Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Cl[CH2:29][C:30](=O)[CH3:31].CN(C)C=O>O>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:27][CH:29]=[C:30]([CH3:31])[N:26]=1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Reactant: CC(=O)CCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)n1
Temperature: 85 °C
Reaction time: 0.67 h
Yield: 82.5 %

Procedure:
A mixture of 0.76 g (1.98 mmol) of the starting material I, 1.10 g (11.88 mmol) of chloroacetone and 15 ml of dimethylformamide was stirred at 80-90° C. for 40 min. Then the reaction mixture was diluted with water, the precipitated crystals were filtered off, dried and purified by refluxing in ethanol to yield 0.69 g (82%) of the title compound; Mp.: 188-189° C.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CC(C)=O>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:13][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=2[CH:2]([OH:1])[CH3:3])=[CH:24][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(O)c1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COc2cccc([N+](=O)[O-])c2C(C)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
To a stirred solution of 2-(1-hydroxyethyl)-3-nitrophenol (0.300 g, 1.638 mmol) in acetone (5 mL) was added potassium carbonate (0.25 g, 1.802 mmol). The mixture was stirred at room temperature for 15 min, and 4-methoxybenzyl chloride (0.22 mL, 1.638 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 hrs and at 60° C. for 3 hrs. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1). The purified compound was washed with diisopropyl ether to give 1-{2-[(4-methoxybenzyl)oxy]-6-nitrophenyl}ethanol as a white solid (0.201 g, yield; 41%).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.Cl.[CH3:29][O:30][C@@H:31]1[CH2:35][NH:34][CH2:33][C@H:32]1[NH2:36]>>[NH2:36][C@H:32]1[C@H:31]([O:30][CH3:29])[CH2:35][N:34]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=3)=[O:7])=[CH:4][N:3]=2)[CH2:33]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: CO[C@@H]1CNC[C@H]1N
Agent: Cl
Product: CO[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccn[nH]2)C[C@H]1N

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 38 using 6-chloro-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 38.1) and trans-4-methoxypyrrolidin-3-amine dihydrochloride (Stage 78.1) to afford a white solid. HPLC (Condition 7) tR=5.675 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=463.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.58 (br. s, 2H) 2.83-2.98 (m, 1H) 3.07-3.18 (m, 1H) 3.21 (s, 3H) 3.26-3.43 (m, 2H) 3.45-3.59 (m, 2H) 6.39 (br. s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.49-7.91 (m, J=8.60 Hz, 3H) 8.03 (br. s, 1H) 8.72 (br. s, 1H) 10.18 (s, 1H) 12.76-13.24 (m, 1H).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[CH2:8]([NH:10][CH2:11][CH3:12])[CH3:9]>C(Cl)Cl.[OH-].[Na+]>[Cl:1][CH:2]([CH2:6][CH3:7])[C:3]([N:10]([CH2:11][CH3:12])[CH2:8][CH3:9])=[O:4]
Reactant: CCC(Cl)C(=O)Cl
Reactant: CCNCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC(Cl)C(=O)N(CC)CC
Yield: 65.7 %

Procedure:
Following the procedure of Kem K. M.; Nguyen N. V.; Cross D. J. J. Org. Chem. 1981;46:5188 for the preparation of chloroacetamides, a solution of 2-chlorobutyryl chloride (61.91 mmol, 8.73 g, Lancaster) in 28 mL of CH2Cl2 was added to diethylamine (56.28 mol, 4.12 g, Aldrich) in a mixture of CH2Cl2 (56 mL) and NaOH (56 mL, 20% aqueous) at −25° C. to furnish 2-chloro-N,N-diethyl-butyramide (7.23 g, 72%). 1HNMR (400 MHz, CDCl3) δ 0.98 (t, J=7.33 Hz, 3H, CH2CH3), 1.12 (t, J=7.08 Hz, 3H, CH2CH3), 1.19-1.23 (m, 3H, CH2CH3), 1.89-2.00 (m, 1H, CH2CH3), 2.03-2.14 (m, 1H, CH2CH3), 3.22-3.38 (m, 2H, NCH2CH3), 3.41-3.52 (m, 2H, NCH2CH3), 4.26 (t, J=7.08 Hz, 1H, CHCl); MS(APCI+): m/z 177.9 (M+1), 179.9 (M+3).
Reaction SMILES: C(O)(C)C.[OH:5][CH:6]([CH2:16][OH:17])[CH2:7][NH:8][C:9]([CH3:15])=[CH:10][C:11]([O:13][CH3:14])=[O:12].[Cl:18][C:19]1[N:20]=[C:21]([N+:27]([O-:29])=[O:28])[C:22]([NH2:26])=[N:23][C:24]=1Cl>C(N(CC)CC)C>[NH2:26][C:22]1[N:23]=[C:24]([C:10](=[C:9]([NH:8][CH2:7][CH:6]([OH:5])[CH2:16][OH:17])[CH3:15])[C:11]([O:13][CH3:14])=[O:12])[C:19]([Cl:18])=[N:20][C:21]=1[N+:27]([O-:29])=[O:28]
Reactant: COC(=O)C=C(C)NCC(O)CO
Reactant: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COC(=O)C(=C(C)NCC(O)CO)c1nc(N)c([N+](=O)[O-])nc1Cl

