Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]1([C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:24]([O:23][CH2:22][N:10]1[C:9](=[O:14])[C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:12][C:11]1=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Reactant: ClCOCc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1COCc1ccccc1
Temperature: 25 °C

Procedure:
5,5-Diphenylhydantoin sodium (27.5 g) was suspended in 250 ml of dimethylformamide. To the suspension was added 15 ml of chloromethylbenzylether with good stirring and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into 1 liter of ice cold water and stirred for one hour. The solid product was removed by filtration and dissolved in 150 ml of hot ethanol. To the boiling solution 1 g of activated carbon was added and the hot solution was filtered through a Buchner funnel which contained a compacted layer of finely-divided diatomaceous silica. The cake was washed three times with 10 ml of ethanol and the hot solution together with the washings was allowed to cool to room temperature. The resulting crystals were filtered and recrystallized two more times in the same manner as described for the first crystallization. There was obtained 13.1 g of 3-benzyloxymethyl-5,5-diphenylhydantoin, m.p. 151°-152°.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[N+:21]([O-])=O)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:34])[CH:33]=1)[C:28](Cl)=[O:29].Cl>N1C=CC=CC=1>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:34])[CH:33]=1)[C:28]([NH:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[CH:19]=[CH:20][C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)=[N:12]2)=[O:29]
Reactant: O=[N+]([O-])c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-Indan-1-yl-(5-nitro-quinolin-2-yl)-amine (0.15 g, 0.545 mmol) was dissolved in 1.5 mL pyridine and 3,5-difluorobenzoylchloride (0.98 g, 0.554 mmol) was added. The reaction mixture was stirred at room temperature overnight. 1 N HCl was added until pH5. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from isopropanol and diisopropylether. The title compound was obtained as a brown solid (44 mg, 19%), MS: m/e=416.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:54][O:55][CH2:56][CH2:57][NH2:58]>O.CN(C)C=O>[CH3:54][O:55][CH2:56][CH2:57][NH:58][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1
Reactant: COCCN
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.3 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), 2-methoxyethylamine (100 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 20 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (200 mg, 59%) as pale yellow prisms. MS 519 (MH+). mp 175-176° C.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.C(OCC)(OCC)OCC.[CH:20]1[CH:25]=CC(C2C=CC=CC=2)=C[CH:21]=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[N:4]1[C:5]2[C:6](=[N:9][CH:21]=[CH:20][CH:25]=2)[CH:7]=[CH:8][CH:3]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(N)cn1
Solvent: CCOC(OCC)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: c1cnc2cccnc2c1

Procedure:
An alternative synthetic sequence to obtain the key intermediate E is described in Scheme 2. Commercially available 2-methoxy-5-aminopyridine F is converted by heating in the presence of ester B and triethyl orthoformate to the condensation product G as a mixture of olefin isomers (Scheme 2). Intermediate G is added to hot Dowtherm™ A to facilitate the ring closure and to yield the 1,5-naphthyridine H. Demethylation at the 6-position of H is conducted by treatment with trimethylsilyl chloride and sodium iodide in refluxing acetonitrile to give intermediate I, which may be used, without purification, for the reaction with phosphorus oxychloride to provide the key intermediate E (Scheme 2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([O:23]CC)=O)[N:9]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]1>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[O:23])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: CN1CCN(CCN)CC1
Solvent: CCO
Product: CN1CCN(CCNC(=O)Cn2nc(-c3ccccc3O)nc2-c2ccccc2O)CC1

