Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Br)cc2)nc1
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
4-Bromophenol (5.5 g, 32 mmol) was added to 42 mL of 50% w/w aqueous sodium hydroxide. After stirring for 30 min, 44 mL of toluene was added, followed by 2-chloro-5-nitropyridine (5.0 g, 32 mmol) and tetrabutylammonium bromide (10 g, 32 mmol). After stirring for 1.5 hours at 23° C., the mixture was diluted with 200 mL of water, neutralized with 12M aqueous hydrochloric acid and the mixture was extracted 3× with ether. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo, affording 6 g of 2-(4-bromo-phenoxy)-5-nitro-pyridine. 1H NMR (CDCl3, 500 MHz): 9.05 (d, 1H, J=3.5 Hz), 8.51 (dd, 1H, J=3.5, 9.5 Hz), 7.58 (d, 2H, J=9.0 Hz), 7.08 (m, 3H) ppm. MS (APCl, m/z): 295 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(NC(c1ccncc1)c1cccc([N+](=O)[O-])c1)c1ccc(F)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(NC(c1ccncc1)c1cccc(N)c1)c1ccc(F)c(F)c1
Yield: 36 %

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (1b). 2.07 g of N-[1-(3,4-difluorophenyl)ethyl]-N-[(3-nitrophenyl)(pyridin-4-yl)methyl]amine [prepared as described in step (a) above], 2.66 g of nickel chloride hexahydrate and 848 mg of sodium borohydride were reacted, to obtain 684 mg of the title compound as a colorless oil.
Reaction SMILES: CS[C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]=1.[CH3:21][O:22][CH2:23][C:24]([NH:26][NH2:27])=O>CN(C)P(=O)(N(C)C)N(C)C>[CH3:21][O:22][CH2:23][C:24]1[N:4]2[C:5]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:6]=3[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8][CH2:9][C:3]2=[N:27][N:26]=1
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: COCC(=O)NN
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A solution of 10.0 g of 2-(methylthio)-5-phenyl-7-chloro-3H-1,4-benzodiazepine and 4.85 g of 2-methoxyacetic acid hydrazide (cp. E. J. Browne and J. B. Polya, J.Chem.Soc. 1962, 5149-5152) in 70 ml of abs. hexamethylphosphoric acid triamide is heaated for 11 hours at 140°. The solvent is then distilled off in vacuo. The residue is taken up in methylene chloride; the solution is washed with water and then with saturated sodium chloride solution, dried over sodium sulphate, and concentrated by evaporation. Crystallisation of the concentration residue from ethyl acetate/petroleum ether yields 1-(methoxymethyl)-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine, M.P. 185°-191°. After chromatography of the mother liquor on 100 g of silica gel "Merck", a further amount of final product of the same melting point can be isolated.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.C[N:14](C)[CH2:15][CH2:16]CN=C=NCC.C(N)C>ClCCl>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:14][CH2:15][CH3:16])=[O:5]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: Cl
Solvent: ClCCl
Product: CCNC(=O)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
A mixture of 1.0 g (4.65 mmol) alpha-bromophenylacetic acid (Aldrich), 1.16 g (6.05 mmol) (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (Aldrich), 2.80 mL (5.6 mmol) ethyl-amine (Aldrich, 2 M in dichloromethane) in dichloromethane (30 mL) is stirred at room temperature for 18 h. The reaction mixture is washed with NaOH 1 M (15 mL) and the organic phase is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (gradient: cyclohexane/ethyl acetate 90:10 to 50:50) to yield the title compound (0.32 g, content ca. 90%).
Reaction SMILES: Cl.F[C:3]1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([C:59]2[CH:60]=[C:61]3[C:67]([C:68]4[CH:69]=[N:70][N:71]([CH2:73][C:74]5[CH:79]=[CH:78][CH:77]=[C:76]([F:80])[CH:75]=5)[CH:72]=4)=[CH:66][N:65]([S:81]([C:84]4[CH:90]=[CH:89][C:87]([CH3:88])=[CH:86][CH:85]=4)(=[O:83])=[O:82])[C:62]3=[N:63][CH:64]=2)[CH:50]=[CH:51][C:52]=1[CH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([C:59]2[CH:60]=[C:61]3[C:67]([C:68]4[CH:69]=[N:70][N:71]([CH2:73][C:74]5[CH:79]=[CH:78][CH:77]=[C:76]([F:80])[CH:75]=5)[CH:72]=4)=[CH:66][N:65]([S:81]([C:84]4[CH:85]=[CH:86][C:87]([CH3:88])=[CH:89][CH:90]=4)(=[O:83])=[O:82])[C:62]3=[N:63][CH:64]=2)[CH:50]=[CH:51][C:52]=1[CH:53]1[CH2:54][CH2:55][N:56]([CH3:3])[CH2:57][CH2:58]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)c(F)c4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C)CC5)c(F)c4)cnc32)cc1
Yield: 20.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 5-(3-fluoro-4-(piperidin-4-yl)phenyl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (88 mg, 0.138 mmol) was hydrolyzed with lithium hydroxide (58 mg, 1.381 mmol) in THF/methanol/water (12/4/4 mL) to yield 17 mg (20.7% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.68-8.67 (d, 1H), 8.60 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.60-7.30 (m, 4H), 7.13-7.00 (m, 3H), 5.44 (s, 2H), 3.70-3.50 (m, 2H), 3.30-3.10 (m, 3H), 2.93 (s, 3H), 2.16-2.02 (m, 4H). MS: m/z=484.4 (M+1), HPLC: 97.49% in method A.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:22]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncn1
Reaction time: 0.33 h

