Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22]Cl.[NH2-].[Na+].CO.C(Cl)(Cl)Cl>O>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH:17]=[CH:16][CH:15]=[CH:14][C:6]1=2
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: CN(C)CCCCl
Agent: [NH2-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC1=Cc2ccccc2N(CCCN(C)C)c2ccccc21
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A 500 ml round bottom flask containing 9.87 g (0.044 moles) of 10-methoxy-5H-dibenz[b,f]azepine prepared in Example 3 and 13.9 g (0.088 moles) of 3-dimethylaminopropylchloride was evacuated for several days. Anhydrous toluene (250 ml) was added followed by 7.04 g (0.176 moles) of sodium amide. The heterogeneous solution was stirred at ambient temperature for a few minutes and then refluxed for 16 hours. After 16 hours of refluxing, tlc analysis of the reaction mixture (silica gel GF plates, methanol:chloroform 1:9; visualized under UV lamp and sulfuric acid-ceric sulfate spray) revealed that the reaction was complete and that no starting material remained. Enough water was added to slowly decompose the excess sodium amide. The dark-brown solution was placed in a 1 liter separatory funnel and extracted with four 250 ml portions of water. The organic phase was dried over anhydrous magnesium sulfate, charcoal was added and the mixture was filtered through a Celite pad. The filtrate was concentrated leaving a brown oil (12.6 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:38]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:41][C:42]1[N:46]([CH3:47])[CH:45]=[N:44][N:43]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH2:41][C:42]5[N:46]([CH3:47])[CH:45]=[N:44][N:43]=5)=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:38]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2)CCN3CCC)cc1
Reactant: Cn1cnnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(OCc4nncn4C)cc2)CCN3CCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To 7-[4-(2-butoxyethoxy)phenyl]-N-(4-hydroxyphenyl)-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.62 g), 3-chloromethyl-4-methyl-4H-1,2,4-triazole hydrochloride (0.24 g) and potassium carbonate (0.5 g), N,N-dimethylformamide (15 ml) was added and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(4-methyl-4H-1,2,4-triazol-3-yl) methoxy]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 24) (0.48 g) as yellow amorphous.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[F:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH2:21][CH2:22][NH2:23])=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1.Cl>O.ClCCl>[F:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH2:21][CH2:22][NH:23][C:7](=[O:9])[CH3:8])=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCOc1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.1 %

Procedure:
Pyridine (1.5 ml, 18.6 mmol) and acetic anhydride (0.97 g, 10.3 mmol) were added to a dichloromethane solution of 3-(4-fluoro-2-nitrophenoxy)propylamine (2.0 g, 9.33 mmol), while being cooled with ice, and then dichloromethane (4 ml) was further added. The resulting mixture was stirred at room temperature for 15 hours. 2N-hydrochloric acid (9.5 ml) was added to the reaction mixture, and the mixture was stirred. Water was added to the mixture, and the resulting mixture was extracted with dichloromethane. After being washed with a saturated sodium chloride aqueous solution, the organic layer was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=30:1→20:1). The purified product was concentrated under reduced pressure to thereby obtain 2.13 g of oily yellow N-[3-(4-fluoro-2-nitrophenoxy)propyl]acetamide (yield: 89%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].O=C1N(C(OCC2C=CC=CC=2)=O)[C@H](C(O)=O)CN1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:42][C:43]([F:46])([F:45])[F:44])(=O)=O>CN(C)C=O>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:4]([CH2:42][C:43]([F:46])([F:45])[F:44])[C:3]1=[O:14]
Reactant: CN1CC(C(=O)OC(C)(C)C)NC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(C(=O)OC(C)(C)C)N(CC(F)(F)F)C1=O
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 42.1 %

