Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:50]([O:57][C:58]1[CH:59]=[C:60]([CH:63]=[CH:64][CH:65]=1)[CH2:61][NH2:62])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]([NH:62][CH2:61][C:60]1[CH:63]=[CH:64][CH:65]=[C:58]([O:57][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:59]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cccc(OCc2ccccc2)c1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCc1cccc(OCc2ccccc2)c1
Reaction time: 18 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)methionine (1.20 g, 4.8 mmol) in dry CH2Cl2 (25 mL) under argon were added PYBOP (2.90 g, 5.6 mmol), 3-benzyloxybenzylamine, as described above in Step I, (1.0 g, 4.7 mmol), and N,N-diisopropylethylamine (0.89 mL, 5.1 mmol). The reaction mixture was stirred for 18 hours, then extracted with saturated aqueous NaHCO3 (25 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane—25% EtOAc to yield the product as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([CH:16]2[CH2:22][C:21](=O)[O:20][C:18](=[O:19])[CH2:17]2)=[CH:12][CH:11]=1.[ClH:30]>ClCCl.O1CCOCC1>[ClH:30].[C:10]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=[CH:14][C:13]([CH:16]([CH2:22][C:21]2[NH:9][C:4]3[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][C:5]=3[N:8]=2)[CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)CC(=O)O1
Reactant: Nc1ccc(I)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CC(Cc1nc2ccc(I)cc2[nH]1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Iodo-1,2-phenylenediamine (0.47 g) and 3-(biphenyl-4-yl)glutaric anhydride (0.53 g) were dissolved in dichloromethane (5 ml) with heating. The dark solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried in vacuo to give a mixture of regioisomeric amides (0.74 g) as light brown solid. This solid was dissolved in 1,4-dioxane (1 ml) with heating. 4M HCl in 1,4-dioxane (3 ml) was added and the solution was heated to reflux for 1 h. All volatiles were removed at the water aspirator and the amorphous residue is fractionally crystallised to provide 3-(biphenyl-4-yl)-4-(5-iodo-2-benzimidazolyl)butanoic acid HCl (0.43 g) as off-white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:20](O)=[O:21])[CH:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][N:19]=3)[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:56][C@@H:57]([CH2:71][C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=1)[C@H:58]([OH:70])[CH2:59][NH:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([CH2:68][CH3:69])[CH:63]=1>C(Cl)Cl>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:20]([NH:56][C@@H:57]([CH2:71][C:72]3[CH:73]=[C:74]([F:79])[CH:75]=[C:76]([F:78])[CH:77]=3)[C@H:58]([OH:70])[CH2:59][NH:60][CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[C:64]([CH2:68][CH3:69])[CH:63]=3)=[O:21])[CH:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][N:19]=3)[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCOc2c(-c3ncco3)cc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN1CCOc2c(-c3ncco3)cc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 8 h

Procedure:
A solution of 4-Butyl-8-(1,3-oxazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (450 mg, HBTU (853 mg), and diisopropylethylamine (580 mg) was stirred in methylene chloride (15 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (606 mg) in methylene chloride (7 mL) was added and the reaction mixture was stirred overnight. The mixture was filtered with methylene chloride, dried (magnesium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided 400 mg of the title compound: ESI MS m/z 619 [M+H]+.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH3:12])[CH:3]=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Cn1cc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc(OCc3ccccc3)cc2)c2c(N)ncnc21

Procedure:
A solution of 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5 mg, 0.018 mmol), 4-(benzyloxy)phenylboronic acid (21 mg, 0.091 mmol), K3PO4 (19.3 mg, 0.091 mmol) and Pd(PPh3)4 (12.5 mg, 0.011 mmol) in DMF (3 mL) was heated to 60° C. under an argon atmosphere. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 331.1, found 331.3.
Reaction SMILES: [CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[CH2:23][C:24]([NH2:26])=[O:25]>CN(C=O)C>[CH2:1]1[CH:12]2[CH:4]([N:5]([CH2:23][C:24]([NH2:26])=[O:25])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)NC1CCCC21
Reactant: NC(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)CN1c2ccccc2C2CCCC21
Temperature: 100 °C
Yield: 69.2 %