Procedure:
To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (0.955 g, 4.80 mmol) in 2 mL of DMF at 0° C. is added NaH (60% in oil, 0.349 g, 8.72 mmol) in one portion. After stirring for 20 min, 4,6-dichloropyrimidine can be added. The mixture is stirred at 0° C. for 30 minutes, and then at room temperature until formation of the desired compound. After quenching with saturated ammonium chloride solution, the mixture is poured in water and ethyl acetate mixture. The compound can be purified by HPLC.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27](Cl)=[O:28].C(Cl)Cl.CO>O1CCCC1>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27]([N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19])=[O:28]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1c(F)cccc1F)N1c2nc(N3CCOCC3)cc(=O)n2CC[C@H]1C(F)(F)F
Yield: 5 %

Procedure:
The product is prepared according to the procedure described in Example 18, using 300 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 47 mg of sodium hydride and 174 mg of 2,6-difluorobenzoyl chloride in 4 ml of tetrahydrofuran. After three successive purifications by silica chromatography (eluent: CH2Cl2/MeOH; gradient of 100/0 to 98/02 then 98/1 and 98/2), 22 mg of (8S)-9-[(2,6-difluorophenyl)carbonyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4 H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][C:24]1[O:28][N:27]=[C:26]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:30]([NH:29][C:26]2[CH:25]=[C:24]([CH3:23])[O:28][N:27]=2)=[O:31])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cc1cc(NC(=O)Oc2ccccc2)no1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C)on4)c3)c2cc1OC
Yield: 25 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) and phenyl 5-methylisoxazol-3-ylcarbamate from the previous step (98 mg, 0.42 mmol) were reacted using Example 115C to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-methylisoxazol-3-yl)urea (31 mg, 0.074 mmol, 25%). 1H NMR (300 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.01 (s, 1H), 8.56 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.45-7.35 (m, 2H), 7.26 (d, 1H), 6.97 (d, 1H), 6.51 (s, 1H), 3.99 (s, 6H), 2.35 (s, 3H); LC-MS (ESI) m/z 422 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:18][CH3:19])=[CH:11][C:12](Br)=[C:13]([O:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:25](OCC)([O:29]CC)[O:26]CC>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:18][CH3:19])=[CH:11][C:12]([B:25]([OH:29])[OH:26])=[C:13]([O:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(Br)c(OC)cc1OCc1ccccc1
Reactant: CCOB(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(B(O)O)c(OC)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 71.6 %

