro-N-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]benzamide; mp. 193.7° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:8](=[O:10])[CH3:9].[NH2:22]/[C:23](/[CH3:32])=[CH:24]\[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(O)CCC>[C:8]([C:7]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:23]([CH3:32])[NH:22][C:6]=1[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:10])[CH3:9]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCCCCl
Reactant: C/C(N)=C/C(=O)OC(C)(C)C
Solvent: CCCCO
Product: CC(=O)C1=C(CCCCCl)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1

Procedure:
24 g (79 mmol) 1-chloro-6-(3-nitrophenyl-methylene)-5,7-octanedione and 25 g (0.159 mol) tert-butyl β-amino-crotonate are boiled under reflux in 200 ml 1-butanol for 18 h. The mixture is filtered and concentrated, and the residue is chromatographed over silica gel with toluene/acetone=9/1. The title compound is obtained as a yellow oil. Yield: 19.7 g (57%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O[CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([O:1][C:2]2[CH:11]=[C:10]([N:12]([CH3:13])[CH3:14])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(N(C)C)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a mixture of methyl 2-hydroxy-4-(N,N-dimethylamino)benzoate (7.809 g, 40 mmol), 4-hydroxy-1-tert-butoxycarbonylpiperidine (8.048 g, 40 mmol), triphenylphosphine (11.02 g, 42 mmol), and THF (250 mL) at 0° C. was added diethyl azodicarboxylate (7.1 mL, 45.1 mmol), dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated, chromatographed (hexane to 30% EtOAc/hexane), and triturated with ether/hexane to give the desired product as a white solid (5.55 g, 37%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.C([Li])CCC.CN(C)[CH:33]=[O:34]>>[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14]([CH:15]=1)[CH:33]=[O:34])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: Cl
Agent: [Li]C
Agent: [Li]CCCC
Product: Cc1csc(Nc2ncc(C=O)cc2OCc2ccccc2)n1
Yield: 75.1 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1; 1.0 g, 2.66 mmol), MeLi (1.83 ml, 2.92 mmol), butyl lithium (1.17 ml, 2.92 mmol), and N,N-dimethylformamide (0.823 ml, 10.6 mmol) were reacted according to the method of Example 7 to provide the title compound (650 mg, 75.2% yield) as a pale yellow solid. 1H NMR (CDCl3) δ 9.91 (s, 1H), 8.88 (bs, 1H), 8.40 (d, 1H), 7.56 (d, 1H), 7.42 (m, 5H), 6.51 (m, 1H), 5.17 (s, 2H), 2.35 (s, 3H). Mass spectrum (apci) m/z=326.0 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)=[O:12])[O:8][N:7]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CO>[Cl:21][C:16]1[CH:15]=[C:14]([NH:13][C:11]([C:9]2[O:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:10]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1cc(OCCCBr)no1
Reactant: C1CCNC1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cc(OCCCN2CCCC2)no1
Yield: 92.4 %

Procedure:
A solution of 3-(3-bromopropoxy)-N-(3-chloro-4-fluorophenyl)isoxazole-5-carboxamide (38 mg, 0.10 mmol), and pyrrolidine (100 μL, 1.20 mmol) in tetrahydrofuran (1.5 mL) was stirred at room temperature for 4 h. The reaction was diluted with methanol and purified by preparative LCMS to give the desired product (34 mg, 92%). MF=C17H20ClFN3O3; LCMS calculated for C17H20ClFN3O3 (M+H)+: m/z=368.
Reaction SMILES: [C:1]1(=[O:10])[C@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][O:2]1.C[O-].[Na+].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[OH:2][CH2:3][C@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]1[C:1]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:10]
Reactant: O=C1OC[C@H]2CCCC[C@@H]12
Reactant: C1CCNC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C([C@H]1CCCC[C@@H]1CO)N1CCCC1

