Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[CH2:10](Br)[C:11]#[CH:12]>[OH-].[Na+]>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1)[C:11]#[CH:10]
Reactant: C#CCBr
Reactant: OCc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Product: C#CCOc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.4 %

Procedure:
To an aqueous solution of 3-hydroxybenzyl alcohol (2.00 g, 16.1 mmol) in sodium hydroxide (35 mL, 1.5 M) was added propargyl bromide (2.11 g, 17.7 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was extracted with diethyl ether and washed with a 1.5 M aqueous sodium hydroxide solution and saturated brine, and the organic layer was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=5:5) to give the title compound (0.82 g, yield 31%) as an oily matter.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH:19]=O)[CH2:15][C:16](=O)[CH3:17])=[C:10]([O:21][CH3:22])[CH:9]=1.C([O-])(=O)C.[NH4+:28]>C(OCC)(=O)C>[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:15]=[C:16]([CH3:17])[N:28]=[CH:19]2)=[C:10]([O:21][CH3:22])[CH:9]=1
Reactant: COC(=O)c1ccc(N(C=O)CC(C)=O)c(OC)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
An acetic acid (255 mL) solution of 4-(formyl-(2-oxopropyl)amino)-3-methoxybenzoic acid methyl ester (118 g) and ammonium acetate (172 g) was heated under stirring at 140° C. for 1 hour. The reaction solution was neutralized with an ammoniac solution under ice-cooling after the reaction completed. Ethyl acetate was added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was filtered with a silica gel pad after dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. Tert-butylmethyl ether and heptane were added to the residue and the deposited solids were separated by filtering and washed with a 50% heptane solution of tert-butylmethyl ether. 68.4 g of the title compound was obtained by air-drying the obtained solids overnight. Furthermore, crystallization mother liquid was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system), and 22.3 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:35]2[CH2:34][CH2:33][N:32]([C:25]3[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:37][CH2:36]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Reactant: COc1ccc(OC)c(N2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(OC)c(N2CCN(CC(O)COc3ccc(OCc4ccccc4)cc3)CC2)c1
Yield: 33.9 %

Procedure:
2.56 g of 1-(4-benzyloxyphenoxy)-2,3-epoxypropane was dissolved in 100 ml of dioxane, and to this were added 2.95 g of 1-(2,5-dimethoxyphenyl)piperazine dihydrochloride and 3.5 ml of triethylamine and reaction and workup were carried out as in Example 1-A. The residue obtained was purified by column chromatography (silica gel, elution with ethyl acetate:hexane=1:1) to give 1.62 g of brown oil.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:14]([O:16][C:17](=[O:27])[C:18]([CH:25]=O)([CH3:24])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17](=[O:27])[C:18]([CH2:24][NH:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)([CH3:25])[CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[CH3:15]
Reactant: CCOC(=O)C(C)(C=O)CCC(C)C
Reactant: NC1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(CCC(C)C)CNC1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
Cyclobutylamine (1.23 mL, 14.4 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.81 g, 28.8 mmol) were added sequentially to a solution of crude rac-2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (prepared as described in Example 19c; 2.88 g, 14.4 mmol) in ethanol (40 mL) at 25° C. The mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (self-packed glass column, gradient elution: 20-30% ethyl acetate in hexanes) to afford rac-2-cyclobutylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (1.76 g, 6.89 mmol, 48%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.87 (3H, d, J=3.0 Hz), 0.88 (3H, d, J=4.0 Hz), 0.99-1.07 (1H, m), 1.17 (3H, s), 1.26 (3H, t, J=7.5 Hz), 1.42-1.68 (4H, m), 2.43 (1H, d, J=11.7 Hz), 2.73 (1H, d, J=11.7 Hz), 3.15-3.23 (1H, m), 4.13 (2H, q, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)=[O:4].[BH4-].[Na+]>CN(C)C=O.CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N=Cc2ccccc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCc2ccccc2)cn1
Temperature: -20 °C