Procedure:
Under a nitrogen atmosphere, 16.70 g (52.00 mmol) of 5-benzyloxy-2-bromo-4-ethyl-1-methoxybenzene (4) was added to 110 mL of anhydrous THF. The solution was cooled to −78° C., and 22.88 mL (57.19 mmol) of a 2.5 M solution of butyl lithium was added dropwise while maintaining the temperature below −70° C. The reaction mixture was stirred at −78° C. for 45 minutes. 9.73 mL (57.19 mmol) of triethyl borate was then added, and the reaction was allowed to stir at −78° C. for an additional 2 hours. The reaction mixture was then allowed to warm to 23° C. over a 30 minute period and was quenched with 100 mL of saturated NH4Cl. The pH was adjusted to 5.0 with 1M HCl, and the resultant solution was extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield crude product as a greenish-tan solid. The crude product was triturated with hexane and filtered to afford 10.65 g (64%) of 4-benzyloxy-5-ethyl-2-methoxy-phenylboronic acid (5) as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:14][C:15]2[NH:19][CH:18]=[N:17][CH:16]=2)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.Cl[C:32]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:33]>C(Cl)Cl>[CH3:37][C:36]([CH3:39])([CH3:38])[CH2:35][O:34][C:32]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:21][CH:20]=2)[CH:9]([CH2:14][C:15]2[NH:19][CH:18]=[N:17][CH:16]=2)[CH2:10]1)=[O:33]
Reactant: N#Cc1ccc(CN2CCNCC2Cc2cnc[nH]2)cc1
Reactant: CC(C)(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)COC(=O)N1CCN(Cc2ccc(C#N)cc2)C(Cc2cnc[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1-(4′-Cyanobenzyl)imidazol-5-ylmethyl piperazine prepared as described in EXAMPLE 2 (0.416 mmol) in methylene chloride was added DIEA (0.832 mmol) and commercially available neopentyl chloroformate (0.499 mmol). This solution was stirred for 2 hours at 25° C. and then the title compound was purified on preparative hpic and isolated via lyophilization. FAB-MS: calc: 395.5 found: 396.2. 1H-NMR (CD3OD): 8.9 ppm (s, 1H); 7.8 ppm (d, 2H); 7.5 ppm (s, 1H); 7.45 ppm (d, 2H); 5.65 ppm (s, 2H); 3.8 ppm (s, 2H); 3.45 ppm (s, 2H); 3.3 ppm (m, 4H): 2.3 ppm (m, 4H); 0.95 ppm (m, 9H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[CH:38](=O)[CH3:39]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:38][CH3:39])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CC=O
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Product: CCN[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) as described in general procedure F using acetaldehyde. The final product was obtained in 64% yield.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:21])[C@H:7]([CH2:17][CH:18]([CH3:20])[CH3:19])[NH:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:15])[CH3:4].[CH3:22]I>C1COCC1>[CH2:3]([O:5][C:6](=[O:21])[C@H:7]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:8]([CH3:22])[C:9](=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:15])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(C)C)N(C)C(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Sodium hydride (60% dispersion in oil; 2.0 g, 50 mmol) was added to a stirred solution of N-6-bromohexanoyl-L-leucine ethyl ester (15.0 g, 45 mmol) in anhydrous THF (150 ml) at 0° C. After the effervesence had ceased methyl iodide (8.4 ml) was added. The reaction mixture was allowed to warm up to room temperature and was stirred overnight. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate, washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated to give crude N-methyl-N-6-bromohexanoyl-L-leucine ethyl ester (14.0 g, 89%) as a pale yellow oil which was used directly in the next step.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:29]2[N:38]=[CH:37][C:36]3[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:35]=3)[C:30]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH2:24][CH3:25])[N:21]([CH3:26])[N:20]=2)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=1)(=O)C.[OH-].[Li+].O>C1COCC1.C(O)(C)C.O>[C:39]([C:34]1[CH:35]=[C:36]2[C:31](=[C:32]([F:43])[CH:33]=1)[C:30](=[O:44])[N:29]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH2:24][CH3:25])[N:21]([CH3:26])[N:20]=4)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:38]=[CH:37]2)([CH3:40])([CH3:41])[CH3:42]
Reactant: CCc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)nn1C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nn1C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
To a solution of 122c (150 mg, 0.25 mmol) in THF/i-propanol/water (2.5/1/0.5 mL) was added lithium hydroxide (70 mg, 2.5 mmol) at 35° C. After the reaction was stirred for 3 h, LCMS indicated the reaction was completed. The mixture was poured into water (15 mL) and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was purified by reverse-phase prep-HPLC to afford 122 (49 mg, 35%) as a white solid. MS-ESI: [M+H]+ 557.8. 1H NMR (500 MHz, CDCl3) δ 8.59 (d, J=5.0 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.88 (d, J=1.5 Hz, 1H), 7.73 (m, 1H), 7.64 (d, J=5.0 Hz, 1H), 7.41 (d, J=1.5 Hz, 1H), 5.92 (s, 1H), 4.59 (s, 2H), 3.72 (s, 3H), 3.68 (s, 3H), 2.64 (m, 2H), 1.47 (s, 9H), 1.27 (t, J=2.5, 3H)
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13](S(C)=O)=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[F:29])[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:31][CH2:32][C@H:33]([OH:38])[C@@H:34]([OH:37])[CH2:35][OH:36]>>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:31][CH2:32][C@H:33]([OH:38])[C@@H:34]([OH:37])[CH2:35][OH:36])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[F:29])[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(S(C)=O)nc3N(C3CCCC3)C2=O)c1
Reactant: NC[C@H](O)[C@@H](O)CO
Product: COc1cc(OC)c(F)c(N2Cc3cnc(NC[C@H](O)[C@@H](O)CO)nc3N(C3CCCC3)C2=O)c1