Procedure:
To 75 ml of isopropanol is added 3.3 g (0.017 m) methyl 3-(2,3-dihydroxypropyl)amino-2-butenoate (3), 4.18 g (0.02 m) 5,6-dichloro-3-nitropyrazinamine (5), and 2.0 g (0.02 m) triethylamine. This solution is heated at 60°-65° for two days. The reaction mixture is then stripped on the rotary evaporator and the residue chromatographed on silica gel eluted with 12% methanol/chloroform. Material with Rf =0.5 is collected and after crystallization from acetonitrile the desired product is an orange solid, m.p. 184°-186° (dec).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH:15]1[CH2:16][CH2:17][N:12]([C:9]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[O:10])[CH2:13][CH2:14]1)[CH3:23]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 18 h
Yield: 98.7 %

Procedure:
Benzyl chloridocarbonate (10.5 g, 61.3 mmol) was added to a solution of ethyl piperidin-4-ylacetate (10.0 g, 58.4 mmol) and sodium carbonate (46.2 g, 438 mmol) in dichloromethane (320 mL). After 18 h, the reaction mixture was filtered and concentrated. Purification by silica gel chromatography [75% hexanes/ethyl acetate→50% hexanes/ethyl acetate)] gave the title compound (17.6 g). MS 306.1 (M+1).
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[Br:27][C:28]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:29]=1[CH:30]=O>O1CCCC1.O>[Br:27][C:28]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:29]=1[CH:30]=[CH2:2]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)ccc1Br
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A mixture of methyltriphenylphosphonium iodide (1.195 g, 2.96 mmol) in tetrahydrofuran (25 mL) was added BuLi (1.182 mL, 2.96 mmol) at 0° C. and stirred at 0° C. for 0.5 h. It was then added 2-bromo-5-fluorobenzaldehyde (0.5 g, 2.463 mmol) and stirred at rt for 16 h. The reaction was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 5% EtOAc/hexane to obtain 1-bromo-4-fluoro-2-vinylbenzene (320 mg, 1.592 mmol, 64.6% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.56-7.48 (m, 1H), 7.33-7.23 (m, 1H), 7.09-6.96 (m, 1H), 6.89 (td, J=8.3, 3.1 Hz, 1H), 5.73 (d, J=17.4 Hz, 1H), 5.45 (d, J=11.0 Hz, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:34]([C:37]1[CH:38]=[N:39][C:40]2[C:45]([C:46]=1[NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH3:55])[CH:49]=1)=[CH:44][C:43]([S:56]([C:59]1[CH:60]=[C:61]([CH:65]=[CH:66][CH:67]=1)[C:62](O)=[O:63])(=[O:58])=[O:57])=[CH:42][C:41]=2[CH3:68])(=[O:36])[NH2:35].[NH2:69][C:70]1[CH:75]=[CH:74][C:73]([C:76]2([CH2:81][CH2:82][CH2:83][CH2:84][N:85]([CH2:93][C@H:94]([O:107][Si:108]([C:111]([CH3:114])([CH3:113])[CH3:112])([CH3:110])[CH3:109])[C:95]3[CH:104]=[CH:103][C:102]([OH:105])=[C:101]4[C:96]=3[CH:97]=[CH:98][C:99](=[O:106])[NH:100]4)[C:86](=[O:92])[O:87][C:88]([CH3:91])([CH3:90])[CH3:89])[S:80][CH2:79][CH2:78][S:77]2)=[CH:72][CH:71]=1>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[Si:108]([O:107][C@H:94]([C:95]1[CH:104]=[CH:103][C:102]([OH:105])=[C:101]2[C:96]=1[CH:97]=[CH:98][C:99](=[O:106])[NH:100]2)[CH2:93][N:85]([CH2:84][CH2:83][CH2:82][CH2:81][C:76]1([C:73]2[CH:74]=[CH:75][C:70]([NH:69][C:62](=[O:63])[C:61]3[CH:65]=[CH:66][CH:67]=[C:59]([S:56]([C:43]4[CH:44]=[C:45]5[C:40](=[C:41]([CH3:68])[CH:42]=4)[N:39]=[CH:38][C:37]([C:34](=[O:36])[NH2:35])=[C:46]5[NH:47][C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([O:54][CH3:55])[CH:49]=4)(=[O:57])=[O:58])[CH:60]=3)=[CH:71][CH:72]=2)[S:80][CH2:79][CH2:78][S:77]1)[C:86](=[O:92])[O:87][C:88]([CH3:91])([CH3:90])[CH3:89])([C:111]([CH3:114])([CH3:113])[CH3:112])([CH3:110])[CH3:109]
