Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH2:3][C@@H:4]1[NH:8][CH2:7][C@@H:6]([OH:9])[CH2:5]1.[C:10](#[N:13])[CH:11]=[CH2:12]>C(=O)([O-])[O-].[K+].[K+].C(#N)C>[OH:9][C@@H:6]1[CH2:7][N:8]([CH2:12][CH2:11][C:10]#[N:13])[C@@H:4]([CH2:3][OH:2])[CH2:5]1
Reactant: OC[C@H]1C[C@H](O)CN1
Reactant: C=CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCN1C[C@@H](O)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(3S,5R)-5-Hydroxymethylpyrrolidin-3-ol hydrochloride (0.4 g) described in Biochemistry, Vol. 5, pp. 1154–1155 (1966) was dissolved in aqueous potassium carbonate solution (2 mL) and acetonitrile (2 mL). Acrylonitrile (0.5 mL) was added and the mixture was stirred at room temperature for 5 hr. After the completion of the reaction, the reaction mixture was concentrated and the obtained residue was suspended in chloroform-methanol and dried by adding magnesium sulfate. Magnesium sulfate was filtered off and the solvent was concentrated to give 3-[(2R,4S)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile (0.47 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=O>C(O)(=O)C>[C:9]1([C:7]([C:6]2[CH:5]=[N:4][N:3]3[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)=[CH:18][CH:17]=[N:1][C:2]=23)=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A reaction mixture of 1.87 g of (3-amino-1H-pyrazol-4-yl)phenyl-methanone and 2.43 g of 3-dimethylamino-1-[3-(trifluoromethyl)phenyl]-2-propen-1-one in 25 ml of glacial acetic acid was refluxed for 6 hours and then the solvent was removed in vacuo giving a crystalline residue. This residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was dried with anhydrous sodium sulfate and then passed through a short pad of hydrous magnesium silicate. The addition of hexane to the refluxing eluate induced crystallization. After cooling, the desired product was collected as crystals, mp 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:11](=[O:17])[N:10]([CH2:18][C:19]([OH:21])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:11](=[O:17])[N:10]([CH2:18][C:19]([NH:28][CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=3)=[O:21])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COCCn1c(-c2ccc(Cl)cc2)nn(CC(=O)O)c1=O
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1c(-c2ccc(Cl)cc2)nn(CC(=O)NCc2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.0 mg (0.160 mmol) of 2-[3-(4-chlorophenyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 90A, 30.9 mg (0.176 mmol) of 3-trifluoromethylbenzyl-amine and 40.0 mg (0.209 mmol) of HOBt are placed in 2 ml of dimethylformamide and treated with 26.0 mg (0.192 mmol) of EDC hydrochloride. This is stirred overnight at room temperature, then stirred with 15 ml of water and the resulting precipitate recovered by filtration. The crude product is washed with water and dried in vacuo. 66.9 mg (89% of theory) of the target compound are thus obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9](=O)[C:8]2[N:12]([CH3:15])[CH:13]=[CH:14][C:7]=2[S:6]1(=[O:17])=[O:16].Cl.[NH2:19][OH:20].C([O-])(=O)C.[K+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9](=[N:19][OH:20])[C:8]2[N:12]([CH3:15])[CH:13]=[CH:14][C:7]=2[S:6]1(=[O:17])=[O:16]
Reactant: Cn1ccc2c1C(=O)CN(CCCCl)S2(=O)=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cn1ccc2c1C(=NO)CN(CCCCl)S2(=O)=O
Yield: 87.9 %

