Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([Na])[C:4](=[O:6])[CH3:5])#[N:2].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[C:11]=1[CH3:20]>CN(C)C=O.[Cl-].[NH4+]>[CH3:20][C:11]1[C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH:3]([C:4](=[O:6])[CH3:5])[C:1]#[N:2]
Reactant: CC(=O)C([Na])C#N
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)C(C#N)Cc1cccc(C(F)(F)F)c1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of (1-cyano-2-oxopropyl)sodium (3.5 g, 33.2 mmol) in N,N-Dimethylformamide (25 mL) stirred under nitrogen at 0° C. was added a solution of 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (7.0 g, 27.7 mmol) in 10 ml of DMF dropwise during 30 min. The reaction mixture was stirred at 40° C. for 2 hours. Then this solution was diluted with saturated ammonium chloride solution. This solution was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried, concentrated to dryness in vacuo. The crude product was purified with on a silica gel column to give 2-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3-oxobutanenitrile. (5.2 g, 74%). To a solution of 2-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}3-oxobutanenitrile (5.2 g, 20.4 mmol) in ethanol (400 mL) stirred under nitrogen at 20° C. was added neat hydrazine monohydrate (2.25 g, 30.6 mmol) dropwise during 5 minutes. The reaction mixture was stirred at 100° C. for overnight. After cooled to room temperature, the reaction mixture was evaporated to dryness in vacuo. The residue was purified on a silica gel column (methanol/DCM gradient solvent system) to provide titled product. (2.16 g, 39%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (s, 3H) 2.39 (s, 3H) 3.63 (s, 2H) 4.30 (br. s., 2H) 7.19 (d, J=7.58 Hz, 1H) 7.27 (t, J=7.71 Hz, 1H) 7.49 (s, 1H) 11.09 (br. s., 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][C:24]=1[C:36]([F:39])([F:38])[F:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>O.C1(C)C=CC=CC=1>[ClH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:9][CH2:10][CH:11]([N:32]3[CH2:33][CH2:34][C:29]([C:26]4[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([C:36]([F:38])([F:37])[F:39])[CH:25]=4)([OH:35])[CH2:30][CH2:31]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Reactant: O=C1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1

Procedure:
A mixture of 14.3 g of 4,4-bis(p-fluorophenyl)cyclohexanone, 14 g of 4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol, 0.5 g of p-toluenesulfonic acid and 100 ml of toluene is stirred under reflux for 145 hours, water formed being removed as an azeotropic mixture with toluene. The toluene is then removed, and the residual oil is dissolved in 100 ml of 90% methanol. To the solution is added slowly 19 g of sodium borohydride under cooling. After the addition is complete, the methanol is removed under reduced pressure, water is added to the residue, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate. The residual oil is purified by column chromatography on silica gel using a mixture of chloroform and methanol (9:1) as an eluent. The objective base thus obtained is converted in a conventional manner into the hydrochloride. Thus is obtained 1-[4,4-bis(p-fluorophenyl)cyclohexyl]-4-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol hydrochloride as colorless crystals, melting at 274°-277° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][C:4]([C:6]1[C:7]([C:22](OCC)=[O:23])=[N:8][N:9]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[CH:10]=1)=O.[CH3:28][NH:29][NH2:30]>C(O)C.O>[CH3:28][N:29]1[C:22](=[O:23])[C:7]2=[N:8][N:9]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[CH:10]=[C:6]2[C:4]([CH2:3][CH:2]([CH3:27])[CH3:1])=[N:30]1
Reactant: CCOC(=O)c1nn(Cc2cccc3ccccc23)cc1C(=O)CC(C)C
Reactant: CNN
Solvent: CCO
Solvent: O
Product: CC(C)Cc1nn(C)c(=O)c2nn(Cc3cccc4ccccc34)cc12

Procedure:
A mixture of ethyl 4-(3-methyl-1-oxobutyl)-1-(1-naphthalenylmethyl)-1H-pyrazole-3-carboxylate (0.15 g) and methylhydrazine (0.1 ml) in ethanol (2 ml) was heated at reflux for 18 hours. The reaction was diluted with water and then extracted into ethyl acetate. The organic phase was washed with brine, dried, filtered and evaporated. The residue was chromatographed, eluting with dichloromethane:ethanol (19:1), to give the title compound (0.08 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])C=CN=3)[S:10][C:3]=12.Br[C:18]1[N:19]=[CH:20]N(C)C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:16][N:19]([CH3:20])[CH:18]=3)[S:10][C:3]=12
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: Cn1cnc(Br)c1
Product: Cn1cnc(-c2cc3nccc(Cl)c3s2)c1