Procedure:
1-Cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-([S,S]-2,3,4-trihydroxy-butylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as in Example 2 using 0.40 g (0.92 mmol) 1-cyclopentyl-3-(2-fluoro-3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.33 g (2.76 mmol) (S,S)-4-amino-1,2,3-butanetriol. The final product was purified by column chromatography (20:1 dichloromethane/methanol) to get 0.05 g (11%) as a white solid: mp 86° C.–88° C.; MS (APCI) m/z 492.2, 493.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[S:13][C:14]([NH:20][C:21](=[O:36])[CH2:22][CH2:23][CH2:24][N:25]2C(=O)C3=CC=CC=C3C2=O)=[C:15]([C:17]([NH2:19])=[O:18])[N:16]=1.CN>CCO>[NH2:25][CH2:24][CH2:23][CH2:22][C:21]([NH:20][C:14]1[S:13][C:12]([NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:16][C:15]=1[C:17]([NH2:19])=[O:18])=[O:36]
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)CCCN1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CCO
Product: NCCCC(=O)Nc1sc(Nc2ccc3ccccc3c2)nc1C(N)=O
Temperature: 70 °C
Yield: 28.6 %

Procedure:
A mixture of 2-(naphthalen-2-ylamino)-5-(4-phthalimidobutanamido)thiazole-4-carboxamide (180 mg, 0.36 mmol) and 33% methylamine in EtOH (5 mL) was heated at 70° C. for 4 hrs. The solvent was removed, and water was added to the residual oil. The resulting solids were collected by filtration and washed successively with ether, DCM and MeOH to give 38 mg (29% yield) of the titled compound.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].ClCCl.[O:30]1[C:34](B(O)O)=[CH:33][C:32]2[CH:38]=[CH:39][CH:40]=[CH:41][C:31]1=2>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:30]1[C:34]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)=[CH:33][C:32]2[CH:38]=[CH:39][CH:40]=[CH:41][C:31]1=2
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OB(O)c1cc2ccccc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Yield: 62.3 %

Procedure:
To a flask containing 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (400 mg, 1.30 mmol) in dimethyl glycol ether (15 mL) was added potassium phosphate (2.75 g), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (106 mg, 0.130 mmol), and benzo[b]furan-2-boronic acid (315 mg, 1.95 mmol). The reaction mixture was brought to 90° C. under nitrogen conditions for 18 hours. The mixture was condensed and extracted with water (25 mL) and ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated. The residue was then purified by chromatography (SiO2, 20% ethyl acetate/hexanes) to afford the title compound (278 mg, 62%). ES-MS (m/z) 344[M+1]+.
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10]2.O.O.O.C([O-])(=O)C.[Na+].[N+](C1C(S(O)(=O)=O)=C(C=CC=1)C([O:43][C:44](=O)[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([N+:51]([O-:53])=[O:52])[C:46]=1[S:54]([OH:57])(=[O:56])=[O:55])=O)([O-])=O>O>[Na+:1].[Na+:1].[Na+:1].[Na+:1].[N+:51]([C:47]1[C:46]([S:54]([OH:57])(=[O:55])=[O:56])=[C:45]([CH:50]=[CH:49][CH:48]=1)[C:44]([NH:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10]2)=[O:43])([O-:53])=[O:52]
Reactant: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Reactant: O=C(OC(=O)c1cccc([N+](=O)[O-])c1S(=O)(=O)O)c1cccc([N+](=O)[O-])c1S(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12)c1cccc([N+](=O)[O-])c1S(=O)(=O)O
Yield: 353.6 %

Procedure:
To a solution of 20.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid trisodium salt and 8.75 g of sodium acetate trihydrate in 180 ml of water at room temperature is added 12.0 g of 3-nitrosulfobenzoic anhydride with stirring. A 400 ml portion of water is added. The mixture is stirred at room temperature for 21/2 hours and then filtered. The filtrate is cooled, acidified with 2-3 ml of concentrated hydrochloric acid an diluted with ethanol. The pink solid is collected by filtration, washed with 85% ethanol, ether and dried. The filtrate is concentrated to a low volume and diluted with ethanol giving a second crop which is collected and combined with the first crop giving a total of 27.6 g of 8-(3-nitro-2-sulfobenzamido)-1,3,6-naphthalene trisulfonic acid tetrasodium salt.
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:40]=1>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:45]([C:41]3[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=3)(=[O:47])=[O:46])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cccnc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
Diisopropylethylamine (0.3 mL, 1.7 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in CH2Cl2 (6 mL). The solution was stirred at room temperature for 30 minutes and then a solution of pyridine-3-sulfonyl chloride (which may be prepared as described above; 320 mg, 1.8 mmol) in CH2Cl2 (1 mL) was added. The mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 30% ethyl acetate/hexanes, to give {6-fluoro-4-[1-(pyridine-3-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (85 mg, 53%) as a sticky white solid. MS cald. for C23H24FN2O4S [(M+H)+]: 443, obsd. 443.2.