Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH2:10]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>C(OCC)C>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH2:10][CH2:11][C:12]1[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:13]=1
Reactant: C#CCCOC1CCCCO1
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CCOC2CCCCO2)on1

Procedure:
Ethyl chlorooximidoacetate (1 g, 6.60 mmol) and 2-(but-3-ynyloxy)tetrahydro-2H-pyran (3.05 g, 19.80 mmol) were dissolved in diethyl ether (20 ml). Triethylamine (0.668 g, 6.60 mmol) was diluted with diethyl ether (10 ml) and added dropwise into previous mixture. After addition the reaction mixture was extracted with water and the organic layer was dried with Na2SO4, filtered and evaporated. LC-MS: [M+1]=172.17.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][NH2:25])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][NH:25][CH2:6][C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1cc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNCc1cc2ccccc2s1
Yield: 47.2 %

Procedure:
Experimental conditions were analogous to Example 1, from 0.28 g (1.78 mmol) of benzo[b]thiophene-2-carbaldehyde, 0.35 g (1.78 mmol) of (S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, 10 mL dichloromethane, and 565 mg (2.64 mmol) of sodium triacetoxyborohydride. The reaction was quenched with aqueous sodium bicarbonate. The residue from the organic layer was purified using flash chromatography (ethyl acetate in hexane). The reaction gave 291 mg of the free base as a colorless oil. LC-MSD, m/z for C19H26N2O2S [M+H]+: 347.5
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C@@H:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[C@H:10]1[OH:23])#[N:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.C(OCC)(=O)C>[C:24]([O:23][C@H:10]1[C@H:9]([N:5]2[CH2:6][CH2:7][NH:8][C:4]2=[N:3][C:1]#[N:2])[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]1([CH3:21])[CH3:22])(=[O:26])[CH3:25]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCNC2=NC#N)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1[C@H](N2CCNC2=NC#N)c2cc(C#N)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of trans-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.62 g) and acetic anhydride (0.47 ml) in dry pyridine (3.1 ml) was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate (30 ml) and washed with 5% hydrochloric acid (20 ml×2), brine (20 ml), saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml), successively. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and methanol (50:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from a mixture of dichloromethane and n-hexane to give trans-3-acetoxy-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.44 g).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][CH2:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#[N:21])=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:26].[Na+].Cl>O1CCOCC1>[O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][CH2:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]([NH2:21])=[O:26])=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: [OH-]
Reactant: N#Cc1ccccc1CNc1ccc2c(=O)[nH]c3ncccc3c2c1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)c1ccccc1CNc1ccc2c(=O)[nH]c3ncccc3c2c1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
462 (51 mg, 0.16 mmol) and NaOH (1M, aqueous, 2 mL) were suspended in dioxane (2 mL), and stirred for 30 minutes at 150° C. The reaction mixture was acidified with HCl (2M in diethyl ether, 1.6 mL), concentrated, and purified via prep-LC-MS to provide 481 (4 mg, 7% yield) as a white powder. LC-MS (M+H=345, obsd.=345). 1H NMR (400 MHz, DMSO-D6) δ 8.56 (d, J=7.9, 1H), 8.43 (d, J=3.1, 1H), 8.05 (d, J=8.6, 1H), 7.94 (d, J=6.7, 1H), 7.45 (s, 1H), 7.25 (m, 3H), 6.92 (d, J=8.6, 1H), 6.66 (s, 1H), 5.98 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[O:17][C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][C:20]=1[C:21]#[N:22].[OH-].[Na+]>CN(C=O)C>[C:23]1([C:18]2[O:17][C:16]([NH:15][C:2]3[C:7]4[C:8]5[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=5[Se:10][C:6]=4[N:5]=[CH:4][N:3]=3)=[C:20]([C:21]#[N:22])[CH:19]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#Cc1cc(-c2ccccc2)oc1N
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccccc2)oc1Nc1ncnc2[se]c3c(c12)CCCC3
Yield: 78 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (250 mg, 0.917 mmol, from step b of example 1) in DMF (10 mL) was added sequentially 2-amino-5-phenylfuran-3-carbonitrile (160 mg, 0.917 mmol; Matsuda, T.; Yamagata, K.; Tomioka, Y.; Yamazaki, M. Chem. Pharm. Bull., 1985, 33, 937-943) and powdered NaOH (110 mg, 2.751 mmol) at rt. Work-up as described in example 2, gave the product as a yellow color solid (300 mg, 78%), mp 252-256° C. (decomp). 1H NMR (400 MHz, CDCl3): δ 9.82 (1H, s, H-2), 7.78-7.81 (2H, m, Ph), 7.41-7.45 (2H, m, Ph), 7.31-7.35 (1H, m, Ph), 7.16 (1H, br s, exchangeable with D2O, —NH), 7.01 (1H, s, H-4′), 3.35 (2H, br s, H-8), 2.98 (2H, br s, H-5), 1.93-1.95 (4H, m, H-6,7); 13C NMR (100 MHz, CDCl3): δ 162.3, 158.6, 153.7, 151.9, 145.3, 143.3, 137.0, 133.9, 129.5, 128.9, 128.4, 126.1, 124.3, 102.7, 100.1, 29.1, 28.4, 23.1, 22.5; LC-MS (positive ion mode): m/z 419, 421 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22](Cl)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)c(F)c4)nc23)CC1
Yield: 85.9 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.055 mMol) 3,4-difluorobenzoyl chloride, 0.014 gm (80%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.CC1C=CC(S([N:46]=[N+:47]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=[N+:46]=[N-:47])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[C:30]#[N:31])=[CH:32][CH:33]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C(=[N+]=[N-])c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Reaction time: 4 h
Yield: 114 %