Procedure:
The solution of 24.9 g of 5-benzylideneaminopyridine-2-carboxylic acid methyl ester in 70 ml of hot dimethylformamide is added all at once to the solution of 7.0 g of sodium borohydride in 300 ml of methanol while stirring at -20° C. The temperature of the reaction mixture raises spontaneously to 20° and is lowered to 0° by cooling. After 2 hours the mixture is warmed to room temperature for 15 minutes to ensure complete reaction. Approximately 1/2 of the methanol is distilled off, the concentrate is cooled to 0° and 3 ml of acetic acid and the solution of 12 ml of 12 N hydrochloric acid in 100 ml ice water is added. A precipitate begins to separate and 200 ml more ice water are added. After 30 minutes the precipitate is collected and washed well with water and recrystallized from acetonitrile, to yield the 5-benzylaminopyridine-2-carboxylic acid methyl ester, melting at 104°-107°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:27])=[C:6]([C:8]2[C:23](=[O:24])[N:22]([O:25][CH3:26])[C:11]3[N:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:14]=[CH:15][C:10]=3[CH:9]=2)[CH:7]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](O)=[O:65])=[CH:62][C:61]=1[C:69]([F:72])([F:71])[F:70]>CN(C=O)C>[Cl:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([Cl:27])=[C:6]([C:8]3[C:23](=[O:24])[N:22]([O:25][CH3:26])[C:11]4[N:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:14]=[CH:15][C:10]=4[CH:9]=3)[CH:7]=2)=[O:65])=[CH:62][C:61]=1[C:69]([F:70])([F:71])[F:72]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COn1c(=O)c(-c2cc(N)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COn1c(=O)c(-c2cc(NC(=O)c3ccc(Cl)c(C(F)(F)F)c3)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Temperature: 25 °C
Yield: 70 %

Procedure:
In a 3 ml vial equipped with a small triangular magnetic stirring bar was placed 6-(5-amino-2-chlorophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin -7(8H)-one (348 μmol). Triethylamine (344 μmol) was added, followed by aliquots of DMF stock solutions of HATU (320 μmol) and 4-chloro-3-(trifluoromethyl)benzoic acid (129 μmol), and the mixture was stirred at room temperature over night. The solution was transferred to maximum recovery HPLC vials and purified by prep. HPLC-MS. The collected fractions were transferred to centrifuge vials and lyophilized, giving 4-chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl) -3-(trifluoromethyl)benzamide as a solid (70%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)O1.Br[C:32]1[CH:41]=[CH:40][C:35]([C:36]([NH:38][CH3:39])=[O:37])=[C:34]([F:42])[CH:33]=1>>[F:42][C:34]1[CH:33]=[C:32]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)=[N:14][C:13]=3[CH:29]=2)[CH:41]=[CH:40][C:35]=1[C:36](=[O:37])[NH:38][CH3:39]
Reactant: CNC(=O)c1ccc(Br)cc1F
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Product: CNC(=O)c1ccc(-c2ccc3oc(C4CCN(C(=O)OC(C)C)CC4)nc3c2)cc1F
Yield: 33.7 %

Procedure:
Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.54 mmol) and 4-bromo-2-fluoro-N-methylbenzamide (200 mg, 0.54 mmol) as a brown solid. M.P.: 116-120° C. MS (m/z): 440.3 [M+H]+.
Reaction SMILES: [C:1](O)(=[O:5])[CH:2]([CH3:4])[OH:3].[OH:7][CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[NH2:10].Cl.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[C:1]([NH:10][C@@H:9]1[C@@H:11]([OH:12])[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][CH:8]1[OH:7])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
75 g of lactic acid (90% pure) was mixed with 22.5 g of glucosamine.HCl and 2.5 g of Dextrose. The mixture was reacted at 120 C for 4 hours. The reacted mixture was cooled down and stored at 4 C.
Reaction SMILES: [C:1]([C:4]1[C:9]2[S:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:20]O>>[CH2:13]([C:12]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([O:3][CH3:20])=[O:2])[C:9]=2[S:10][CH:11]=1)[CH3:14]
Reactant: CCc1csc2c(C(=O)O)cccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCc1csc2c(C(=O)OC)cccc12

