Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:32]([N:34]([CH2:38][CH2:39]O)[CH:35]([CH3:37])[CH3:36])=[O:33])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N2CCN(C(C)C)C(=O)C=12)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:39][CH2:38][N:34]([CH:35]([CH3:36])[CH3:37])[C:32](=[O:33])[C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3cccc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N1CCn2c(CC3(c4ccc(C(F)(F)F)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4cccc(C(F)(F)F)c4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O

Procedure:
9-(Benzyloxy)-2-isopropyl-6-((1-(3-(trifluoromethyl)phenyl)cyclopentyl)methyl)-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (478) was synthesized as a white solid from 5-(benzyloxy)-6-hydroxy-N-(2-hydroxyethyl)-N-isopropyl-2-((1-(3-(trifluoromethyl)phenyl)cyclo-pentyl)methyl)pyrimidine-4-carboxamide (477) following the procedure described for 9-benzyloxy-6-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (247).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(S(C)(=O)=O)cc1N
Yield: 73 %

Procedure:
A solution of ethyl 2-nitro-4-methylsulphonylbenzoate (10.0 g) in methanol was hydrogenated over 5% palladium on charcoal catalyst (1.2 g) at room temperature and atmospheric pressure. The resultant slurry was filtered and the filtrate was evaporated to dryness to give ethyl 2-amino-4-methylsulphonylbenzoate (6.5 g) as a yellow solid NMR (CDC3) 1.4(t,3H) 3.1(s,3H) 4.35(q,2H) 6.1(bs,2H) 7.0(d,1H) 7.2(s,1H) 7.95(d,1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1([C:12]([O:14]C)=[O:13])[CH2:11][CH2:10][CH2:9][O:8]1.B(Br)(Br)Br.CO.O>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9][O:8]1
Reactant: COC(=O)C1(Cc2cccc(OC)c2)CCCO1
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C1(Cc2cccc(O)c2)CCCO1
Temperature: 0 °C
Yield: 99.1 %

Procedure:
To a solution of 2.50 g of methyl 2-(3-methoxybenzyl)-tetrahydro-2-furancarboxylate in 50 ml of dichloromethane was added 22 ml of a 1 M solution of boron tribromide in dichloromethane at −70° C. under an atmosphere of nitrogen gas. After warming to 0° C., the mixture was cooled again to −70° C., and 20 ml of methanol was added. 200 ml of dichloromethane and 100 ml of water were further added. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated, to give 2.20 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:15]([CH3:23])[CH2:16][CH:17]([CH3:22])[CH2:18][CH2:19][CH:20]=[CH2:21])[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:15]([CH3:23])[CH2:16][CH:17]([CH3:22])[CH2:18][CH2:19][CH:20]=[CH2:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a solution of (3R)-ethyl 2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoate (20 g, 0.061 moles) in THF/water (200 mL, 1:1) was added methanol (60 mL) followed by LiOH (7.7 g, 0.183 moles) at room temperature. The reaction mass was stirred at room temperature overnight. The solution was concentrated under reduced pressure and the residue was diluted with water (200 mL). The aqueous solution was acidified with aqueous 1.5 N HCl solution to pH ˜3 and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduce pressure to get crude compound. The crude compound was purified by column chromotography (Silica gel, 3% methanol in DCM) to get 12.4 g (68%) of (3R)-2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoic acid as gummy liquid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.4 (sb, 1H), 6.92-6.85 (m, 1H), 5.81-5.75 (m, 1H), 5.04-4.93 (m, 2H), 4.12-3.91 (m, 1H), 2.18-1.98 (m, 4H), 1.5 (s, 9H), 1.35-1.02 (m, 3H), 0.98-0.85 (m, 6H).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][CH:8](Cl)Cl.C[O:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH:19]2[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[CH:15][CH:14]=1.[OH-].[NH4+]>C(Cl)Cl.O>[NH:26]1[CH:27]=[C:23]([CH2:22][CH:19]2[C:20]3[C:16](=[CH:15][C:14]([CH:13]=[O:12])=[C:8]([O:7][CH3:6])[CH:21]=3)[CH2:17][CH2:18]2)[N:24]=[CH:25]1
Reactant: COc1ccc2c(c1)C(Cc1c[nH]cn1)CC2
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1C=O)CCC2Cc1c[nH]cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tin(IV)chloride (1.60 g) is added dropwise to a stirred solution of dichloromethyl methyl ether (0.68 g) in methylene chloride (12 ml) with ice cooling under a nitrogen atmosphere. The solution is stirred at 0° C. for one hour before adding a solution of 4-(6-methoxyindan-1-ylmethyl)-1H-imidazole (0.60 g) in methylene chloride (4 ml). The resulting mixture is allowed to warm to ambient temperature while being stirred for 4 hours. The mixture is then poured into cold water and is made basic with ammonium hydroxide solution. The product is extracted into methylene chloride which is washed with water, dried with sodium sulfate and evaporated to dryness. The crude product is purified by flash chromatography using methylene chloride-methanol as eluent.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][C:27]([C:30]([OH:32])=[O:31])([CH3:29])[CH3:28])/[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][NH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[C:33]([C:35]1[C:36]([O:44]C(C2C=CC=CC=2)C2C=CC=CC=2)=[N:37][S:38][C:39]=1S(OC)=O)#[N:34].C(N(CC)CC)C.CC(O)=O>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][C:27]([C:30]([OH:32])=[O:31])([CH3:29])[CH3:28])/[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][NH:19][C:39]4[S:38][N:37]=[C:36]([OH:44])[C:35]=4[C:33]#[N:34])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN)CS[C@H]12)c1csc(N)n1)C(=O)O
Reactant: COS(=O)c1snc(OC(c2ccccc2)c2ccccc2)c1C#N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CNc3snc(O)c3C#N)CS[C@H]12)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.9 %