Procedure:
To a stirred solution of 1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole (130 mmol, 21 g) in DMF (50 mL) was added diisopropylethylamine (400 mmol, 70 mL) followed by 2-chloroacetamide (270 mmol, 25 g). The reaction mixture was heated to 100° C. for 18 h. The reaction was concentrated and the diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash column chromatography through silica gel (elution with 60% ethyl acetate-hexanes) to afford a yellow solid (90 mmol, 20 g, 69%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.C([O-])(=O)C.[Na+].O>O1CCCC1>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: Cc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(NC(=O)C(F)(F)F)n2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(N)n2)cc1
Yield: 22.5 %

Procedure:
A mixture of 7-[2-[2-(2,2,2-trifluoroacetamido)-thiazol-4-yl]-2-(4-methylbenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 4.5 g.), sodium acetate 3 hydrate (12.5 g.), water (250 ml.) and tetrahydrofuran (20 ml.) was treated in a similar manner to that of Example 16-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(4-methylbenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.84 g.), m.p. 135°-155° C. (dec.).
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O=[C:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[CH2:7]([O:14][C:15]1[CH:20]=[C:19]2[C:18](=[CH:17][CH:16]=1)[NH:21][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Temperature: 45 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a mixture of sulfuric acid (80.0 mL, 1.50 mol) dissolved in Ethanol (450 mL) at 0° C. was added (4-(benzyloxy)phenyl)hydrazine hydrochloride (90.0 g, 359 mmol) to form a suspension. To the suspension was added ethyl 2-oxopropanoate (43.9 mL, 395 mmol) in EtOH (90 mL) and mechanically stirred for 2 h using a mechanical stirrer. The mixture was heated to 45° C. and maintained for 16 h. The mixture was cooled to room temperature and cold EtOH (200 mL) was added. The mixture was filtered through a course frit. The collected solid was washed sequentially with cold EtOH, hexanes, and water. The solid was dried in a vacuum oven (45° C., 2 Ton) to give ethyl 5-(benzyloxy)-1H-indole-2-carboxylate (73.1 g, 247 mmol, 69% yield). Exact mass calculated for C18H17NO3: 295.1, found: LCMS m/z=296.2, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.41 (t, J=7.1 Hz, 3 H), 4.40 (q, J=7.1 Hz, 2 H), 5.10 (s, 2 H), 7.08 (dd, J1=8.9, J2=2.4 Hz, 1 H), 7.14 (d, J=1.6 Hz, 1 H), 7.20 (d, J=2.3 Hz, 1 H), 7.32 (m, 2 H), 7.39 (m, 2 H), 7.47 (m, 2 H), 8.75 (bs, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)(=[O:36])=[O:35]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:31]=[CH:32][CH:33]=[CH:28][C:29]=2[S:34]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)(=[O:36])=[O:35])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CCCCC1
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Product: O=S(=O)(c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1)N1CCCCC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and 1-((2-bromophenyl)sulfonyl)piperidine. MS (ESI): mass calcd. for C24H24FN3O3S, 453.15; m/z found, 454.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.07-8.03 (m, 1H), 7.82 (d, J=1.0, 1H), 7.73-7.67 (m, 2H), 7.65-7.55 (m, 2H), 7.42-7.39 (m, 1H), 7.36-7.30 (m, 2H), 4.41-4.32 (m, 2H), 3.74-3.71 (m, 2H), 2.91-2.79 (m, 4H), 1.49-1.37 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>C(#N)C>[OH:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][O:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)(CO)CBr
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OC)c1OCC(C)(C)CO
Temperature: 80 °C
Yield: 19.2 %

Procedure:
To a stirring solution of 4-(3-hydroxy-2,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.281 mmol) in acetonitrile (10 mL) was added potassium carbonate (155 mg, 1.124 mmol) and 3-bromo-2,2-dimethyl-propan-1-ol (141 mg, 0.843 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 20%).
Reaction SMILES: [C:1](=[N:14][OH:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][NH:18][CH2:19][CH2:20][CH2:21]Cl>>[CH3:17][NH:18][CH2:19][CH2:20][CH2:21][O:15][N:14]=[C:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(c1ccccc1)c1ccccc1
Reactant: CNCCCCl
Agent: Cl
Product: CNCCCON=C(c1ccccc1)c1ccccc1
Yield: 62 %