Procedure:
7-Carboxy-3-ethylbenzo[b]thiophene (3.20 g) and concentrated sulfuric acid were stirred in methanol (100 ml) at 60° C. for 16 hr. The reaction mixture was concentrated and chloroform was added thereto. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate. The chloroform was separated, and the residue was dried over magnesium sulfate, and concentrated to give the objective compound (3.04 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si](C)(C)[C:9]#[C:10][C:11]([C:13]1[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[N:15](C(OC(C)(C)C)=O)[CH:14]=1)=O.C(=O)(O)O.[C:35]1([NH:41][C:42]([NH2:44])=[NH:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>COCCO>[C:35]1([NH:41][C:42]2[N:44]=[C:11]([C:13]3[C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:16]=4[NH:15][CH:14]=3)[CH:10]=[CH:9][N:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)n1cc(C(=O)C#C[Si](C)(C)C)c2cnccc21
Reactant: N=C(N)Nc1ccccc1
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCO
Product: c1ccc(Nc2nccc(-c3c[nH]c4ccncc34)n2)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.2 104 mg (0.75 mmol) of potassium carbonate are added to a solution of 103 mg (0.30 mmol of tert-butyl 3-(3-trimethylsilylpropynoyl)pyrrolo-[3,2-c]pyridine-1-carboxylate and 148 mg (0.75 mmol) of phenylguanidine carbonate in 1.5 ml of ethylene glycol monomethyl ether, and the mixture is heated at the boil for 68 hours. After cooling, 10 ml of water are added, and the mixture is stirred at 40° C. for 1 h. The precipitate formed is filtered off with suction, washed with water and dried in vacuo, giving phenyl-[4-(1H-pyrrolo[3,2-c]pyridin-3-yl)pyrimidin-2-yl]amine (“A1”) as pale-brown solid; ESI 287;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C)C=O.[NH:19]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25](=[O:33])(=[O:32])[NH:24]2)[CH2:20]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:19]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[S:25](=[O:33])(=[O:32])[NH:24]4)[CH2:20]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: O=S1(=O)NC2(CCNC2)c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: O=C(N1CCC2(C1)NS(=O)(=O)c1ccccc12)C1(c2ccc(Cl)cc2)CC1
Reaction time: 0.05 h

Procedure:
To a solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (40.0 mg, 0.000203 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol) at 0 Celsius were added spiro[1,2-benzisothiazole-3,3′-pyrrolidine]1,1-dioxide (45.6 mg, 0.000203 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (99.0 mg, 0.000224 mol). The reaction mixture was stirred for 3 minutes, then N,N-Diisopropylethylamine (88.6 μL, 0.000508 mol) was added. The solution was then stirred at r.t. overnight. The crude material was purified by prep-HPLC to give the desired compound. MS (ESI): 404.0 (M+H+).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH2:33][CH2:34][CH3:35]>ClCCl.CN(C)C1C=CN=CC=1>[C:32]([NH:18][S:15]([C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:4]2[CH:3]=[CH:2][C:1]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:6][CH:5]=2)[CH:10]=1)(=[O:17])=[O:16])(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: Cc1oc(S(N)(=O)=O)cc1COc1ccc(-c2ccccc2)cc1
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NS(=O)(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a stirred solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid amide (45) (50 mg, 0.146 mmoles) in dichloromethane (5.0 ml) was added triethylamine (26 μl, 0.189 mmoles), dimethyl-pyridin-4-yl-amine (1 mg) and butyryl chloride (19 μl, 0.184 mmoles). After stirring for 16 hours at room temperature the reaction mixture was concentrated in-vacuo, and the residue was purified by HPLC to give compound 61 as an off-white solid (48 mg). LC/MS System C: Rt=3.82 mins, m/z (ES−)=412 ((M−H) for C22H23NO5S).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][CH:16]=3)[N:11]([CH2:26][CH2:27][C:28]#[N:29])[C:10]2=[O:30])=[CH:5][CH:4]=1.[OH-:31].[Na+].OO>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:18][C:17]3[C:12](=[N:13][C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][CH:16]=3)[N:11]([CH2:26][CH2:27][C:28]([NH2:29])=[O:31])[C:10]2=[O:30])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(CCC#N)C2=O)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(CCC(N)=O)C2=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of 3-[-3-(4-methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-1-yl]-propionitrile (60 mg, 0.15 mmol) (from Example 26 supra) in dimethyl sulfoxide (2 mL) at 0 C was added 1.0 N aqueous sodium hydroxide solution (0.42 mL, 0.42 mmol) followed by 35% aqueous hydrogen peroxide (0.35 mL) (Fisher). The reaction mixture was stirred at 0° C. for 2 hours and then at room temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and washed with water (3×20 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude solid (71 mg) which was purified by recrystallization from hexanes-ethyl acetate to give 3-[-3-(4-methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-1-yl]-propionamide as a gray solid. (Yield 28.3 mg, 45.1%).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=O)=[CH:16][C:3]1=2.[CH3:21][N:22](C=O)[CH3:23].S(Cl)(Cl)=O.N(C)C>C(#N)C>[CH3:21][N:22]([CH3:23])[C:18](=[O:20])[CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CN(C)C=O
Agent: CNC
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 2.5 °C
Yield: 60 %