Procedure:
A mixture of 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-aminomethylceph-3-em-4-carboxylic acid (900 mg) and methyl 4-cyano-3-diphenylmethoxyisothiazol-5-sulphinate (800 mg) in solution in DMF (15 ml) containing 1 ml triethylamine was stirred at ambient temperature for five hours. The mixture was neutralised with HOAc and evaporated. The residue was purified by HPLC eluting with a 70/30 v/v mixture of methanol and water, and then with methanol to yield 700 mg of the desired product, nmr in solvent A 1.5 (s, 6 H); 3.8-4.1 (m, 2 H); 4.1-4.3 (m, 2 H); 5.15 (d, 1 H); 5.85 (d, 1 H); 7.0 (s, 1 H); 7.2-7.6 (m, 10 H).
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)C.Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1.C(N(CC)CC)C>C(O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:6]([C:7]3[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=3)=[N:5][CH:4]=[N:2]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(NN)cc1
Reactant: CN(C)C=NC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2ncnc2-c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 7.7 %

Procedure:
A mixture of N-(dimethylamino-methylene)-4-(methyl-sulfonyl)-benzamide (4 g, 15.7 mol), 4-methoxy-phenylhydrazine hydrochloride (2.75 g, 15.7 mmol), triethylamine (2.2 ml, 15.7 mmol) in ethanol (20 ml) was heated to reflux for 25 h. After cooling, the reaction mixture was concentrated to dryness, then diluted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over sodium sulfate. The residue was chromatographed on silica gel using a 70/30 mixture of toluene/dioxane as the eluent, then recrystallized from ethanol to give a light orange solid (0.4 g, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[NH:10][C:9]1=S.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>O=P(Cl)(Cl)Cl>[Cl:22][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=1
Reactant: O=c1c2cc(F)ccc2[nH]c(=S)n1-c1ccccc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2cc(F)ccc2nc(Cl)n1-c1ccccc1Cl