Procedure:
A suspension of 300 mg (1.08 mmol) of Compound 16, 113 mg (1.62 mmol) of hydroxylamine hydrochloride and 159 mg (1.62 mmol) of potassium acetate in 10 ml of methanol was refluxed for 7 hours. To the reaction mixture, 75 mg (1.08 mmol) of hydroxylamine hydrochloride and 106 mg (1.08 mmol) of potassium acetate were added, followed by further refluxing for 13 hours. Post treatment and purification were conducted as in Example 9, whereby 277 mg of the title compound were obtained (yield: 88%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>O>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH2:31][CH2:30][N:29]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
p-Toluenesulfonyl chloride (4.39 g, 23 mmol) was added to a pyridine solution (30 ml) of 4-(4-methoxyphenyl)piperidine (4.0 g, 21 mmol) and the mixture was stirred at room temperature overnight. Water was added to the solution mixture, which was then extracted with ethyl acetate. The organic phase was washed with hydrochloric acid and water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated to dryness under reduced pressure to obtain 4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)piperidine (4.8 g) as white powder.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.Cl.[OH:30][CH2:31][C@H:32]1[NH:36][CH2:35][C@H:34]([NH:37][C:38](=[O:40])[CH3:39])[CH2:33]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:36]3[C@H:32]([CH2:31][OH:30])[CH2:33][C@@H:34]([NH:37][C:38](=[O:40])[CH3:39])[CH2:35]3)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Reactant: CC(=O)N[C@H]1CN[C@H](CO)C1
Agent: Cl
Product: CC(=O)N[C@@H]1C[C@@H](CO)N(C2CCN(C(=O)c3c(C)nn(-c4cccc(C(F)(F)F)c4)c3C3CC3)CC2)C1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and N-((3R,5S)-5-hydroxymethyl-pyrrolidin-3-yl)-acetamide hydrochloride in direct analogy to the general procedure used in example 129. MS: 534.2 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:21][C:22]2[CH:26]=[CH:25][O:24][N:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1>CN1C(=O)CCC1>[F:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11]([C:8]1[N:6]2[N:7]=[C:2]([NH:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]3)[CH:3]=[C:4]([NH:21][C:22]3[CH:26]=[CH:25][O:24][N:23]=3)[C:5]2=[N:10][CH:9]=1)=[O:12]
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Nc3ccon3)cc(Cl)nn12
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccncc1F)c1cnc2c(Nc3ccon3)cc(N[C@H]3CC[C@H](O)CC3)nn12
Temperature: 110 °C

Procedure:
A mixture of 6-chloro-N-(3-fluoropyridin-4-yl)-8-(isoxazol-3-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.054 mmol) and (trans)-4-aminocyclohexanol (61.6 mg, 0.535 mmol) in NMP (0.4 mL) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature, and purified by reversed-phase preparative HPLC. The desired fractions were concentrated and dried to give 15 mg the title compound as a beige solid. HPLC Rt=2.615 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+1]=453.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[C:32](O)=[O:33]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32]([CH:28]3[CH2:29][CH2:30][CH2:31][O:27]3)=[O:33])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)C1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CCCO1

Procedure:
The title compound, off-white solid (74 mg, 70%), MS (ISP) m/z=425.3 [(M+H)+], mp 132° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (RS)-tetrahydro-furan-2-carboxylic acid.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]
Reactant: CC[C@@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(=O)OC
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: CC[C@@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(2-chloro-5-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:19]=[CH:18][C:17]3[O:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[S:9][C:8]=3[CH:7]=2)=[N:4][N:3]=[N:2]1.ClC1C=C(C=CC=1)C(OO)=[O:25]>CC(C)=O.O>[NH:1]1[C:5]([C:6]2[CH:19]=[CH:18][C:17]3[O:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[S:9](=[O:25])[C:8]=3[CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(c1)Oc1ccc(-c3nnn[nH]3)cc1S2
Solvent: CC(C)=O
Solvent: O
Product: O=S1c2ccccc2Oc2ccc(-c3nnn[nH]3)cc21

Procedure:
2-(5-Tetrazolyl)phenoxathiin (0.70g) and m-chloroperoxybenzoic acid (0.45g) were stirred for 2 hours at room temperature in acetone (20 ml.) and water (5 ml.). The reaction mixture was diluted with water, and the solid filtered, dried, washed with ether and re-dried to give 2-(5-tetrazolyl)phenoxathiin-10-oxide m.p. 267°-8° C. Recrystallisation from glacial acetic acid raised the melting point to 280°-1° C.
Reaction SMILES: COC1C=CC(C[N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][CH:22]=[CH:23][C:16]=34)[C:12]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[N:11]2)=CC=1>FC(F)(F)C(O)=O.O>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([C:12]2[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][CH:22]=[CH:23][C:16]=34)=[CH:14][NH:10][N:11]=2)=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: COc1ccc(Cn2cc(-c3ccnc4[nH]ccc34)c(-c3ccc([N+](=O)[O-])cc3)n2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(-c2n[nH]cc2-c2ccnc3[nH]ccc23)cc1
Yield: 64 %

Procedure:
A solution of 4-[1-{[4-(methyloxy)phenyl]methyl}-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine (0.22 mmol) in trifluoroacetic acid (0.75 mL) was heated at 74° C. for 1.5 h. The reaction mixture was diluted with water (4 mL) and extracted with (3×5 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate and were concentrated. Purification of the residue by Gilson reverse phase HPLC afforded the title product as a yellow solid (64%). ESMS [M+H]+: 306.4
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[S:17][C:16]3[C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:14][C:13]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][SiH2]C(C)(C)C(C)(C)C)[CH:25]=4)=[N:12][C:11]=3[CH:10]=2)[CH2:4][CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[S:17][C:16]3[C:15]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[N:14][C:13]([C:24]4[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=4)=[N:12][C:11]=3[CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2cc3nc(-c4cccc(O[SiH2]C(C)(C)C(C)(C)C)c4)nc(N4CCOCC4)c3s2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN1CCN(Cc2cc3nc(-c4cccc(O)c4)nc(N4CCOCC4)c3s2)CC1
Yield: 84.2 %

