Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH3:27])[C:13]2[CH:14]=[CH:15][C:16]([F:26])=[C:17]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([N:12]([CH3:27])[C:13]1[CH:14]=[CH:15][C:16]([F:26])=[C:17]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:22])[F:23])[CH:18]=1)[N:10]=2
Reactant: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc(N)cn1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CN(c1ccc(F)c(NC(=O)C(F)(F)F)c1)c1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
Potassium thiocyanate (2.96 g, 30.5 mmol) was suspended in acetic acid (20 mL), and the suspension was stirred at room temperature for 10 min. To the obtained solution was added N-{5-[(5-aminopyridin-2-yl)(methyl)amino]-2-fluorophenyl}-2,2,2-trifluoroacetamide (2.0 g, 6.96 mmol), and the mixture was further stirred at room temperature for 10 min. To the obtained solution was slowly added dropwise a solution of bromine (1.17 g, 7.30 mmol) in acetic acid (10 mL). After the completion of the dropwise addition, the mixture was stirred at room temperature for 20 hr. The yielded black insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing solution were combined, and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (100 mL), and the suspension was washed with saturated aqueous sodium hydrogen carbonate solution (70 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (1.00 g, 43%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=3)=[O:20])[O:8][C@H:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:6]=2[CH:37]=1.[N-:38]=[N+:39]=[N-:40].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[NH:40][N:39]=[N:38][N:29]=4)[CH:23]=3)=[O:20])[O:8][C@H:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:6]=2[CH:37]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC(=O)Nc2cccc(C#N)c2)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CN1C(=O)[C@@H](CC(=O)Nc2cccc(-c3nnn[nH]3)c2)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 50.9 %

Procedure:
A solution of 0.2 g of trans-7-chloro-5-(2-chlorophenyl)-3-(3-cyanophenylaminocarbonylmethyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine and 80 mg of sodium azide in 5 ml of dimethylformamide was stirred at 90° C. for 60 hours. After water was added, the mixture was washed with water, after which the solvent was removed and the residue was subjected to silica gel column-chromatography to yield 0.11 g of a crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C:9](=O)[CH2:8][CH:7]1[CH3:20])=[O:5])[CH3:2].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C:9](=[N:22][OH:23])[CH2:8][CH:7]1[CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(O)c(OC)cc2C(=O)CC1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1c2cc(O)c(OC)cc2C(=NO)CC1C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
7-Hydroxy-6-methoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (5.10 g, 18.3 mmol) was dissolved in ethanol (100 mL), and hydroxylamine hydrochloride (3.81 g, 54.8 mmol) was added, followed by sodium acetate (3.74 g, 45.7 mmol). The mixture was heated at reflux for 2 h and then left to stand at room temperature overnight. Water (100 mL) was added, and the volatiles were removed in vacuo to give a yellow slurry. This slurry was filtered and washed with water to give the title compound as a fine powder (4.755 g, 89%).
Reaction SMILES: C(N(CC)CC)C.C(O[C@@H:12]1[C@H:18]2[C@H:19]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH2:16][CH3:17])[C:14](=[O:33])[CH2:13]1)[C@@H:27]1[C:22](=[CH:23][C:24](=[O:31])[CH2:25][CH2:26]1)[CH:21]([Cl:32])[CH2:20]3)(=O)C.O>C(O)C>[Cl:32][CH:21]1[C:22]2[C@H:27]([CH2:26][CH2:25][C:24](=[O:31])[CH:23]=2)[C@@H:28]2[C@H:19]([C@H:18]3[C@@:15]([CH2:30][CH2:29]2)([CH2:16][CH3:17])[C:14](=[O:33])[CH:13]=[CH:12]3)[CH2:20]1
Reactant: CC[C@]12CC[C@H]3[C@@H](CC(Cl)C4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](CC(Cl)C4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Temperature: 45 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
Triethylamine (0.5 ml, 3.6 mmol) was added to a suspension of 15α-acetoxy-6-chloro-18-methyl-estra-4-en-3,17-dione (0.5 g, 1.32 mmol) in ethanol (15 ml). The mixture was stirred at 45° C. for 2 h, cooled to 10° C. and water (4 ml) was then added. The precipitate was filtered and washed with an ethanol/water (1/1) mixture. The crude product was crystallized from ethanol and dried under vacuum to afford 6-chloro-18-methyl-estra-4,15-dien-3,17-dione (0.26 g, yield: 62%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[C:16]([Cl:21])[C:17]=3[O:19][CH3:20])[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH2:22][Br:23])[CH:15]=[C:16]([Cl:21])[C:17]=3[O:19][CH3:20])[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(Cl)cc(C)c2cnn(S(=O)(=O)c3ccccc3)c12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(Cl)cc(CBr)c2cnn(S(=O)(=O)c3ccccc3)c12