Procedure:
A suspension of 265 mg (0.87 mmol) of 3-(2-chloro-phenyl)-6-fluoro-2-thioxo-2,3-dihydro-1H-quinazolin-4-one in 2.0 mL of POCl3 was treated with 300 mg of PCl5 and the mixture was refluxed for 2.5 hours. The solvent was evaporated and the residues were taken up in ethyl acetate, washed with water and brine, and then the solvent was evaporated to give 2-chloro-3-(2-chloro-phenyl)-6-fluoro-3H-quinazolin-4-one as a solid. This material was dissolved in 10 mL of absolute ethanol and 216 mg ( 1.73 mmol) of 2-fluorobenzylamine and the mixture was refluxed overnight. The reaction mixture was cooled and the solvent was evaporated. The residues were partitioned between ethyl acetate and dilute HCl and the aqueous phase was extracted further with ethyl acetate. The combined organic extracts were dried with brine and with magnesium sulfate (MgSO4) and evaporated to give a gum which was crystallized from ether to give 157 mg (45%) of the desired product, m.p. 163-165° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[NH:11][C:10]2=[O:17])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.CN(C)C=O.N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>O.C(Cl)(Cl)Cl>[Si:28]([CH:7]([OH:8])[C@H:5]1[O:6][C@@H:1]([N:9]2[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[NH:11][C:10]2=[O:17])[CH2:2][C@@H:3]1[OH:4])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN1CN([C@H]2C[C@H](O)[C@@H](CO)O2)C(=O)NC1=O
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN1CN([C@H]2C[C@H](O)[C@@H](C(O)[Si](C)(C)C(C)(C)C)O2)C(=O)NC1=O
Reaction time: 18 h
Yield: 82.5 %

Procedure:
A reaction mixture consisting of 12.25 gm. (0.050 mole) of 1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione, 50 ml. dimethylforamide, and 8.5 gm. (0.125 mole) of imidazole was warmed to 35° C. and stirred until the imidazole had dissolved. There was then added with continued stirring 7.55 gm. (0.050 mole) tert-butyldimethylsilyl chloride. Stirring was continued for 18 hours at 35° C. The solvent medium was then removed by evaporation under reduced pressure, and the residue thus obtained was dispersed in a solvent mixture consisting of 200 ml. chloroform and 50 ml. water. The two phases were allowed to stabilize and the aqueous phase was recovered. It was washed two times with 50 ml. portions of chloroform. The three chloroform layers (original and two washings) were combined and washed with three-25 ml. portions of water. The washed chloroform solution was dried over anhydrous magnesium sulfate and filtered. The chloroform was then removed by evaporation under reduced pressure to give 14.8 gm. (82.5% yield) of 1-(5-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](F)[N:13]=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(F)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cccc(OCc2ccccc2)n1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
Benzylalcohol (1.88 g, 17.38 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 458 mg, 19.11 mmol) in tetrahydrofuran (15 mL) and the mixture was heated to 50° C. for 45 minutes. The reaction mixture was then cooled to room temperature, a solution of 2,6-difluoropyridine (2 g, 17.38 mmol) in tetrahydrofuran (4 mL) was added dropwise and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was then diluted with ethyl acetate, concentrated in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic layer was separated, washed with brine (20 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was then concentrated in vacuo from dichloromethane to afford the title compound as a clear oil in 98% yield, 3.48 g. LRMS APCI m/z 204 [M+H]+
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([CH2:31]Br)[CH:28]=[CH:27][C:26]=1[N+:33]([O-:35])=[O:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([CH2:31][CH:2]([CH3:1])[C:3](=[O:6])[CH2:4][CH3:5])[CH:28]=[CH:27][C:26]=1[N+:33]([O-:35])=[O:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Reactant: CCC(=O)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(=O)C(C)Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of pentan-3-one (516 mg, 6 mmol) in THF (5 mL) at −78° C. is added dropwise LiHMDS (6.6 mL of 1.0 M solution in THF, 6.6 mmol) over a period of 15 min. The solution is stirred at −78° C. for 2 h then a solution of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (Example 83, step C) (963 mg, 3 mmol) in THF (5 mL) is added dropwise. The mixture is allowed to warm to RT overnight and is quenched with saturated ammonium chloride solution. The mixture is extracted with EtOAc and the organic phase is washed with brine then dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 10-50% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:45]1[CH2:50][CH2:49][CH:48]([CH2:51][S:52](Cl)(=[O:54])=[O:53])[CH2:47][CH2:46]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:36][C:33]1[CH:34]=[CH:35][N:22]2[C:23]=1[C:24](=[O:32])[N:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]([C@@H:18]([NH:17][C:15]1[C:16]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][S:52]([CH2:51][CH:48]5[CH2:49][CH2:50][O:45][CH2:46][CH2:47]5)(=[O:54])=[O:53])[CH:7]=4)=[CH:9][N:10]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[C:11]=3[N:12]=[CH:13][N:14]=1)[CH3:19])=[N:21]2
Reactant: O=S(=O)(Cl)CC1CCOCC1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc(N)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc(NS(=O)(=O)CC5CCOCC5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 54.9 %