Procedure:
Following the procedure described for compound 7 (example 2, step 3) but substituting 2-bromo-1-methyl-1H-imidazole for 4-bromo-1-methyl-1H-imidazole [a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10:1990:1050-1057, b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598, c) Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-1790.], title compound 10 was obtained as an off-white solid (29% yield). MS (m/z): 250.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:25])[N:18]=[C:19]([CH2:20][CH:21]([CH2:23][CH3:24])[CH3:22])[N:12]2[N:11]=1)[CH3:2].[S:26](Cl)([Cl:29])(=[O:28])=[O:27]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:26]([Cl:29])(=[O:28])=[O:27])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:25])[N:18]=[C:19]([CH2:20][CH:21]([CH2:23][CH3:24])[CH3:22])[N:12]2[N:11]=1)[CH3:2]
Reactant: CCOc1ccccc1-c1nn2c(CC(C)CC)nc(C)c2c(=O)[nH]1
Reactant: O=S(=O)(Cl)Cl
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(CC(C)CC)nc(C)c2c(=O)[nH]1

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 7.23 g (0.12 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-(2-ethylpropyl)-1H-imidazo-[5,1-f][1,2,4]-triazin-4-one (Example 18A). This gives 8.56 g (91.9%) of sulphonyl chloride as a white solid which is directly reacted further.
Reaction SMILES: [CH3:1][C:2]1([C:5]([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([N+:24]([O-])=O)=[CH:16][N:15]=3)[CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3]1.C1COCC1.[H][H]>[Pd]>[NH2:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:13][CH:10]2[CH2:11][CH2:12][N:7]([C:5]([C:2]3([CH3:1])[CH2:4][CH2:3]3)=[O:6])[CH2:8][CH2:9]2)=[N:15][CH:16]=1
Reactant: [H][H]
Reactant: CC1(C(=O)N2CCC(Oc3ncc([N+](=O)[O-])c4ccccc34)CC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1(C(=O)N2CCC(Oc3ncc(N)c4ccccc34)CC2)CC1
Temperature: 40 °C

Procedure:
Charge a 3 gallon autoclave with (1-methyl-cyclopropyl)-[4-(4-nitro-isoquinolin-1-yloxy)-piperidin-1-yl]-methanone (368.0 g, 1.04 moles), THF (4.42 L, 54.32 moles), and 5% Pd on carbon (dry, 40.50 g, 19.03 moles). Seal the autoclave and introduce hydrogen to 50 psi. Stir the contents at 1000 rpm at room temperature under 50 psi of hydrogen for 4.5 hours. Filter and rinse with additional THF (2.0 L, 24.58 moles). Treat the filtrate with carbon (20-40 mesh, 42.00 g) and heat to 40° C. for 1 hour. Add additional carbon (60 mesh, 47.00 g) and continue heating for 1 hour. Filter carbon through a micro fiber paper and a bed of Hyflo Super Cel® and rinse with a minimal amount of THF. Remove solvent to obtain [4-(4-amino-isoquinolin-1-yloxy)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone, 348 g (103%) as a dark orange-red oil/foam. 1H NMR (500 MHz, CDCl3): δ 0.59 (t, J=6.0 Hz, 2H), 0.96 (t, J=6.0 Hz, 2H), 1.34 (s, 3H), 1.88-1.94 (m, 2H), 2.06-2.10 (m, 2H), 3.61-3.70 (m, 2H), 3.93-4.00 (m, 2H), 5.48-5.50 (m, 1H), 7.52 (s, 1H), 7.58 (t, J=7.0 Hz, 1H), 7.73 (t, J=7.0 Hz, 1H), 7.81 (d, J=7.0 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H).
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)=[CH:12][CH:11]=[CH:10][C:9]=2[C:22]2[S:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=2)=[CH:3][CH:2]=1.[Br:32]C1C=CC2C(C3C=CC(C)=CC=3)=C(C3C=CC(C)=CC=3)SC=2C=1>>[Br:32][C:10]1[C:9]([C:22]2[S:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=2)=[C:8]([NH:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:31])=[CH:6][CH:5]=2)[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(-c2sc3cc(Br)ccc3c2-c2ccc(C)cc2)cc1
Reactant: Cc1ccc(Nc2cccc(-c3cc4ccccc4s3)c2Nc2ccc(C)cc2)cc1
Product: Cc1ccc(Nc2ccc(Br)c(-c3cc4ccccc4s3)c2Nc2ccc(C)cc2)cc1