Procedure:
A solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (180 mg, 0.9 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml), under argon at −35° C., was treated with sodium hydride (60% dispersion in oil) (36.0 mg, 0.900 mmol). The mixture was stirred at −35° C. for 15 minutes and then 2,2,2-trifluoroethyl trichloromethanesulfonate (507 mg, 1.800 mmol) was added and the reaction mixture was stirred at −35° C. for 2 hours (the temperature increased slowly to −15° C.). The reaction was quenched with water (5 ml) and allowed to warm to room temperature and the reaction mixture was extracted with ethyl acetate (2×20 ml). The organic layer was separated, washed with saturated sodium hydrogen carbonate solution (10 ml), water (2×10 ml) and brine (20 ml) and evaporated. The residue was purified by silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-4-imidazolidinecarboxylate (107 mg, 42%). LC/MS [M+H]+=283. (ii) A solution of 1,1-dimethylethyl 1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-4-imidazolidinecarboxylate (107 mg, 0.379 mmol) in TFA/DCM (1:2, 3 ml) was stirred at room temperature for 4 hours. The solution was evaporated and the residue was co-evaporated with dichloromethane and dried to give crude 1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-4-imidazolidinecarboxylic acid (assume ˜0.38 mmol) which was used in the next reaction. LC/MS [M+H]+=227.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9](NC(C)C)(C)C.[Li].IC.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1Cl
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CNc1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 2-chloro-3-pyridinamine (0.0465 mol) in THF (45ml) at −78° C. under N2 flow, lithium diisopropylamine (0.0513 mol, 2 M) was added dropwise. The mixture was allowed to warm to 0° C. and was stirred for 1 hour and then cooled to −78° C. Then iodomethane (0.0582 mol) was added and the reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. A saturated NH4Cl-solution was added and the mixture was extracted with ethyl acetate. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: hexane/ethyl acetate 80/20). The product fractions were collected and the solvent was evaporated, yielding 5.91 g of 2-chloro-N-methyl-3-pyridinamine (intermediate 28).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5](SC)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(O)(=O)C>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: CN1CCNCC1
Reactant: CSC1=Nc2ccccc2N(C)c2cscc21
Solvent: CC(=O)O
Product: CN1CCN(C2=Nc3ccccc3N(C)c3cscc32)CC1

Procedure:
A solution of 1.2 g. of 4-methyl-10-(methylthio)-4H-thieno[3,4-b] [1,5] benzodiazepine in 6 ml. of N-methylpiperazine is treated with 2-3 drops of glacial acetic acid and heated under reflux for 4 days. The solution is concentrated to dryness and the residue is warmed with dilute acetic acid. The acidic solution is filtered, cooled, and made alkaline with concentrated ammonium hydroxide solution. The precipitate is collected, washed with water and dissolved in chloroform. The chloroform solution is dried and concentrated to an oil, which slowly crystallizes. Recrystallization from ethanol gives yellow crystals, m.p. 83°-85°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Br[C:20]1[S:24][C:23]([C:25]#[N:26])=[N:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:20]3[S:24][C:23]([C:25]#[N:26])=[N:22][N:21]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: N#Cc1nnc(Br)s1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C#N)s3)cc(C)c21
Temperature: 60 °C
Yield: 70 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.44 g, 1.75 mmol) in acetonitrile (30 mL) was added 5-bromo-[1,3,4]thiadiazole-2-carbonitrile (0.6 g, 3.16 mmol) and potassium carbonate (0.73 g, 5.25 mmol). The suspension was heated at 60° C. for 6 hours. The mixture was cooled to 0° C., diluted with water and extracted with EtOAc (2×50 mL). The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (30-60% EtOAc/hexane) to give [6-(5-cyano-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.44 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.41 (s, 1H), 7.55 (d, J=2.21 Hz, 1H), 7.43 (d, J=1.62 Hz, 1H), 5.59 (dd, J=8.72, 2.73 Hz, 1H), 4.04 (q, J=6.92 Hz, 2H), 3.16 (dd, J=15.56, 2.94 Hz, 1H), 2.37-2.43 (m, 1H), 2.35 (s, 3H), 1.14 (t, J=7.17 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[C@@:16]([CH2:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:25])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[Cl:40][CH2:41][CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45]>CN(C)C=O.O>[Cl:40][CH2:41][CH2:42][CH2:43][S:44]([NH:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[C@@:16]([CH2:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:25])[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:23]=3[OH:24])[NH:7][C:6]=2[S:5][CH:4]=1)(=[O:46])=[O:45]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN)csc3N2)=C(O)c2ccccc21
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CNS(=O)(=O)CCCCl)csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 186B (64 mg, 0.14 mmol) in 1.5 mL of N,N-dimethyl formamide was cooled to 0° C., treated with triethylamine (30 μL, 0.28 mmol) and 3-chloropropylsulfonyl chloride (19 μL, 0.15 mmol), stirred for 30 minutes, allowed to warm to room temp, stirred for 2 h, diluted with water and extracted with ethyl acetate. The organic phase was washed with water and concentrated in vacuo to afford a solid. This crude material was purified by chromatography on silica gel with a gradient of methanol in dichloromethane (0-2%) to afford the title compound as a pale compound (42 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.39 (td, J=12.8, 3.5 Hz, 1H), 0.72 (s, 9H), 0.82 (m, 1H), 1.56 (s, 3H), 2.13 (m, 4H), 3.21 (m, 2H), 3.75 (t, J=6.4 Hz, 2H), 4.28 (d, J=5.9 Hz, 2H), 7.33 (s, 1H), 7.51 (m, 1H), 7.72 (m, 2H), 7.90 (t, J=6.3 Hz, 1H), 8.13 (d, J=7.7 Hz, 1H), 14.09 (s, 1H); MS (APCI−) m/z 612 (M−H)−; Anal calc'd for C26H32ClN3O6S3: C, 50.84; H, 5.25; N, 6.84. found: C, 51.07; H, 5.28; N, 6.51.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH3:63])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH3:63])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: COc1cccc(CCNCc2ccc(C(C)(C)C)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cccc3cc[nH]c23)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
To a solution of 80 mg of 1H-indole-7-carboxylic acid (0.5 mmol) and 159 mg of TBTU (0.5 mmol) in 10 ml DMF, were added 0.425 ml (2.48 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 174 mg (0.68 mmol) of (4-tert-butyl-benzyl)-[2-(3-methoxy-phenyl)-ethyl]-amine were added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted twice with EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; heptane/EtOAc 2:1) to give 168 mg (75%) of a white solid. MS (ISP) 441.4 (M+H)+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][NH:20]2)=[CH:16][CH:15]=1.C1(C)C=CC=CC=1>CN(C=O)C>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([NH:13][C:2](=[O:4])[C:1]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH2:6])[CH:22]=2)[CH:18]=[CH:19]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc2cc[nH]c2c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)Nc1ccc2cc[nH]c2c1
Yield: 52.7 %