Procedure:
(S)-2-(1-((5-(2-Aminopyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with (tetrahydro-2H-pyran-4-yl)methanesulfonyl chloride (26 mg, 0.13 mmol) and triethylamine (36 μl, 0.26 mmol) in pyridine (2 ml) according to the method described in Preparation 15b. The residue was purified using SP1® Purification System (hexane-ethyl acetate) to give 55 mg (53% yield) of the title compound. Purity 98%.
Reaction SMILES: CO[C:3]1[C:6](=O)[C:5](=[O:8])[C:4]=1[O:9]C.[Br:11][C:12]1[CH:13]=[C:14]([CH3:23])[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[N:16][CH:17]=1.[CH3:24][NH2:25]>CCOCC.C(O)C.C(Cl)(Cl)Cl>[CH3:24][NH:25][C:6]1[C:5](=[O:8])[C:4](=[O:9])[C:3]=1[NH:22][CH2:21][CH2:20][CH2:19][CH2:18][C:15]1[C:14]([CH3:23])=[CH:13][C:12]([Br:11])=[CH:17][N:16]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: CN
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CNc1c(NCCCCc2ncc(Br)cc2C)c(=O)c1=O

Procedure:
Treatment of 1,2-dimethoxycyclobut-1-ene-3,4-dione with 4-(5-bromo-3-methylpyrid-2-yl)-butylamine in dry ether at 0° C. followed by methylamine in ethanol and chromatography in chloroform on silica gel yielded 1-methylamino-2-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]-cyclobut-1-ene-3,4-dione m.p. 190°-191° C. after recrystallisation from acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[CH3:8].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH2:30])[CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:30][CH2:29][C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1Br
Reactant: NCc1cccnc1
Product: Cc1ccc(Nc2c(C#N)cnc3cnc(NCc4cccnc4)cc23)cc1Br
Yield: 14 %

Procedure:
Following the procedure described above in Example 1, 4-[(3-bromo-4-methylphenyl)amino]-6-fluoro-[1,7]naphthyridine-3-carbonitrile (300 mg, 1.1 mmol, 1 eq) was reacted with pyridine-3-ylmethylamine (2.8 mL, 20 eq). The crude product was purified via preparative HPLC to obtain 55 mg product (14% yield): HRMS (ESI+) calcd for C22H17BrN6 445.0771 (M+H), found (M+H) 445.0761.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([N:19]2[CH2:20][CH:21]([CH3:23])[CH2:22][CH:17]([CH3:16])[CH2:18]2)(=[O:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)cc(S(=O)(=O)Cl)c1
Reactant: CC1CNCC(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CC(C)CN(S(=O)(=O)c2cc(Cl)cc(C(=O)O)c2)C1
Reaction time: 1.5 h