Procedure:
Benzophenone O-(3-methylamino-propyl)oxime was prepared in 62% yield from benzophenone oxime and N-methyl-3-chloropropylamine hydrochloride by the procedure described above for the preparation of benzophenone O-(2-N-methylaminoethyl)oxime (Preparation 13, Step 1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>>[CH3:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccc(N)cc1C
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1ccc(Nc2ccccc2CC(=O)O)cc1C

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3,4-dimethylaniline to yield 2-[(3,4-dimethylphenyl)amino]phenylacetic acid.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1.[CH2:39](I)[CH3:40]>O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]([CH2:39][CH3:40])[C:30](=[O:38])[O:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:27][CH:28]=1
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCC4)cc3)c2cc1OC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC1CCCCC1)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (7 mg), and cyclohexyl N-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (35 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (52 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (35 mg, yield 93%).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:13]=1[C:14](OC)=[O:15])(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCO>[F:22][C:20]1[CH:21]=[C:12]2[C:13](=[CH:18][CH:19]=1)[C:14](=[O:15])[NH:3][N:2]=[C:4]2[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: COC(=O)c1ccc(F)cc1C(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)c2cc(F)ccc12
Yield: 81.4 %

Procedure:
A solution of hydrazine hydrate (0.26 mL, 4.6 mmol) and the product of example 35C (0.390 g, 1.5 mmol) in EtOH (4.5 mL) was stirred at 80° C. for 3 hours, concentrated, and chromatographed on SiO2 (3% MeOH/CH2Cl2) to give 293.5 mg of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.42 (dd, 1H), 7.76 (ddd, 1H), 7.53-7.63 (m, 5H), 7.32 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH2:17])=[O:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:14]([C:12]([NH:11][CH3:10])=[O:13])[CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1cc(N)ccc1OC
Product: CNC(=O)c1cc(Nc2nc(Cl)ncc2F)ccc1OC

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-methylaminocarbonyl-4-methoxyaniline were reacted to produce 2-chloro-5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-4-pyrimidineamine R940305. 1H NMR (DMSO-d6): δ 9.91 (1H, s), 8.31 (1H, d, J=3.6 Hz), 8.11 (1H, d, J=2.7 Hz), 7.78 (1H, dd, J=9 Hz, J=2.7 Hz), 7.59 (1H, m), 6.87 (1H, d, J=9 Hz), 3.90 (3H, s), 2.96 (3H, d, J=4.5 Hz); purity 93%.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[S:28]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br>C(O)(=O)C.C(OCC)C>[C:31]1([S:28]([C:22]2[C:21]3[C:25](=[CH:26][CH:27]=[C:19]([O:18][CH2:17][CH:14]4[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]4)[CH:20]=3)[NH:24][N:23]=2)(=[O:29])=[O:30])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(OCc1ccccc1)N1CCC(COc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OCC3CCNCC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-[3-(1-naphthylsulfonyl)-1H-indazol-5-yloxymethyl]-piperidine-1-carboxylic acid benzyl ester (0.3 g, 0.54 mmoles) and 33 wt % HBr in acetic acid (1.5 mL) was stirred at room temperature for 30 minutes, diluted with ethyl ether and filtered. The filtercake was washed with ether, dried, treated with 1N NaOH and saturated NaCl and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated under vacuum to afford the title compound as an off-white solid; mp 175-177° C., identified by HNMR and mass spectral analyses, MS (ES) m/z 420.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[CH2:8][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)ccc1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Cl)cc1CBr

Procedure:
A mixture of 5-chloro-2-fluorotoluene (2.9 g; prepared by a modified Schiemann reaction on 4-chloro-2-methylaniline), NBS (3.6 g) benzoyl peroxide (100 mg) and carbon tetrachloride (25 ml) was refluxed 2h. The mixture was cooled, filtered and the solvent removed. Distillation gave 5-chloro-2-fluorobenzyl bromide (3 g), b.p. 104°/15 mm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[C:14](=[O:15])[O:13][C:12]([CH3:17])([CH3:16])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([Mg]Cl)[CH:20]=[CH2:21]>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:9]2[C:10](=[O:18])[O:11][C:12]([CH3:16])([CH3:17])[O:13][C:14]2=[O:15])[CH2:21][CH:20]=[CH2:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(=Cc2cccc(O)c2)C(=O)O1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CCC(c1cccc(O)c1)C1C(=O)OC(C)(C)OC1=O
Yield: 36.6 %