Reactant: CC(C)(C)OC(=O)N(CCCCC1(c2ccc(N)cc2)SCCS1)C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)O)c4)cc23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C6(CCCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c7ccc(O)c8[nH]c(=O)ccc78)C(=O)OC(C)(C)C)SCCS6)cc5)c4)cc23)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
DMAP (20 mg), HATU (110 mg, 0.29 mmol) and DIEA (0.15 mL, 0.87 mmol) were added to a stirring mixture of 3-[[3-carbamoyl-4-[(3-methoxyphenyl)amino]-8-methylquinolin-6-yl]sulfonyl]benzoic acid (144 mg, 0.29 mmol) and Intermediate 105 (0.18 g, 0.35 mmol) in NMP (3 mL). The reaction mixture was stirred overnight in an 80° C. oil bath and then purified by reverse-phase high performance liquid chromatography (RP-HPLC, acetonitrile/water/0.1% TFA) to provide, after concentration, the title compound as a dark yellow solid (90 mg, 27%). ES/MS calcd. for C60H71N6O10S3Si+ 1159.4. Found m/z=1159.6 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[O:12])=[C:6]([O:21][C:22]([F:25])([F:24])[F:23])[CH:5]=1.CO.O.[OH-].[Li+]>O>[CH3:20][C:17]1[N:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][C:6]=2[O:21][C:22]([F:25])([F:23])[F:24])=[N:15][CH:16]=1
Reactant: COC(=O)c1ccc(NC(=O)Nc2cnc(C)cn2)c(OC(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cnc(NC(=O)Nc2ccc(C(=O)O)cc2OC(F)(F)F)cn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a stirred suspension of 4-[3-(5-methyl-pyrazin-2-yl)-ureido]-3-trifluoromethoxy-benzoic acid methyl ester (136 mg, 0.37 mmol) in 4 mL 3:1 MeOH:H2O under nitrogen was added lithium hydroxide monohydrate (154 mg, 3.7 mmol), and the reaction heated to 65° C. The reaction turned yellow/green and eventually became a solution. After stirring overnight, the reaction was cooled to RT and partially concentrated by rotovap to remove most of the MeOH. The residual suspension was neutratized with 2N HCl until pH=6. The reaction formed a floculent precipitate which was filtered off with H2O and dried overnight under high vacuum to give the acid as a white solid (102 mg, 78%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:12])=[CH:4][C:5]([Cl:11])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C>[Br:12][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH:8]([O:10][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:9])=[CH:7][C:2]=1[NH2:1]
Reactant: CC(O)c1cc(N)c(Br)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)c1cc(N)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
To a solution of 1-(5-amino-4-bromo-2-chloro-phenyl)-ethanol (0.195 g, 0.778 mmol) in DMF (3 ml) was added tert-butyl-dimethylsilyl chloride (0.152 g, 1.011 mmol) and imidazole (0.069 g, 1.011 mmol). The mixture was stirred at room temperature for six hours. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/9:1) gave 2-bromo-5-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-chloro-phenylamine (0.262 g, 92%) as a clear oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:10]=1)=[O:8].[Br:23]N1C(=O)CCC1=O>CC(O)=O>[Br:23][C:5]1[S:1][C:2]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:10]=2)=[O:8])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(Nc1nccs1)c1cn(CC2CC2)c2cc(F)ccc12
Solvent: CC(=O)O
Product: O=C(Nc1ncc(Br)s1)c1cn(CC2CC2)c2cc(F)ccc12
Yield: 32 %