Procedure:
3 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 2.5 g of 2-(4-methylpiperazin-1-yl)ethylamine are boiled under reflux for 20 h in 40 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel. After concentration and drying, 2-[3,5-bis(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-N-[2-(4-methylpiperazin-1-yl)ethyl]acetamide is obtained as a colorless foam. Rfvalue: 0.17 (silica gel 60, methylene chloride/methanol=9/1). 1H-NMR (DMSO-d6): 2.1 (s, 3H), 2.3 (m, 10H), 3.15 (m, 2H), 4.9 (s, 2H), 7.0 (m, 4H), 7.4 (m, 3H), 8.0(m, 2H), 11.0 ppm (s, 1H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:31]1[CH2:32][CH2:33][N:28]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:29][CH2:30]1)=[O:13])[CH2:8]2
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCN(Cc2ccccc2)CC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and N-benzylpiperazine (0.54 mL; 3.1 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-(4-benzyl-piperazin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (50 mg, 38%) as an off-white powder. ES-HRMS m/e calcd for C26H35N5O (M+H+) 434.2915, found 434.2910.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:33]([CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[CH3:34])=[CH:9][C:10]([O:31][CH3:32])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[C:17]([C:29]#[N:30])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:29]([C:17]1[C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:31][CH3:32])=[CH:9][C:8]([N:33]([CH2:35][CH2:36][N:37]([CH3:38])[CH3:39])[CH3:34])=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:30]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(C#N)c(-c2cnn3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cnn4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
A solution of acryloyl chloride (0.087 mL, 1M, THF, 0.09 mmol) was added dropwise to a mixture of 2-{[5-amino-4-(2-dimethylaminoethyl-methylamino)-2-methoxyphenyl]-amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile (Intermediate 121, 0.036 g, 0.08 mmol) and DIPEA (0.017 mL, 0.09 mmol) in THF (5 mL) which was cooled to 0° C. The mixture was stirred at 0° C. for 3 h, then concentrated in vacuo. Purification by FCC, eluting with 0-20% CH3OH in CH2Cl2 have crude product which appeared to contain the hydrochloride salt of DIPEA. The material was dissolved in CH2Cl2 (10 mL) and stirred with sat. NaHCO3 solution (10 mL). The phases were separated and the organic solution was concentrated in vacuo to give the title compound (24 mg, 60%) as a yellow gum; 1H NMR: (CDCl3) 2.22 (6H, s), 2.26 (2H, dd), 2.67 (3H, d), 2.77-2.86 (2H, m), 3.81 (3H, s), 5.61 (1H, dd), 6.16-6.35 (2H, m), 6.76 (1H, s), 6.88 (1H, d), 7.23 (1H, s), 7.65 (1H, s), 8.50 (2H, dd), 8.59 (1H, s), 9.02 (1H, s), 9.28 (1H, s), 10.08 (1H, s); m/z: ES+ MH+ 512.29.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=3[CH:15]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:21]Br>C(Cl)(Cl)(Cl)Cl.ClCl>[CH2:1]([O:3][C:4]([C:6]1([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=3[C:15]=2[Br:21])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2cc3cc(C)ccc3o2)CCCC1
Reactant: BrBr
Agent: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1(c2oc3ccc(C)cc3c2Br)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of product of Step 4, above (58) (1.0 mmol) in 2 ml CCl4 was added bromine (1.0 mmol) at ambient temperature and the reaction mixture was stirred for 2 hours, refluxed for 1 hour to ensure completion of the reaction, cooled to ambient temperature, diluted with CH2 Cl2 and washed with saturated sodium bicarbonate and brine. The combined organics were dried over MgSO4, filtered and concentrated to dryness. The crude residue was chromatographed on silica gel using 5% EtOAc in hexanes as the eluant to obtain the title compound (59).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl.[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH:32]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][N:14]2[CH2:15][CH2:16][CH:11]([O:10][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=3[C:7]#[N:8])[CH2:12][CH2:13]2)[CH2:29][CH2:30]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: N#Cc1cc(F)ccc1OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3C#N)CC2)CC1

Procedure:
The title compound was prepared analogously to example 1 (1.3) starting from 5-Fluoro-2-(piperidin-4-yloxy)-benzonitrile; hydrochloride and Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester with sodium triacetoxyborohydride in 1,2-dichloroetane. MS (m/e): 446.3 (M+H+)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Cl[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24].[I-].[Na+]>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: OCCCCCCCl
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 34.0 g (0.2 mole) or p-phenylphenol (Eastman) and 10.8 g (0.2 mole) of sodium methoxide (MCB) in 500 ml of dry dimethylformamide is heated and stirred on a steam bath for 0.5 hour, after which 27.3 g (0.2 mole) of 6-chlorohexan-1-ol (MCB) and about 2 g of sodium iodide are added. The mixture is heated to reflux with stirring, and then allowed to cool to room temperature. The reaction mixture is partitioned between ether/acetone and water, and the organic phase is extracted with base, washed with water and brine, dried (Na2SO4), and the solvent evaporated. The resultant white solid product is recrystallized twice from methanol/acetone, to give the desired product, m.p. 103°-105° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[C@H:21]12[CH2:27][C@H:24]([NH:25][CH2:26]1)[CH2:23][N:22]2[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:25]3[CH2:26][C@@H:21]4[CH2:27][C@H:24]3[CH2:23][N:22]4[CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Reactant: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3Cc2ccc(Oc3ccc(-c4ncco4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99.6 %

Procedure:
4-[4-(2-oxazolyl)phenoxy]benzaldehyde (10.2 g, 38.5 mmol) and methyl 4-[[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate (9.9 g, 40.4 mmol, 1.05 equiv.) were dissolved in dichloroethane (200 mL). After 75 minutes, sodium triacetoxyborohydride (9.8 g, 46.1 mmol, 1.2 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature. Then, 1N NaOH was added. The reaction mixture was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with 0.5 M H2SO4, and MeOH was added to the mixture until the precipitated gummy solid dissolved. The layers were separated and the aqueous layer was cooled to −5 C. and saturated K2CO3 was added slowly enough to keep the temperature below 0 C. to prevent ester hydrolysis. Once the pH was 11, the solution was extracted with EtOAc (2×), and the combined EtOAc fractions were dried and concentrated to give 19.0 g (100%) of methyl 4-[[(1S,4S)-5-[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate as the free base, which was 98% pure by HPLC; 1H NMR (300 MHz, CDCl3) δ 8.02 (d, 2H), 8.02 (d, 2H), 7.69 (d, 1H), 7.47 (d, 2H), 7.40 (d, 2H), 7.22 (d, 1H), 7.08 (d, 2H), 7.05 (d, 2H), 3.92 (s, 3H), 3.84 (d, 1H), 3.78 (d, 1H), 3.77 (d, 1H), 3.71 (d, 1H), 3.35 (s, 1H), 3.31 (s, 1H), 2.89 (d, 1H), 2.88 (d, 1H), 2.71 (dd, 1H), 2.70 (dd, 1H), 1.79 (s, 2H) ppm.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[I:22]I>O1CCCC1>[C:1]([NH:5][S:6]([C:9]1[C:10]([O:15][CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=1[I:22])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: COc1ccccc1S(=O)(=O)NC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(I)c1S(=O)(=O)NC(C)(C)C
Temperature: -30 °C
Reaction time: 8 h