Procedure:
4 g of (3aS,cis) hexahydro-1-(3H)-isobenzofuranone in 20 ml of methanol and 4.76 ml of pyrrolidine with 0.386 g of sodium methylate were refluxed for 20 hours and one half of the methanol was distilled off at 50° C. under reduced pressure. Water and ice were added and the pH was adjusted to 1 by adding 2N hydrochloric acid. Extraction was done with methylene chloride and the extracts were washed with water, dried, filtered, evaporated to dryness under reduced pressure and crystallized from isopropyl ether to obtain 3.89 g of (1S,trans) 1-[(2hydroxymethyl-1-cyclohexyl)-carbonyl]-pyrrolidine melting at 115° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2)=[O:5].C(O)(=O)C.[Br:20]Br>O>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Br:20])[CH2:12][CH2:11][CH2:10]2)=[O:5]
Reactant: COCC(=O)Nc1ccc2c(c1)CCC2
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc2c(cc1Br)CCC2
Temperature: 10 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 5-methoxyacetamidoindan (5.50 g, 0.027 mol) and glacial acetic acid (25 ml) was cooled in an ice-water bath (˜10° C.). Bromine (1.5 ml, 0.029 mol) was then dropwise added over a 20 min period while the temperature was kept between 10-15° C. The reaction mixture was then stirred for a longer 1 hour and then it was poured into an ice-water bath (100 ml) with the aid of water (70 ml). The precipitate was collected by filtration, washed with plenty of water (150 ml) and dried in vacuo over P2O5 to afford the title compound (6.98 g, 91%), m.p. 84-86° C.; 1H-NMR (250 MHz, CDCl3, TMS) 2.09 (m, 2H, 2-CH2), 2.88 (m, 4H, 1-CH2 and 3-CH2), 3.55 (s, 3H, OCH3), 4.04 (s, 2H, 2-CH2OMe), 7.34, 8.22 (2×s, 2H, 4-H, 7-H), 8.83 (s, 1H, CONH);
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.[CH2:18]([O:20][C:21](Cl)=[O:22])[CH3:19]>ClCCl>[CH2:18]([O:20][C:21](=[O:22])[NH:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 35.2 %

Procedure:
To a stirred solution of 1H-indol-5-amine (11 g, 83.2 mmol) and triethyl amine (25.22 g, 250 mmol) in dichloromethane (110 mL) at −10° C., ethyl-chloro-formate (13.5 g 124.8 mmol) was added dropwise and stirred at 0° C. for 2-3 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the resultant residue was purified by flash column chromatography to give ethyl-1H-indol-5-ylcarbamate (5.980 g, 35.2%); MS: 205 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[S:12][C:11]3[S:13][C:14](C(O)=O)=[CH:15][C:10]=3[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C.O.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[S:12]1[C:11]2[S:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[C:6]([C:5]1[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C(O)c1cc2cc(C(=O)c3ccc(F)cc3)sc2s1
Agent: [Cu]
Agent: Cl
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: O=C(c1ccc(F)cc1)c1cc2ccsc2s1
Temperature: 0 °C
Yield: 92.5 %

Procedure:
5-(4-Fluorobenzoyl)-thieno[2,3-b]thiophene-2-carboxylic acid (48.1 g) and copper powder (8.2 g) are suspended in quinoline (410 cc) and heated at the boiling point for 5 minutes. After cooling, decolourizing charcoal (0.5 g) is added to the reaction mixture which is then filtered. The solution obtained is added dropwise to a mixture of distilled water (620 cc) and a 12 N aqueous solution of hydrogen chloride (289 cc), cooled in an ice bath, the rate of addition being regulated in such a way that the temperature of the mixture remains below 10° C. Distilled water (500 cc) is added to the reaction mixture, which is stirred for a further 30 minutes in the ice bath, and then the resulting crystals are filtered off, washed four times with distilled water (total 2000 cc) and dried in air. Crude (4-fluorophenyl) (thieno[2,3-b]thien-2-yl) ketone (38.1 g), melting at 113° C., is thus obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[N:9]=[CH:10][C:3]=12.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[C:19]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:11][CH2:12][N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[N:9]=[CH:10][C:3]=23)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ncnc2c1cnn2CCN1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ncnc3c2cnn3CCN2CCCCC2)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
A mixture of 4-chloro-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.19 mmol), phenylboronic acid (73 mg, 0.60 mmol) and anhydrous K2CO3 (82 mg, 0.59 mmol) in toluene (3 mL) was introduced in a microwave vial. It was degassed by argon for 30 minutes followed by the addition of Pd(PPh3)4 (4.0 mg, 0.003 mmol) after which the mixture was degassed for 10 additional minutes. The mixture was stirred at 150° C. for 30 min under microwave irradiation (150 W). After cooling to rt, the mixture was filtered on decalite and the solvent was removed at reduced pressure. The crude was purified by flash chromatography to provide 4-phenyl-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (19.1 mg, 0.06 mmol, 33%).