Procedure:
1-Benzenesulfonyl-6-chloro-7-methoxy-4-methyl-1H-indazole (2.45 g, 7.3 mmol), recrystallized N-bromosuccinimide (1.36 g, 7.6 mmol) and benzoyl peroxide (90 mg, 0.37 mmol) are dissolved in carbon tetrachloride (25 mL). The reaction is degassed and then placed in a 80° C. bath. The reaction is heated (about 2 h) until no starting material remains by TLC analysis (PhMe). The reaction is cooled, diluted with EtOAc, and washed with water. The solution is dried with MgSO4, concentrated and purified by column chromatography (silica, PhMe) to provide 1-benzenesulfonyl-4-bromomethyl-6-chloro-7-methoxy-1H-indazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:31][CH2:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(O[C@@H]2CCOC2)c(-c2ccc(Cl)cc2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(O[C@@H]2CCOC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using (R)-5-(4-chlorophenyl)-6-(tetrahydrofuran-3-yloxy)nicotinic acid (example CJ) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 94.6%, 469.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[O:50]1[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][C@@H:58]([NH:67][C:68]2[CH:73]=[CH:72][C:71]([S:74]([NH2:77])(=[O:76])=[O:75])=[CH:70][C:69]=2[S:78]([C:81]([F:84])([F:83])[F:82])(=[O:80])=[O:79])[CH2:59][S:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:52][CH2:51]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([NH:30][S@:31]([C:33]([CH3:34])([CH3:35])[CH3:36])=[O:32])[CH:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH:77][S:74]([C:71]4[CH:72]=[CH:73][C:68]([NH:67][C@H:58]([CH2:57][CH2:56][N:53]5[CH2:54][CH2:55][O:50][CH2:51][CH2:52]5)[CH2:59][S:60][C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)=[C:69]([S:78]([C:81]([F:83])([F:84])[F:82])(=[O:80])=[O:79])[CH:70]=4)(=[O:75])=[O:76])=[O:26])=[CH:28][CH:29]=3)[CH2:19][CH2:20]2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 130, 0.150 g, 0.29 mmol), DMAP (70 mg, 0.57 mmol), and EDC (0.110 g, 0.57 mmol) were placed in a 40 ml vial and flushed with nitrogen. DCM (4.0 ml) and DIPEA (0.10 ml, 0.57 mmol) were added, and the solution was stirred at r.t for 10 minutes. A solution of (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 69, 0.158 g, 0.29 mmol) in DCM (1.6 ml) was added to the solution and the reaction mixture was stirred at r.t overnight. The mixture was diluted with DCM and washed with 1N sodium bisulfate (aq.) followed by a saturated aq. sodium bicarbonate. The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give a residue which was purified by column chromatography (ISCO, silica gel column, eluting with 0→100% DCM/MeOH/NH3 (10:1:0.1 v/v/v)) to provide the title compound (0.21 g, yield: 69%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(N)c1ccc(F)cc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccc(F)cc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(4-fluorophenyl)acetate hydrochloride (prepared from 4-fluorophenylglycine (Fluka) and ethanol using General Procedure H), the title compound was prepared as a solid (mp=169-183° C.). The reaction was monitored by tlc (Rf=0.3 in 4% MeOH/CHCl3) and the product was purified by silica gel chromatography using 4% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: Cl.[CH2:2]([NH2:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[S-:11][C:12]#[N:13].[NH4+]>BrC1C=CC=CC=1.O>[CH2:2]([NH:10][C:12]([NH2:13])=[S:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCCc1ccccc1
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: Brc1ccccc1
Product: NC(=S)NCCc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
Phenethylamine hydrochloride (257 grams, 1.63 moles) and ammonium thiocyanate (123.6 grams, 1.63 moles) were heated to 160° C. in 340 ml bromobenzene under nitrogen. After heating for 90 minutes, the mixture was cooled to room temperature and then to 5° C. This procedure was repeated with a further batch of 257 grams of phenethylamine hydrochloride. The combined solids obtained in the above reaction were stirred in 1.5 l water and filtered. Recrystallization from isopropyl alcohol yielded 261.5 grams (45%) N-phenethylthiourea, m.p. 132°-134°.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19][C:20]([NH:22][C:23]1S[CH:25]=[CH:26][N:27]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:29]1[CH:34]=CC=CN=1>>[CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19][C:20]([NH:22][C:23]1[CH:34]=[CH:29][CH:25]=[CH:26][N:27]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccn1
Reactant: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1nccs1
Product: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1ccccn1