Procedure:
Intermediate C was synthesized in the same manner as in Synthesis Example 1, except that 2,3-di-p-tolylaminophenyl-benzo[b]thiophene was used instead of 2,3-di-p-tolyl-benzo[b]thiophene used to synthesize Intermediate B in Synthesis Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:24])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:15][C:14]=2[CH:23]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:25])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:24])[C:9]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([CH2:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[N:15][C:14]=2[CH:23]=1)=[CH:28][N:29]([CH3:31])[CH3:30]
Reactant: Cc1nsc(NC(=O)Cc2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)C(=CN(C)C)c2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Temperature: 110 °C
Yield: 27.3 %

Procedure:
N-(4-Choro-3-methylisothiazol-5-yl)-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]acetamide (2.5 g, 0.0066 mole) [prepared as in Example 1] and N,N-dimethylformamide dimethylacetal (1.5 g, 0.013 mole) were added to a mixture of N,N-dimethylformamide (5 ml) and toluene (20 ml) and the resulting mixture was heated to 110° C. for 4 hours. The mixture as cooled to room temperature and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate and washed sequentially with brine and water, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue was further purified by flash column chromatography, eluting with ethyl acetate:hexane at 1:1 by volume. Further flash column chromatography, eluting with ethyl acetate:dichloromethane at 1:9 by volume gave N-(4-chloro-3-methylisothiazol-5-yl)-α-[(dimethylamino)methylene]-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]acetamide (0.78 g) as a single geometrical isomer.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O[C:7](=[O:31])[CH2:8][N:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[N:17]=[C:16]2[CH3:29])=[CH:11][C:10]1=[O:30])C>C(O)C>[CH3:1][N:2]([CH3:3])[C:7](=[O:31])[CH2:8][N:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[N:17]=[C:16]2[CH3:29])=[CH:11][C:10]1=[O:30]
Reactant: CNC
Reactant: CCOC(=O)Cn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O
Solvent: CCO
Product: Cc1cccc(C#Cc2cn(-c3ccn(CC(=O)N(C)C)c(=O)c3)c(C)n2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 2 ml of a 5.6M solution of dimethylamine in ethanol were added 70 mg (0.19 mmol) of [4-(2-methyl-4-m-tolylethynyl-imidazol-1-yl)-2-oxo-2H-pyridin-1-yl]-acetic acid ethyl ester (Example 13). The reaction vessel was closed and the yellow solution was stirred for 2 days at room temperature. The solution was then evaporated to dryness, the residue was triturated with a small amount of ethyl acetate and the product was filtered off, yielding 59 mg of the title compound as a white solid, MS: m/e=375.3 (M+H+).
Reaction SMILES: [P:1](Cl)([Cl:6])([O:3][CH2:4][CH3:5])=[S:2].[O-:8][CH2:9][CH2:10][CH3:11].[Na+].C(O)CC>O1CCCC1>[P:1]([Cl:6])([O:8][CH2:9][CH2:10][CH3:11])([O:3][CH2:4][CH3:5])=[S:2]
Reactant: CCC[O-]
Reactant: CCOP(=S)(Cl)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCO
Product: CCCOP(=S)(Cl)OCC
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To 30 g (167 mmole) of O-ethyl dichlorothiophosphate in 100 ml of tetrahydrofuran (THF) cooled to -70° C. was added a solution of sodium propoxide (from 7.4 g of 60% NaH (184 mmole) and 11 g (176 mmole) of 1-propanol) in 50 ml of THF. After warming to room temperature over 2 hours, the THF was removed in vacuo and the residue was partitioned between 50 ml diethyl ether, 50 ml hexanes, and 25 ml cold water. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and distilled (bp 45-50° C. 1 torr) yielding 20 g of the title compound, an oil. nmr 1.0 t 3H, 1.4 t 3H, 1.8 sextet 2H, 4.4 m 4H.