Procedure:
To a solution of 8.1 (8.00 g, 32 mmol) in THF (100 mL) was added allylmagnesium chloride (available from Aldrich) (2.0 M in THF) (97 mL, 193 mmol) dropwise at 0° C. over 1 hour. When the addition was complete, the reaction was quenched with 1 N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The crude product was chromatographed on silica gel (20-30% EtOAc/hexane) to afford 43.1 (3.4 g, 36%) as a pale yellow oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][O:23][CH2:24][CH2:25][NH2:26]>>[CH3:22][O:23][CH2:24][CH2:25][NH:26][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: COCCN
Product: COCCNc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Yield: 36 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with 2-methoxy-ethylamine according to the GPA affording 8.5 mg (36%) of a red powder. Rt=3.84 min.
Reaction SMILES: [F:1][C:2]([F:10])([C:7]([F:9])=[O:8])[C:3](OC)=[O:4].[F:11]S(O)(=O)=O>>[F:10][C:2]([F:1])([C:3]([F:11])=[O:4])[C:7]([F:9])=[O:8]
Reactant: O=S(=O)(O)F
Reactant: COC(=O)C(F)(F)C(=O)F
Product: O=C(F)C(F)(F)C(=O)F
Yield: 66 %

Procedure:
A mixture of 84 g (0.54 mol) of methyl difluorofluoroformylacetate, 104 g (1.0 mol) of fluorosulfonic acid and 9 g (0.038 mol) of HSbF6 was heated at 100° to 115° for 20 h. Then, 25.6 g of volatile product, collected through a condenser in a -80° trap, and boiling in the range of -25° to +10°, was identified by IR as difluoromalonyl fluoride (66% yield) based on the stoichiometry 2 FOCCF2CO2CH3 :CF2 (COF)2. Dimethyl difluoromalonate was also formed.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][CH2:16][CH2:15][C:2]2([OH:1])[CH2:14][CH2:13][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:4][CH2:3]2)[CH3:27])=[CH:22][CH:21]=1
Reactant: COc1ccc([C@H](C)N)cc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: COc1ccc([C@H](C)NCCC2(O)CCC3(CC2)OCC(C)(C)CO3)cc1
Yield: 45 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-methoxy-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 45% of theory; LC (method 1): tR=1.44 min; Mass spectrum (ESI+): m/z=378 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[S:16][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:26])[CH:10]=1)C1C=CC=CC=1>[Pd].O1CCCC1>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[S:16][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:26])[CH:10]=1
Reactant: CCOC(=O)c1sc(-n2ccc(OCc3ccccc3)cc2=O)nc1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-n2ccc(O)cc2=O)nc1C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
A mixture of ethyl 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylate (7.00 g, 18.0 mmol) and 20 wt. % palladium on activated carbon (3 g) in anhydrous tetrahydrofuran (300 mL) was stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was recrystallized from ethyl acetate to afford the title compound as a colorless solid (4.00 g, 80%): mp 270-273° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.58 (d, J=8.0 Hz, 1H), 6.27 (dd, J=8.0, 2.5 Hz, 1H), 5.81 (d, J=2.5 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 2.58 (s, 3H), 1.26 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 168.0, 162.5, 161.7, 156.5, 155.3, 132.4, 119.0, 104.7, 97.9, 61.2, 17.6, 14.6; MS (ES+) m/z 281.0 (M+1).
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[CH:27][C:28]=1[CH3:29].N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:26]1/[C:25]([OH:30])=[CH:24][C:23](=[NH:22])[C:28]([CH3:29])=[CH:27]/1
Reactant: Nc1c(N)n2n(c1=O)CCC2
Reactant: Cc1ccc(O)cc1N
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: CC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(O)=CC1=N

Procedure:
0.05 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 3-amino-4-methylphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.