Procedure:
The product from Example 1, Part E (200 mg, 0.68 mmol) and 2-aminopyridine (95 mg, 1.02 mmol) were converted to the title compound in a manner analogous to the method described in Example 2 (10 mg, 4%). 1H NMR (300 MHz, acetone-d6) δ 9.13 (br s, 1H), 8.02 (m, 2H), 7.63 (m, 2H), 7.48 (m, 3H), 7.20 (m, 5H), 6.91 (m, 1H), 5.13 (d, J=15 Hz, 1H), 4.48 (m, 1H), 4.24 (d, J=15 Hz, 1H), 2.35 (m, 2H), 1.84 (m, 2H). MS: m/z (MH+) 372.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].Cl[CH2:12][CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][CH2:12][CH:13]=[O:14]
Reactant: O=CCCl
Reactant: Cc1ccc(C)c(N)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C)c(NCC=O)c1C
Temperature: 150 °C

Procedure:
2,3,6-Trimethylaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at about 150°C for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2,3,6-trimethylanilino)acetaldehyde.
Reaction SMILES: [C:1]1(/[CH:11]=[C:12]2/[CH:13]([OH:22])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:38](O)(=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C1C=CN=CC=1)C>[C:1]1(/[CH:11]=[C:12]2/[CH:13]([O:22][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCC(=O)O
Reactant: OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCCCCCCC(=O)OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
To a solution of Compound 20b (10.0 mg, 3.50×10−2 mmol), DCC (7.2 mg, 3.50×10−2 mmol), and DMAP (8.5 mg, 6.99×10−2 mmol) in dry Ch2Cl2 (4 mL) cooled in an ice-water bath was added n-octanoic acid (7.5 mg, 5.24×10−2 mmol) followed by stirring at room temperature for 4 hours. The reaction mixture was filtered through a short plug of Celite with rinsing by EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 11.2 mg (78 percent) of Compound 37: pale yellow oil; Rf=0.65 (20 percent EtOAc in hexane); IR (neat) 2932, 1724, 1177, 1037 cm−1; 1H NMR (300 MHz, CDCl3) δ8.31 (d, J=7.26 Hz, 1H), 8.01 (d, J=7.41 Hz, 1H), 7.86-7.78 (m, 2H), 7.56-7.46 (m, 3H), 7.44 (s, 1H), 6.24 (s, 1H), 2.54-2.22 (m, 4H), 2.42 (t, J=7.53 Hz, 2H), 1.97-1.60 (m, 6H), 1.40-1.16 (m, 8H), 0.84 (t, J=7.02 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ173.9, 134.2, 133.0, 132.7, 132.2, 129.6, 129.3, 127.0, 127.0, 126.5, 126.0, 124.2, 123.8, 103.2, 93.6, 80.9, 79.5, 69.2, 35.2, 32.3, 29.7, 29.6, 28.3, 28.2, 25.7, 23.3, 22.6, 21.4, 14.7; MS (+CI) m/z (relative intensity) 413 (M+, 6), 269 (100).
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O=P[O:14][P:15]=[O:16].[OH2:17]>O1CCCC1>[C:4]([NH:3][CH2:2][P:15]([OH:16])(=[O:17])[OH:14])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=POP=O
Reactant: O
Reactant: O=C(NCO)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NCP(=O)(O)O)c1ccccc1
Temperature: 5 °C
Yield: 116.2 %

Procedure:
30.2 g (0.2 mol) of N-hydroxymethylbenzamide were dissolved in 50 ml of tetrahydrofuran and cooled to 5° C. with stirring, then a solution of 11 g (0.1 mol) of diphosphorus trioxide (P2O3) in 20 ml of tetrahydrofuran was added dropwise at 5°-15° C. during the course of 30 minutes under a nitrogen atmosphere. The reaction solution obtained was then cooled to 2° C. for 10 minutes. Cooling was then omitted, the internal temperature rising to 35° C. The mixture was then heated to reflux for 2 hours; a clear solution was not formed in this case. It was then cooled. 4.5 g (0.25 mol) of water were then added dropwise at 30°-35° C. with cooling. The mixture was then heated to reflux for 1 hour, then cooled and additionally stirred and finally filtered with suction. 25 g of benzoylaminomethanephosphonic acid having a melting point of 175° to 178° C. were obtained. A further 5.5 g were isolated from the mother liquor. Altogether, 30.5 g (71% of theory) of product were thus obtained.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)CBr>CN.CO.CN(C)C=O>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)[CH2:7][CH2:6][NH2:3]
Reactant: CCN(CC)CC
Reactant: BrCc1cc(Br)cc(Br)c1
Agent: CN
Solvent: CN(C)C=O
Solvent: CO
Product: NCCc1cc(Br)cc(Br)c1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
Triethylamine (5.28 g; 52.2 mmol) was dissolved in 40% methylamine in methanol (100 ml). While the mixture was stirred at room temperature, 3,5-dibromobenzyl bromide (17.2 g; 52.2 mmol) in N,N-dimethylformamide (20 ml) was added dropwise. The mixture was stirred overnight at room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in 2N hydrochloric acid (150 ml), and the mixture was extracted with diethyl ether (150 ml), to thereby exclude impurities. The aqueous layer was alkalinized with aqueous sodium hydroxide solution, and extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 11.3 g of the target compound as orange oily matter (yield: 77.7%).
Reaction SMILES: [C:1]([N:8]([CH3:20])[C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][NH:22][CH2:23][CH2:24][CH2:25][S:26][CH3:27].C(OC(=O)C)C.C1CCCCC1>C(OC(=O)C)C.C1CCCCC1>[CH3:21][N:22]([CH2:23][CH2:24][CH2:25][S:26][CH3:27])[C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNCCCSC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CSCCCN(C)C(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C