Procedure:
A mixture of isatoic anhydride (5.06 g, 31 mmol), 6-aminoindole (4.103 g, 31 mmol), toluene (300 mL) and DMF (30 mL) was heated to reflux for 18 hours. The reaction was cooled, filtered, and chromatographed to yield 4.103 g (53%) of the title compound as a tan solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>[OH-].[K+].O>[CH2:12]([O:11][C:9]([NH:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC[C@H](N)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 g of 2(S)-aminobutyric acid (97 mmol) are dissolved in aqueous 4M KOH solution (100 ml) and the mixture is cooled to 0° C. 24.7 g of benzyl chloroformate (145 mmol) are added and the mixture is stirred while allowing its temperature to rise to room temperature over 2 hours 30 minutes. The mixture is then diluted with water (100 ml) and extracted with ether (2×200 ml). The aqueous phase is acidified to a pH<1 with concentrated HCl and is extracted with ethyl acetate (3×200 ml). The ethyl acetate fractions are combined and dried (Na2SO4) and the solvent is removed. A white solid is obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH:29](N(CC)C(C)C)([CH3:31])[CH3:30].[CH3:38][N:39]([CH3:42])[CH:40]=[O:41]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:38]4[N:39]([CH3:42])[C:40](=[O:41])[CH:30]=[CH:29][CH:31]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cccc(=O)n2C)C3)cc1
Reaction time: 8 h
Yield: 4.4 %

Procedure:
To a solution of 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (bf) (115 mg, 0.300 mmol) in N,N-Dimethylformamide (2.00 mL) and N,N-Diisopropylethylamine (0.104 mL, 0.600 mmol) was added 6-chloror-1-methylpyridin-2(1H)-one (129 mg, 0.90 mmol) at room temperature. The reaction was kept at 140° C. overnight, followed by RPHPLC purification. The desired product pv (6.4 mg, 4.4% yield) was obtained as white powder: 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.19 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.38 (m, 1H), 6.19-6.10 (m, 2H), 6.01 (d, J=6.6, 1H), 4.15 (s, 2H), 3.80-3.71 (m, 4H), 3.53 (m, 4H), 3.48 (s, 3H), 3.24-3.06 (m, 4H), 2.86 (s, 2H), 1.06 (t, J=7.2 Hz, 3H); LC-MS m/z=490 (M+H).
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:1][CH2:2][CH2:3]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CNCCS2
Product: CC(=O)N1CCSc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (1.5 g, prepared as described in the first paragraph of Example 6 above) in acetic anhydride (15 ml) was stirred at room temperature for one hour. The reaction mixture was poured into ice and extracted with dichloromethane. The organic layer was dried and the solvent removed by evaporation to give 4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine [a compound known as a Friedel Crafts catalyst from Example 46 of EP 368063 (Bayer)]. The product was recrystallised from hexane. Yield 1.55 g (m.p. 69°-70° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1>>[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]2)=[CH:3][CH:4]=1
Reactant: OC1CCCNC1
Reactant: Brc1ccc(-c2ncco2)cc1
Product: OC1CCCN(c2ccc(-c3ncco3)cc2)C1
Yield: 44.8 %