Procedure:
To a solution of 6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(1,1,2,2-tetramethyl-propylsilanyloxy)-phenyl]-thieno[3,2-d]pyrimidine (6.95 g, 12.89 mmol) in THF (100 mL) cooled to 0° C. was added a 1.0 M solution of tetrabutyl ammonium fluoride in THF (14.2 mL, 1.1 eq.). After 30 minutes the solvent was removed in vacuo and the residue was purified using flash chromatography (silica, 8% methanol in dichloromethane) and then triturated using ethyl acetate/methanol to yield the title compound as a white solid (4.62 g, 85%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C@@H:11]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([OH:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>O1CCCC1>[CH:5]1([C@@H:11]2[C:12](=[O:14])[O:13][C:1](=[O:2])[N:15]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)CN[C@@H](C(=O)O)C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)OC(=O)[C@H]1C1CCCCC1
Reaction time: 0.75 h
Yield: 95 %

Procedure:
Phosgene (28.9 kg, 291.9 mol) was added to (2R)-2-cyclohexyl-2-[(2-ethoxy-2-oxoethyl) amino]ethanoic acid (44.2 kg, 182 mol, obtained analogously to the method described in step (c) (Alternative A) above) in tetrahydrofuran (340 kg) at 40° C. over one hour. The reaction was deemed to be complete after a further hour. The mixture was concentrated at reduced pressure. The residue was diluted with tetrahydrofuran (272.6 kg) and the pH was adjusted at 0° C. to 6.5 with N-methylmorpholine (15.3 kg). The reaction was continued for a further 45 minutes. HCI/dioxane (0.34 kg) was then added and the residue was filtered through Celite®. The filter cake was washed twice with tetrahydrofuran. The combined filtrates were concentrated at reduced pressure at 20° C. To the residue was added heptane (250 kg), and the mixture was concentrated again. To the resultant residue further heptane (81 kg) was added. The temperature was adjusted to 0° C. and the mixture was allowed to crystallise for five hours. The crystals were filtered, washed (3×30 kg heptane) and dried (low pressure, 20° C.), to yield 46 kg (95%) of the sub-title compound.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:11]=3[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[F:27][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])[C:11]=3[CH:12]=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a cooled (0° C.) solution of (rac)-tert-butyl 2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetate (example 97) (235 mg, 0.597 mmol) in CH2Cl2 (2 mL) was added 4M HCl in dioxane (1.49 mL, 5.97 mmol) and the reaction mixture was stirred at room temperature for 16 h. The mixture was evaporated to dryness to give the title compound (221 mg, 99%) as a grey solid. MS: 338.5 (M+H+).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Product: O=c1[nH]cnc2cnc(OCc3ccccc3)cc12
Yield: 84 %

Procedure:
6-Chloro-3H-pyrido[3,4-d]pyrimidine-4-one (9.08 g, 50.0 mmol) was reacted with sodium hydride (60% dispersion on mineral oil, 8.14 g, 203.5 mmol) in benzyl alcohol at 150° C. for 18 hours. The mixture was partitioned between water and ether (water layer at pH14 from the excess sodium hydride) and the layers separated. The aqueous layer was further washed with ether, and then acidified to pH1 with dilute HCl, giving a cream precipitate. This was collected by filtration and dried at 60° C. in vacuo to give 6-benzyloxy-3H-pyrido[3,4-d]pyrimidin-4-one (10.59 g, 84%); δH [2H6]-DMSO 8.71 (1H,s), 7.79 (1H,s), 7.25-7.48 (6H,m), 5.40 (2H,s); m/z (M+1)+254. 6-Benzyloxy-3H-pyrido[3,4-d]pyrimidine-4-one (1.033 g, 4.08 mmol) was reacted with thionyl chloride (10 ml) and dimethyl formamide (2 drops) at reflux under a nitrogen atmosphere for 5 hours, and then left at room temperature overnight. The mixture was concentrated in vacuo, azeotroping twice with toluene to remove the excess thionyl chloride, to give 6-benzyloxy4-chloropyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 8.73 (1H,s), 8.10 (1H,s), 7.25-7.55 (6H,m), 5.41 (2H,s). 6-Benzyloxy-4-chloropyrido[3,4-d]pyrimidine (ca. half the above material, ca. 2 mmol) was reacted with 4-benzyloxyaniline (0.430 g, 2.25 mmol) in acetonitrile (10 ml) according to Procedure A for 5 hours. The resulting brown solid was 6-benzyloxy4-(4-benzyloxyanilino)pyrido[3,4-d]pyrimidine (0.621 g, 71%); δH [2H6]-DMSO 8.99 (1H,s), 8.73 (1H,s), 8.22 (1H,s), 7.71 (2H,d), 7.15-7.55 (10H,m), 7.10 (2H,d), 5.50 (2H,s), 5.13 (2H, s); m/z (M+1)+435.
Reaction SMILES: [NH:1]([C:25]([O:27]C(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH3:7])=[O:4].Cl.O1CCOCC1.[NH:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40]C(O)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[NH:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][C:25]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:9])[CH3:7])=[O:4])=[O:27]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: C[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 85.9 %