Procedure:
This was prepared by coupling BOCMePheOH with N-methyl-3-methylthiopropylamine by the method of Example 1(b). The pure product was obtained after silica gel column chromatography in ethylacetate/cyclohexane (1:3). Rf=0.52 (ethylacetate:cyclohexane, 1:1)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]3[N:15]([C@:28](O[SiH3])([CH3:46])[C:29](C4C=CC=CC=4)(C4C=CC=CC=4)C(C)(C)C)[C:16](=[O:27])[N:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH2:18][C:12]3=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[F-:49].C([N+](CCCC)(CCCC)CCCC)CCC.[O:67]1CCCC1>>[OH:67][CH2:29][C@@H:28]([N:15]1[C:13]2=[N:14][C:9]([NH:8][C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=3)=[N:10][CH:11]=[C:12]2[CH2:18][N:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][C:24]=2[F:49])[C:16]1=[O:27])[CH3:46]
Reactant: COc1ccc(N2Cc3cnc(Nc4ccc(F)cc4)nc3N([C@@](C)(O[SiH3])C(c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Reactant: C1CCOC1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@@H](C)CO)C2=O)c(F)c1

Procedure:
(S)-7-(4-Fluoro-phenylamino)-1-(2-tert-butyl-diphenyl-silanyloxy-1-methyl-ethyl)-3-(4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.30 g, 0.45 mmol) was dissolved in anhydrous tetrahydrofuran (3.5 mL) and treated with tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 1.80 mL, 1.80 mmol) (Aldrich) at room temperature for 6 hours. The reaction was then concentrated. The residue was redissolved in ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography (Biotage 40S, ethyl acetate-hexanes gradient [60–100% ethyl acetate]) followed by crystallization from ethyl acetate-hexanes gave (S)-(+)-1-(2-hydroxy-1-methyl-ethyl)-3-(2-fluoro-4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.13 g, 66.2%). Melting Point: 188–198° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C@@H:4](C2SC=CC=2)[C@H:3]1[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OC(N/C(=C\[C:46]1[CH:50]=[CH:49][O:48][CH:47]=1)/C(OC)=O)=O)C1C=CC=CC=1>>[CH2:21]([O:20][C:19](=[O:28])[NH:18][C@H:3]1[C:2](=[O:1])[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C@@H:4]1[C:46]1[CH:50]=[CH:49][O:48][CH:47]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)/C(=C/c1ccoc1)NC(=O)OCc1ccccc1
Reactant: O=C(N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cccs1)OCc1ccccc1
Product: O=C(N[C@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccoc1)OCc1ccccc1

Procedure:
A method similar to that used for the preparation of (99b) was used except that methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(3-furyl)acrylate (102a) (530 mg) was used as starting material to afford the title compound as a white solid (235 mg). 1H NMR (300 MHz, d6-DMSO) δ 4.66 (t, 1H, J=4 Hz), 4.97 (s, 2H), 5.20 (d, 1H, J=6 Hz), 6.38 (d, 2H, J=7 Hz), 6.5 (s, 1H), 7.07-7.75 (m, 1H), 10.44 (s, 1H). LC/MS: 2.32 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][C:3]=1[CH3:20].[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][C:3]=1[CH3:20]
Reactant: COCCOc1ncc(N)cc1-c1ccc(Cl)c(C)c1
Reactant: O=C(O)c1ccccc1
Product: COCCOc1ncc(NC(=O)c2ccccc2)cc1-c1ccc(Cl)c(C)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3-methyl-phenyl)-6-(2-methoxy-ethoxy)-pyridin-3-ylamine (example 69 c) and benzoic acid as starting materials; LC-MS (UV peak area/ESI) 100%, 397.1307 (M+H)+.