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30](OCC)=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:36][C@H:37]([CH3:40])[CH2:38][OH:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:36][C@H:37]([CH3:40])[CH2:38][OH:39])=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-2-amino-1-propanol using methods similar to Example 563 to provide a tan solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.74 Hz, 3 H), 1.65-1.81 (m, 6 H), 2.19 (t, J=5.79 Hz, 2 H), 3.21 (t, J=5.90 Hz, 2 H), 3.37 (t, J=6.95 Hz, 2 H), 3.48 (t, J=5.05 Hz, 2 H), 4.05 (t, J=6.00 Hz, 1 H), 4.14-4.23 (m, 4 H), 5.00 (t, J=5.16 Hz, 1 H), 7.10-7.18 (m, 2 H), 7.37-7.44 (m, 2 H), 7.98 (s, 1 H), 8.56 (d, J=1.26 Hz, 1 H), 10.31-10.39 (m, 1 H), 17.24 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][C@@H:5]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:37][N:38]1[C:42](=[O:43])[C:41]([CH3:45])([CH3:44])[N:40]([CH3:46])[C:39]1=[O:47]>COCCOC>[CH:1]1([CH2:4][C@@H:5]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:6]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:37][N:38]2[C:42](=[O:43])[C:41]([CH3:44])([CH3:45])[N:40]([CH3:46])[C:39]2=[O:47])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(C(=O)OCc1ccccc1)[C@@H](CC1CC1)C(=O)OCc1ccccc1
Reactant: CN1C(=O)N(CBr)C(=O)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1C(=O)N(CC(C(=O)OCc2ccccc2)(C(=O)OC(C)(C)C)[C@@H](CC2CC2)C(=O)OCc2ccccc2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A solution of 6.4 g of 2,3-dibenzyl 3-tert-butyl 1-cyclopropyl-2(R),3(R,S),3-propanetricarboxylate (1:1 mixture of diastereoisomers) in 30 ml of 1,2-dimethoxyethane was treated with 0.446 g of an 80% dispersion of sodium hydride in mineral oil. The mixture was stirred at room temperature for 30 minutes. A solution of 3.84 g of 1-(bromomethyl)-3,4,4-trimethyl-2,5-imidazolinedione in 20 ml of 1,2-dimethoxyethane was added dropwise over 15 minutes. The mixture was stirred at room temperature for 36 hours, the solvent was evaporated and the residue was dissolved in ethyl acetate and washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the solvent was evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (7:3) and subsequently hexane/ethyl acetate (6:4) for the elution to give 6.4 g of 2,3-dibenzyl 3-tert-butyl 1-cyclopropyl-4-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-2(R),3(R,S),3-butanetricarboxylate as a 1:1 mixture of diastereoisomers in the form of a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10](Cl)(=[O:13])[CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:13])[CH2:11][CH3:12])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(F)c(Cl)c1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
3-chloro-4-fluoroaniline (10 g, 67.32 mmol) dissolved in CH2Cl2 was added with propionyl chloride (6.6 mL, 74.10 mmol) and triethyl amine (10.2 mL, 73.58 mmol) dropwise under water bath, and the mixture was stirred for 2 h. The resulting solution was washed with water (2×50 mL) and saturated aqueous NaHCO3 solution (12 mL). The CH2Cl2 layer dried over MgSO4 was evaporated to give title compound as light purple solid (13.01 g, 96.3%). 1H NMR (400 MHz, DMSO-d6) δ 1.06 (t, J=7.6 Hz, 3H), 2.30 (q, J=7.6 Hz, 2H), 7.31 (dd, J=9.2 and 8.8 Hz, 1H), 7.44 (ddd, J=8.8 and 4 and 2.8 Hz, 1H), 7.91 (dd, J=7.2 and 2.8 Hz, 1H), 10.04 (br s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 9.4, 29.4, 116.6, 116.8, 118.8, 119.0, 119.1, 120.2, 136.55, 136.58, 151.5, 153.9, 172.1;
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[NH2:10][C:11](=[O:26])[C@@H:12]([NH:18]C(OC(C)(C)C)=O)[CH2:13][CH2:14][C:15]([OH:17])=O.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.CN>C(#N)C>[NH2:18][C@@H:12]([CH2:13][CH2:14][C:15]([NH:4][CH3:1])=[O:17])[C:11]([NH2:10])=[O:26]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(N)=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CNC(=O)CC[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (2.0 ml) was added to a solution of (4S)-5-amino-4-[[(1,1-dimethylethoxy)carbonyl]amino]-5-oxo-pentanoic acid (0.49 g), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (1.20 g) and methylamine (0.16 g) in acetonitrile (20 ml). The reaction mixture was stirred at room temperature for 2 hours then concentrated. The residue was taken into 4M HCl in 1,4-dioxane (20 ml), stirred for 4 hours then concentrated. Purification (Preparative C18 125 Å bulk packing material, water:methanol, gradient elution 0:100 to 100:0) gave the sub-title compound (0.48 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([CH3:49])([O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][O:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:19][C:20]([CH3:49])([O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][OH:29])[CH3:21])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNCCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.4 %