Procedure:
1-(4-(Oxazol-2-yl)phenyl)piperidin-3-ol (245 mg, 1.00 mmol) was synthesized, in 45% yield, as described in General Procedure B using 2-(4-bromophenyl)oxazole (500 mg, 2.232 mmol) and piperidin-3-ol (451 mg, 4.46 mmol). Anal. Calcd. for C14H16N2O2 m/z 244.2, found: 245.0 (M+H)+.
Reaction SMILES: [CH2:1]([OH:6])CCCO.COC(=O)[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.C([O-])(=O)C1C(=CC=CC=1)[C:24]([O-])=[O:25]>>[C:24]([O:6][CH3:1])(=[O:25])[C:11]1[CH:10]=[CH:19][CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: OCCCCO
Reactant: O=C([O-])c1ccccc1C(=O)[O-]
Product: COC(=O)c1cccc(C(=O)OC)c1

Procedure:
The block copolyester is sold by E. I. du Pont de Nemours and Company and is characterized by a melt index (2160 g./200° C.) of 6-8, a TMA S.P. of 144° C. and a DTA crystalline M.P. of 154° C. The 1,4-butanediol/PTMEG mole ratio is 5.0 and the dimethylterephthalate to total phthalate ratio is 0.78.
Reaction SMILES: ClC[CH:3]([OH:16])[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.[CH3:17][NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[CH2:25](O)C>>[NH2:5][CH2:4][CH:3]([OH:16])[CH2:17][N:18]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:25]
Reactant: CCO
Reactant: O=C1c2ccccc2C(=O)N1CC(O)CCl
Reactant: CNC1CCCCC1
Product: CN(CC(O)CN)C1CCCCC1
Temperature: 25 °C
Yield: 31 %

Procedure:
A mixture of 2-(3-chloro-2-hydroxypropyl)isoindoline-1,3-dione 7.2 g (0.03 mol) (Weizmann, M. et al. Bull. soc. chim. 1930, 47:356-61) and N-methylcyclohexanamine 6.8 g (0.06 mol) in 25 ml ethanol was refluxed for 6 hours, then evaporated in vacuo. The oil residue was added into 60 ml 20% aq. HCl and refluxed for another 3 hours. After cooled to room temperature, the precipitate was filtered off. The filtrate was concentrated to about 15 ml in vacuo, then basified to pH 13 to 14 with solid NaOH and extracted with CH2Cl2. The organic layer separated was dried over anhydrous Na2SO4 and concentrated in vacuo to give 1.75 g (31%) 1-amino-3-(cyclohexyl(methyl)amino)propan-2-ol as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].[SH2:13].C(NCC)C>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[S:13])[NH2:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12]
Reactant: CCCc1cc(C#N)ccc1O
Reactant: S
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCCc1cc(C(N)=S)ccc1O
Temperature: 7 °C
Reaction time: 54 h
Yield: 93 %

Procedure:
A solution of 4-hydroxy-3-propylbenzonitrile (35.63 g, 0.221 mol) (Example 33) in DMF (300 mL) was saturated with hydrogen sulfide at rt (moderate flow over 45 minutes). Temperature was monitored (increase of about 7° C.). To the solution was added diethylamine (45.73 mL, 0.442 mol). The temperature increased by 10° C., and the green reaction mixture became darker green. Hydrogen sulfide was passed into the dark green solution for another 30 minutes (at this point the reaction temperature was 40° C.). The reaction mixture was warmed to 60° C. Hydrogen sulfide was again passed into the solution at 60° C. over 2 h. The reaction mixture was cooled and stirred at rt for 54 h and most of the solvent removed under reduced pressure. The resultant residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (4×100 mL), then brine, and dried over sodium sulfate, filtered, and concentrated. The resultant orange oil was triturated in hexanes (300 mL) and ether (25 mL) to give a yellow solid (39.97 g, 93%) after drying for 1 h under suction. LC/MS m/z 196.1 (M+H)+, RT 2.16 min. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.44 (s, 1H), 9.14 (s, 1H), 7.73-7.65 (m, 2H), 6.73 (d, 1H), 2.51-2.47 (m, 2H), 1.59-1.50 (m, 2H), 0.90 (t, 3H).