Procedure:
A solution of 30.00 g (123.29 mmol) of N-(tert-butyl)-2-methoxybenzenesulfonamide in 400 ml of tetrahydrofuran is cooled to −70° C. and slowly admixed with a solution of 110.96 ml (277.41 mmol) of a 2.5 molar n-butyllithium solution in THF. The solution is subsequently warmed briefly to −30° C. and then cooled again to −60° C. At this temperature a solution of 31.29 g (123.29 mmol) of iodine in 200 ml of tetrahydrofuran is added dropwise. Subsequently the reaction solution is stirred at room temperature overnight. Following extraction with water, the organic phase is dried over sodium sulfate and evaporated to dryness. This gives 42.40 g (93% of theory) of N-(tert-butyl)-2-iodo-6-methoxybenzenesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:62]1[C:67](=[O:68])[CH2:66][CH2:65][C:63]1=[O:64])=[N+](C)C)C>C1COCC1>[C:1]([O:5][C:6](=[O:39])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][N:62]2[C:67](=[O:68])[CH2:66][CH2:65][C:63]2=[O:64])=[O:36])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)NCCCC(=O)O)cc(C(=O)OC(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)NCCCC(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 5-[9-(3-Carboxy-propylcarbamoyl)-nonyloxy]-isophthalic acid di-tert-butyl ester (62 mg, 0.11 mmol) in dry THF (2 ml) was added DIPEA (0.05 ml) and TSTU (41 mg, 0.14 mmol). The mixture was stirred at room temperature under nitrogen over night. The mixture was concentrated and EtOAc was added to the residue. The precipitate was removed by filtration. The filtrate was washed with 0.1 N HCl (2×) and brine (1×), dried (Na2SO4) and concentrated to give a clear syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:10][C:9]2=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:10]=[C:9]2[N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cccc(C)c1CNc1ccc2nc(-n3cc(C(=O)O)cn3)nc(N3CCCC3)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI/CI): predicted mass C25H26N6O2, 442.2.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[C:15]([O:19][C:20]([N:22]1[CH2:29][CH:28]2[O:30][CH:24]([CH2:25][NH:26][CH2:27]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH:24]2[O:30][CH:28]([CH2:27][N:26]([CH2:2][CH2:3][NH:4][S:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)(=[O:7])=[O:6])[CH2:25]2)[CH2:29]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: O=S(=O)(NCCBr)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCNS(=O)(=O)c3ccc(F)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of N-(2-Bromo-ethyl)-4-fluoro-benzenesulfonamide (7 g, 0.0179 mol; see step (i) above) and 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (11.2 g, 0.159 mol; see WO 01/28992) and K2CO3 (9.7 g, 0.0798 mol) in dry acetonitrile (70 ml) was stirred at 60° C. overnight under nitrogen atmosphere. The reaction mixture was partitioned between brine and ethyl acetate. Organic layer was washed with brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by column chromatography over silica gel using 7% ethyl acetate in petroleum ether as eluent afforded the sub-title compound as a solid. Yield: 4 g
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[CH3:14][S:13][C:4]1[N:3]=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of 5.0 g (21.49 mmol) of ethyl 4-chloro-2-methylsulfanyl-5-pyrimidinecarboxylate and 4.9 mL (53.72 mmol) of aniline in 75 mL of THF are added 7.49 mL (53.72 mmol) of triethylamine. The mixture is stirred at room temperature overnight. After evaporating off the THF, aqueous 1N HCl solution is added and the mixture is extracted with ethyl acetate. The organic phase is washed with saturated aqueous NaHCO3 solution and then with NaCl solution. The organic phase is dried over MgSO4. After filtering, the filtrate is concentrated to give 3.99 g of the expected product in the form of a beige-coloured solid, which is used as obtained in the following step. Yield=64%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CCCO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of the (R)-(tetrahydrofuran-2-yl)methanol (Aldrich, 12 g, 0.12 mol) in 40 mL CH2Cl2 and 40 mL pyridine was added 4-dimethylaminopyridine (DMAP, 0.72 g, 5.9 mmol). This mixture was cooled to 0° C. and p-toluenesulfonyl chloride (23.5 g, 0.123 mol) was added portionwise over 20 minutes. The mixture stirred at ambient temperature for 16 hours, then quenched with excess 5% aqueous HCl. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 65% hexanes in EtOAc) provided the title compound. MS (DCI/NH3) m/z 257 (M+H)+; m/z 274 (M+NH4)+.