Procedure:
8 g (0.029 moles) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid were dissolved in 30 ml of acetonitrile and 0.15 ml of DMF were added to this solution. 2.3 ml (0.032 moles) of thionyl chloride were added to the resulting solution at 20-25° C. Once the reaction had ended, the reaction mixture is slowly poured over an aqueous solution of 40% Me2NH (14.4 g, 0.32 ml) cooled at 0-5° C. and stirring was maintained at this temperature for 30 minutes. Subsequently, the organic part was distilled under reduced pressure and 80 ml of methylene chloride were added. The phases were decanted, separating the organic phase. The solvent was distilled, obtaining an oil with the product of the title with a yield of 60%.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1cccc(Cl)c1
Yield: 17 %

Procedure:
In analogy to the procedure described in Example 25, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 3-chlorophenyl isocyanate gave the titled compound in 17% yield as white foam. MS: 463.2 (MH+, Cl).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=2[OH:26])[CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10])=[CH:7][CH:6]=1)([O-])=O.[H][H]>O=[Pt]=O.CO>[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=2[OH:26])[CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10])=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(O)c(NC(=O)c2ccc(N)cc2)c1

Procedure:
A mixture of 3-(4-nitrobenzamido)-4-hydroxy-α-(tert.butylaminomethyl)benzylalcohol hydrochloride (7.37 g, 0.018 mole), PtO2 (250 mg), and methanol (225 ml) was placed in a pressure hydrogenation apparatus at a starting pressure of 2 atm. The hydrogenation was started, and the calculated amount of hydrogen was taken up within 17 minutes. The hydrogenation was interrupted and the platinum catalyst was filtered off. The clear colorless filtrate was evaporated on a rotary evaporator at 40° - 50° C. The residue, a cream-colored foam (7.3 g), was recrystallized three times from methanol/ether, and 3.50 g (50%), m.p. 228.8° - 230° C, of analytically pure 3-(4-aminobenzamido)-4-hydroxy-α-(tert.butylaminomethyl)benzylalcohol hydrochloride, was obtained.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](CN4CCOCC4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.COC1C=C(C=CC=1)C=O>>[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:4][CH3:3])[CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: O=C(O)C(F)(F)F
Agent: COc1cccc(C=O)c1
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1cccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c1
Yield: 34 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-methoxybenzaldehyde were reacted to produce the title compound (34%). 1H NMR (d-chloroform): 15.77 (br s, 1H) 8.43 (d, J=8 Hz, 1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.66 (m, 1H), 7.44 (t, J=8 Hz, 1H), 7.04 (d, J=8 Hz, 1H), 6.51 (m, 1H), 6.42 (m, 1H), 5.93 (br s, 1H), 5.55 (br s, 1H), 5.36 (t, J=8 Hz, 1H), 3.93 (s, 3H), 3.17 (s, 1H), 3.05 (s, 1H), 2.69 (d, J=8 Hz, 1H), 2.32 (d, J=9 Hz, 1H), 1.67 (d, J=9 Hz, 1H). MS: 466.07 (M+H). HPLC retention time: 2.42 minutes (G Method).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.C([C:22]1[C:23]([N:31]=[CH:32][N:33]([CH3:35])C)=[N:24][C:25]([CH:28]2[CH2:30][CH2:29]2)=[CH:26][CH:27]=1)#N.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:28]1([C:25]2[CH:26]=[CH:27][C:22]3[C:35]([NH:1][C:2]4[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=4[S:9][C:10]4[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=4)=[N:33][CH:32]=[N:31][C:23]=3[N:24]=2)[CH2:29][CH2:30]1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ncnc3nc(C4CC4)ccc23)cc1

Procedure:
The product from Example 7b was reacted with the product from Example 119A using the procedure from Example 102 substituting the product from Example 7b for the product from Example 6c and substituting the product from Example 119A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.13 (d, J=6.25 Hz, 4H), 2.02 (s, 3H), 2.22-2.38 (m, 1H), 2.31 (s, 3H), 7.07 (s, 2H), 7.20 (d, J=8.82 Hz, 2H), 7.30 (s, 1H), 7.50 (d, J=8.82 Hz, 2H), 7.56 (d, J=8.46 Hz, 1H), 8.49 (s, 1H), 8.68 (d, J=8.82 Hz, 1H), 9.99 (s, 2H); MS (ESI+) m/z 442 (M+H)+.