Procedure:
2-(Ethoxymethyl)-1-[2-methyl-2-[2-(3-trityloxypropylamino)ethoxy]propyl]-imidazo[4,5-c]quinolin-4-amine (10 mg, 15.2 μmol) was combined with DCM (1 mL) to give a colorless solution. TFA (100 μl, 1.3 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel-NH2, 0% to 30% methanol in ethyl acetate) to give the title compound (2.3 mg, 36%) as colorless gum; LC-MS (UV peak area, ESI) 95.6%, 416.2661 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C1COCC1.[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)[CH3:17]
Reactant: CC1(CCl)COC(=O)N1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC1(C)COC(=O)N1
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (2.97 g, 19.9 mmol) in 2.0 M dimethylamine in THF (50 ml, 100 mmol) in a sealed tube was heated to 85° C. for 24 h, cooled to RT, and filtered through a coarse glass filter to remove precipitated dimethylammonium chloride. The filtrate was concentrated, and the residue purified by flash chromatography (3%→10% MeOH in CH2Cl2) to afford the oxazolidinone as a brown oil (1.02 g, 6.45 mmol, 32%), and the dihydrooxazole as a yellow oil (1.62 g, 10.2 mmol, 52%). Rf=0.5 in 10% MeOH in CH2Cl2. 1H NMR (CDCl3, 400 MHz) δ 1.35 (s, 3H), 2.33 (s, 6H), 2.37 (d, J=13.6 Hz, 1H), 2.43 (d, J=14.4 Hz, 1H), 4.02 (d, J=8.4 Hz, 1H), 4.18 (d, J=8.4 Hz, 1H), 5.2 (br s, 1H). ESI/APCI expected for C7H14N2O2: 158.11. Found: 159 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1.[I-].[K+].[CH3:33][NH2:34].O>C(O)C>[CH3:33][NH:34][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1
Reactant: CN
Reactant: O=C1CC(c2cccc(-c3nc(CCl)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CNCc1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[3-(4-chloromethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 78a) (125 mg) and potassium iodide (5 mg) in a 8M solution of methylamine in ethanol (1.5 mL) was stirred at 20° C. for 16 h. H2O (20 mL) was added and the precipitated collected by filtration and purified by chromatography on silica gel using MeOH as eluent. The product was stirred with 20% aqueous MeOH (10 mL) the pH of the mixture being set to 11 by addition of 1N NaOH solution, and the solid was isolated by filtration to give the title compound (54 mg) as yellow solid.
Reaction SMILES: O.[NH2:2]N.C[N:5](C)[CH:6]=[CH:7][C:8]([C:10]1[CH:33]=[CH:32][CH:31]=[CH:30][C:11]=1[O:12][CH2:13][CH:14]([OH:29])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=O.Cl>C(O)C>[NH:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:33]=[CH:32][CH:31]=[CH:30][C:11]=2[O:12][CH2:13][CH:14]([OH:29])[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[N:2]1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1ccccc1OCC(O)CN1CCN(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: OC(COc1ccccc1-c1cc[nH]n1)CN1CCN(c2ccc(Cl)cc2)CC1
Yield: 88 %

Procedure:
15 ml of hydrazine hydrate are added to 8.0 g (0.017 mole) of 1-[2-(3-Dimethylamino-1-oxo-propenyl)-phenoxy]-3-[4-(4-chlorophenyl)-piperazin-1-yl]-propan-2-ol.HCl (Example 4b) in 100 ml of ethanol, and the mixture is refluxed for 3 days. The solvent is distilled off and the residue is recrystallized from ethanol. 6.2 g (88%) of a product of melting point 120°-121° C. are isolated.