Procedure:
1-Cyclopropylmethyl-6-fluoro-1H-indole-3-carboxylic acid thiazol-2-ylamide (2.5 mmol), N-bromosuccinimide (6 mmol) was stirred in HOAc (25 mL) over night at room temperature. The reaction mixture was evaporated to dryness and the crude product was purified by flash chromatography (Horizon, EtOAc-heptane) to give 1-cyclopropylmethyl-6-fluoro-1H-indole-3-carboxylic acid (5-bromo-thiazol-2-yl)-amide in 32% yield. A solution of 1-cyclopropylmethyl-6-fluoro-1H-indole-3-carboxylic acid (5-bromo-thiazol-2-yl)-amide (0.2 mmol), p-cresol (0.2 mmol) and potassium-t-butoxide (0.44 mmol) in DME (3 mL) was heated in a closed vessel in a Smith Creator microwave oven for 300 s at 120° C. Addition of water followed by extraction with DCM, drying of the organic phase followed by purification by preparative HPLC (Method E) gave the title compound.
Reaction SMILES: [C:1]([N:8]1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].N[N:14]1[CH2:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[S:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3>C(#N)C>[CH2:18]1[C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[S:15][N:14]1[NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2])=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NN1Cc2c(ccc3ccccc23)S1
Solvent: CC#N
Product: S=C(NN1Cc2c(ccc3ccccc23)S1)n1ccnc1
Yield: 27 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (1.8 g, 20 mmol) and 2-aminonaptho[1,2]thiazole (2.0 g, 20 mmol) in acetonitrile (150 mL) was stirred at 65° C. for 24 h. The resulting precipitate was collected by filtration to provide 1.69 g (46%) of the titled product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1>>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][N:16]=[C:15]2[NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(Nc3nc4ccc([N+](=O)[O-])cc4s3)c2cc1OC

Procedure:
(6,7-Dimethoxyquinazolin-4-yl)-(6-nitrobenzothiazol-2-yl)amine was prepared from 2-amino-6-nitrobenzothiazole (Sigma-Aldrich, 976 mg, 5 mmol) and 4-chloro-6,7-di-methoxyquinazoline (Fluorochem, 1.12 g, 5 mmol) according to GP 1. After filtration, the residue was washed thoroughly with dioxane, water and methanol. After drying in vacuo, crude (6,7-dimethoxy-quinazolin-4-yl)-(6-nitrobenzothiazol-2-yl)amine was obtained as an ochre solid (2.25 g) which was used without further purification. LC/ESI-MS: m/z=384 [M+H]+; m/z=382 [M−H]−; Rt=3.67 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: ClCCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCCCCl)cc1
Yield: 93.3 %

Procedure:
A mixture of para-nitrophenol (0.83 g, 6 mmoles), 1-bromo-4-chloro-butane (1.23 g, 7.2 mmoles), and K2CO3 (1.24 g, 9 mmoles) was stirred together in DMF at 80° C. for 1 hour. Reaction mixture was diluted with H2O, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by HPLC using as eluent 30% EtOAc/hexane to afford the title compound as an off-white solid (1.28 g, 5.6 mmoles).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N=C2CCCCC2=O)=[C:4]([F:17])[CH:3]=1.OS(O)(=O)=O.[C:23]([O-:26])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([F:17])[CH:3]=1)[NH:8][C:7]1[C:23](=[O:26])[CH2:5][CH2:4][CH2:3][C:2]2=1
Reactant: O=C1CCCCC1=NNc1ccc(Cl)cc1F
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCCc2c1[nH]c1c(F)cc(Cl)cc21
Temperature: 80 °C
Yield: 25 %

Procedure:
To a solution of 2-(2-(4-chloro-2-fluorophenyl)hydrazono)cyclohexanone (0.5 g, 1.9 mmol) in MeCN (5 mL), H2SO4 (0.31 mL, 5.9 mmol, 1.8M solution) was added slowly and the resulting mixture was heated to 80° C. for 12 h. The reaction mixture was cooled to room temperature, basified with saturated NaHCO3 (pH-8) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over sodium Na2SO4 and concentrated in vacuo to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (1:9) as eluant] to provide the title compound (120 mg, 25%). 1H NMR (200 MHz, CDCl3, δ in ppm): 8.96 (bs, 1H), 7.43 (d, J=1.0 Hz, 1H), 7.12 (dd, 1H, J=10.2, 1.60 Hz, 1H), 2.99 (t, J=5.8 Hz, 2H), 2.71 (t, J=6.0 Hz, 2H), 2.34-2.21 (m, 2H).
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][C:41]=2[C:42](O)=[O:43])[CH:34]=[CH:35][C:36]=1[F:37]>CN(C)C=O>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][C:41]=2[C:42]([NH:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[O:43])[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: Nc1cccnc1
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)O)c1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C