Procedure:
3-Chloro-5-chlorosulfonylbenzoic acid (770 mg., 3 m moles) is added to a solution of 3,5-dimethylpiperidine hydrochloride in 30 ml. of water followed by the portionwise addition of 12 ml. of 1N sodium hydroxide solution with stirring. After 1.5 hrs. at room temperature the reaction mixture is filtered and the filtrate acidified with 12N hydrochloric acid. The product, 600 mg., m.p. 226°-331° C., is recrystallized from acetone-hexane, 390 mg., m.p. 232.5°-234° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1([C:13]2[S:17][C:16](B(O)O)=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.I[C:22]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:42])[CH:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][CH3:35])=[CH:27][C:23]=1[C:24]([NH2:26])=[O:25].C(OCC)(=O)C>O1CCOCC1.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:36]1([CH:33]([CH2:34][CH3:35])[C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:22]([C:16]3[S:17][C:13]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[CH:14][CH:15]=3)=[C:23]([CH:27]=2)[C:24]([NH2:26])=[O:25])=[O:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1ccccc1
Reactant: OB(O)c1ccc(-c2ccccc2)s1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC(C(=O)Nc1ccc(-c2ccc(-c3ccccc3)s2)c(C(N)=O)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.5 ml of saturated aqueous sodium carbonate solution, 37 mg (0.18 mmol) of 5-phenyl-2-thiopheneboronic acid and 14 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium are added to 50 mg (0.12 mmol) of the compound of Example 5A in 3 ml of dioxane. The mixture is stirred at 80° C. overnight and, after addition of 50 ml of ethyl acetate, extracted three times with 50 ml of water. The organic phase is dried over magnesium sulfate and freed of solvent under reduced pressure. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 10:90→95:5). 18 mg (30% of theory) of product are obtained.
Reaction SMILES: C(O)C.COS([O-])(=O)=O.[Cl:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][N:15]1[C:23]([CH2:24][N+](C)(C)C)=[C:22]([CH3:29])[N:21]=[C:16]12.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CS(C)=O>[Cl:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][N:15]1[C:23]([CH2:24][C:31]3[NH:30][CH:34]=[CH:33][N:32]=3)=[C:22]([CH3:29])[N:21]=[C:16]12
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1C[N+](C)(C)C
Reactant: c1c[nH]cn1
Agent: COS(=O)(=O)[O-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1nc2c3cccc(Cl)c3ccn2c1Cc1ncc[nH]1
Temperature: 100 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
Ethanol (50 ml) was added to a mixture of 7-chloro-2-methyl-3-trimethylammoniomethylimidazo[2,1-a]isoquinoline methylsulfate (2.3 g) and imidazole (0.95 g) in dimethyl sulfoxide (20 ml) and heated at 100° C. with stirring for 5 hours. After the removal of ethanol by distillation, the residue was poured into water. The resulting precipitates were collected by filtration, dried and recrystallized from ethyl acetate. The obtained crystals were chromatographed on silica gel (16 g) with a mixture of chloroform and methanol (10:1) as an eluent. The eluates were evaporated in vacuo and the residual solid was recrystallized from ethyl acetate to give 7-chloro-3-(1-imidazolylmethyl)-2-methylimidazo[2,1-a]isoquinoline (0.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[C:9](SC)[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:12]=2[N:13]=1.[S:32]([O-:37])(O[O-])(=O)=[O:33].[K+].[K+].[CH2:40]1COCC1>CO.O>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:3]=1[CH2:4][C:5]1[S:6][C:7]2[N:8]=[C:9]([S:32]([CH3:40])(=[O:37])=[O:33])[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[C:12]=2[N:13]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CSc1nc(Nc2ccc(C(F)(F)F)cc2)c2nc(Cc3c(Cl)cccc3Cl)sc2n1
Reactant: C1CCOC1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1nc(Nc2ccc(C(F)(F)F)cc2)c2nc(Cc3c(Cl)cccc3Cl)sc2n1
Temperature: 40 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of [2-(2,6-dichloro-benzyl)-5-methylsulfanyl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (110 mg, 0.22 mmol) in THF (6 mL) and MeOH (6 mL) was added a solution of potassium peroxymonosulfate (406 mg, 0.66 mmol) in H2O (6 mL). The resulting mixture was stirred vigorously at 40° C. After 24 h, the mixture was concentrated and the crude residue was diluted with satd. aq. NaHCO3 (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried, concentrated, and purified by FCC to afford a colorless solid (100 mg, 85%). MS (ESI): mass calcd. for C20H13Cl2F3N4O2S2, 531.9; m/z found, 532.9 [M+H]+. 1H NMR ((CD3)2SO): 11.02 (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 7.64 (d, J=8.1 Hz, 2H), 7.50 (dd, J=8.5, 7.8 Hz, 1H), 4.89 (s, 2H), 3.37 (s, 3H).