Procedure:
Compound II (65.03 g, 0.15 mole) was deblocked with HCl/dioxane and coupled to Boc-Gly-OH (26.3 g, 0.15 mole) using EDCI with HOBt in the same manner as that described for II to give 63.2 g (yield 85.9%) of III Rf1, 0.3; Rf2, 0.46.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[NH:8][C:9](=[O:20])[CH2:10][C:11](=[O:19])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=1)([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[NH:8][C:9](=[O:20])[CH2:10][C:11](=[O:19])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2c(c1)N(c1ccccc1)C(=O)CC(=O)N2

Procedure:
29.7 g of 7-nitro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione in 200 ml ethanol containing 1.0 g of Raney nickel is hydrogenated at room temperature at an initial hydrogen pressure of 50 p.s.i. The reaction is stopped after 0.3 moles of hydrogen has been absorbed. The reaction mixture is filtered and the filtrate evaporated to give 7-amino-5-phenyl-3H-1,5-benzodiazepine-2,4-dione.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])(=[O:22])=[O:21])[CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[S].[CH2:32](N)[CH2:33][NH2:34]>>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[S:20]([CH2:19][NH:18][CH2:17][CH2:16][CH2:15][N:13]([CH3:14])[C:11](=[O:12])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:34][CH2:33][CH2:32][N:2]=2)=[CH:8][CH:7]=1)(=[O:22])=[O:21]
Reactant: CN(CCCNCS(=O)(=O)c1cccc(Cl)c1Cl)C(=O)CCc1ccc(C#N)cc1
Reactant: NCCN
Agent: [S]
Product: CN(CCCNCS(=O)(=O)c1cccc(Cl)c1Cl)C(=O)CCc1ccc(C2=NCCN2)cc1

Procedure:
Analogously to 13b), N-{3-[(2,3-dichlorobenzenesulphonyl)methylamino]propyl}-3-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylpropionamide was prepared from 0.7 g (1.49 mmol) of 3-(4-cyanophenyl)-N-{3-[(2,3-dichlorobenzenesulphonyl)methylamino]propyl}-N-methylpropionamide, 0.1 g (3.12 mmol) of sulphur and 3 ml of ethylenediamine.
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH2:15][CH2:16]Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:29](=[O:36])[NH:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(C(C)=O)C>[C:1]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][CH2:16][N:33]2[CH2:34][CH2:35][C:30]3([N:26]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=4)[CH2:27][NH:28][C:29]3=[O:36])[CH2:31][CH2:32]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCN(c1ccccc1)c1ccccc1
Reactant: COc1ccc(N2CNC(=O)C23CCNCC3)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(N2CNC(=O)C23CCN(CCCN(c2ccccc2)c2ccccc2)CC3)cc1

Procedure:
A mixture of 940 mg. (0.00325 moles) of 3-[N,N-diphenylamino]-1-bromopropane (prepared according to the procedure of Example 2) and 850 mg. (0.00325 moles) of 1-(4-methoxyphenyl)-1,3,8-triazaspiro[4,5]decan-4-one, 400 mg. of sodium carbonate and 100 mg. of sodium iodide in 15 ml. of methyl ethyl ketone is refluxed for about 16 hours. The preparation of 1-(4-methoxyphenyl)-1,3,8-triazaspiro[4,5]decan-4-one is described in U.S. Pat. No. 3,155,670 to Janssen, issued Nov. 3, 1964. Solvent is evaporated and the residue is dissolved in chloroform, washed with water and chromatographed on a column of silica gel. The product fractions are evaporated and the residue is recrystallized from isopropyl alcohol and again from ethanol, giving 470 mg. of 8-[3-diphenylamino)propyl]-1-(4-methoxyphenyl)-1,3,8-triazaspiro[4,5]decan-4-one, mp. 156.5°-157.5° C.