Procedure:
EDC (0.79 g, 4.11 mmol), HOBT (0.84 g, 5.48 mmol), N-ethylmorpholine (0.87 ml, 6.84 mmol) and 3-pyridinamine (0.48 g, 5.13 mmol) were added to a solution of 2-{[(3,4-difluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared as described in Description 101; 1 g, 3.42 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature. The N,N-dimethylformamide was evaporated under reduced pressure and the residue was diluted with ethyl acetate (100 ml). The organic layer was washed with saturated sodium hydrogencarbonate (2×50 ml) and water (2×50 ml). The organic layer was dried (MgSO4), filtered and evaporated under reduced pressure to yield the title compound as a yellow solid. 1.19 g.
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC.BrCC=CC(OC(=O)C)CCCCC.C([CH:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:45]/[CH:46]=[CH:47]/[CH:48]([O:54]C(=O)C)[CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[S:41]([CH3:44])(=[O:43])=[O:42])[C:32]([OH:34])=[O:33])C>>[OH:54][CH:48]([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])/[CH:47]=[CH:46]/[CH2:45][N:40]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:31][C:32]([OH:34])=[O:33])[S:41]([CH3:44])(=[O:42])=[O:43]
Reactant: CCCCCC(/C=C/CN(CCCCCC(CC)C(=O)O)S(C)(=O)=O)OC(C)=O
Agent: CCCCCC(C=CCBr)OC(C)=O
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CCCCCC(O)/C=C/CN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4-acetoxy-2 -nonene (Example H). The product of Step A is thus ethyl 7-[N-(4-acetoxy-(E)-2-nonenyl)methanesulfonamido]heptanoic acid (B).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)(=O)C.[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1>N1C=CC=CC=1>[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:21]=[C:22]([NH:26][C:5](=[O:7])[CH3:6])[CH:23]=[CH:24][CH:25]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1
Reactant: Cn1c(=O)cc(N)n(Cc2cccc(N)c2)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(Cn2c(N)cc(=O)n(C)c2=O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Using the general procedure for Intermediate 1, (3-nitrobenzyl)-urea [J. Med. Chem. 1996, 39, 1924 ] is converted into 6-amino-3-methyl-1-(3-nitro-benzyl)-1H-pyrimidine-2,4-dione, [M−H]− 275. A suspension of this compound (4.88 g, 17.7 mmol) and 10% Pd/C (0.484 g) in ethanol (200 ml) is hydrogenated at 1 atmosphere for 1.5 hours. The reaction mixture is filtered through a celite plug and evaporated to give 6-amino-1-(3-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt [M−H]− 245. Acetic anhydride (1.85 ml, 19.57 mmol) is added to a cooled (0° C.) suspension of 6-amino-1-(3-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt (5.01 g, 16.35 mmol) in pyridine (50 ml). The reaction mixture is warmed to room temperature, stirred for 6 hours and the solvent evaporated. The residue is triturated with water and the solid collected by filtration and dried to afford N-[3-(6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, 1H NMR (400 MHz, DMSO): δ: 2.00 (s 3H), 3.09 (s 3H), 4.72 (s 1H), 5.02 (s 2H), 6.75 (s 2H), 6.88 (d J 6 1H), 7.25 (t J 6 1H), 7.30 (s 1H), 7.55 (d J 6 1H). Using the general procedure for Intermediate 1, this compound is converted into N-[3-(5,6-diamino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide [MH]+ 304.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]([OH:15])=O)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH2:31])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH:31][C:13]([C:11]2[O:12][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][N:10]=2)=[O:15])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: O=C(O)c1ncc(Cc2ccccc2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[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: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1ncc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-Benzyl-oxazole-2-carboxylic acid (0.86 g, 2.8 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.70 g, 2.8 mmol), HATU (1.4 g, 3.6 mmol) and DIPEA (2.0 mL, 11.7 mmol) in 10 mL DMF was stirred at room temperature for 16 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1 N aq. HCl. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). LCMS (method A) RtA=1.719 min; [M+H]+=437.0