Procedure:
tert-Butyl 2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-cyanophenyl)acetate (0.400 g) and 4-methylbenzenesulfonyl azide (0.193 g) were dissolved in 5 ml of acetonitrile and treated with DBU (0.152 ml). The reaction was stirred for 4 hours, then concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried, filtered, concentrated onto silica gel and purified by silica gel chromatography to provide tert-butyl 2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-cyanophenyl)-2-diazoacetate (0.48 g) as a bright yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]2[O:49][CH2:48][CH:47]([CH2:50][NH2:51])[O:46][C:45]=2[CH:52]=1>CN(C=O)C>[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]2[O:49][CH2:48][CH:47]([CH2:50][NH:51][CH2:15][CH2:14][CH2:13][CH2:12][C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:8][CH:7]=3)[O:46][C:45]=2[CH:52]=1
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Reactant: COc1ccc2c(c1)OC(CN)CO2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccc(OC)cc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
5-Methoxyindole-3-butyric acid (1.0 g, 4.3 mmole), 1-hydroxybenzotriazole hydrate (0.7 g, 5.2 mmole) and 1,3-diisopropylcarbodiimide (1.6 ml, 10.3 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.0 g, 4.3 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as eluant. Evaporation of product-containing fractions gave 1.3 g (74%) of the desired product, (7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-methoxy-1H-indol-3-as an off-white solid.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[C:43]([S:45]([CH2:48][CH:49]([CH3:51])[CH3:50])(=[O:47])=[O:46])[CH:42]=[CH:41][C:40]=1[F:52]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:41]1[CH:42]=[C:43]([S:45]([CH2:48][CH:49]([CH3:50])[CH3:51])(=[O:46])=[O:47])[CH:44]=[CH:39][C:40]=1[F:52])([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CC(C)CS(=O)(=O)c1ccc(F)c(Br)c1
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)CS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1
Yield: 99 %

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-Bromo-1-fluoro-4-(2-methyl-propane-1-sulfonyl)-benzene (Intermediate 131), the title compound was obtained as a colorless oil in 99% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12](OC)OC)[C:5]([NH2:7])=[O:6].[C:17]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([O:39][CH3:40])=[C:27]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]3)[CH:28]=2)[CH2:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O>[C:17]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([O:39][CH3:40])=[C:27]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([N:1]4[C:2]5[C:10](=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=5)[CH:11]=[CH:12]4)[CH2:34][CH2:33]3)[CH:28]=2)[CH2:23][CH2:22][CH2:21]1)(=[O:19])[CH3:18]
Reactant: COC(Cc1ccc(C(N)=O)cc1N)OC
Reactant: COc1cc2c(cc1CCN1CCC(=O)CC1)N(C(C)=O)CCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)N(C(C)=O)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
172 mg of 3-amino-4-(2,2-dimethoxyethyl)benzamide and 127 mg of 1-(2-(1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidin-4-one were dissolved in 5 ml of acetic acid. Thereafter, 0.65 g of sodium sulfate was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 0.16 g of sodium triacetoxyborohydride was added to the reaction solution, and the obtained mixture was then stirred for 1 hour. Thereafter, 5 ml of water was added thereto, and the obtained mixture was then stirred at 100° C. for 2 hours. The reaction solution was cooled to a room temperature, and it was then concentrated under a reduced pressure. A saturated sodium bicarbonate aqueous solution was added to the residue, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) and NH silica gel column chromatography (ethyl acetate-methanol), so as to obtain 146 mg of the subject compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3(O)[C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[C:5]([CH3:23])[O:4][N:3]=1.N1C=CC=CC=1.O=S(Cl)[Cl:32]>C(Cl)Cl>[Cl:32][C:10]1([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:23])[CH:8]=2)[NH:12][C:11]1=[O:16]
Reactant: O=S(Cl)Cl
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccsc1)C(=O)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccsc1)C(=O)N2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-hydroxy-3-(thiophen-3-yl)indolin-2-one (500 mg, 1.53 mmol) in CH2Cl2 (75.0 mL) was added pyridine (1.21 g, 15.3 mmol) followed by SOCl2 (728 mg, 6.12 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and the mixture was evaporated in vacuum to give crude product, which was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:9][CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.C(N(CC)CC)C.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]([C:35]([CH:32]3[CH2:34][CH2:33]3)=[O:36])[CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc2c(cc1Br)CC(C)NN=C2c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1Br)CC(C)N(C(=O)C1CC1)N=C2c1ccc([N+](=O)[O-])cc1
Yield: 92.5 %

Procedure:
0.69 g (1.77 mmol) of 7-bromo-8-methoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (Example 4, Step A) is acylated in methylene chloride (15 ml) in the presence of 0.29 ml (2.1 mmol) of triethylamine with 0.19 ml (2.1 mmol) of cyclopropanoic acid chloride at room temperature for 1.5 hours. After concentration by evaporation and suspension with water, 0.78 g of a crude product, which is purified by suspension in hot ethanol, is obtained. 0.75 g (93%) of 7-bromo-3-cyclopropylcarbonyl-8-methoxy-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine with a melting point of 194-196° C. is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1.C(OC(=O)C)(=O)C.[CH2:25]([OH:27])[CH3:26]>O>[C:25]([C:15]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[C:3]([CH2:2][NH2:1])[C:16]=31)[C:9]1[C:8]2=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:27])[CH3:26]
Reactant: CCO
Reactant: NCC12CC(c3ccccc31)c1ccccc12
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C12CC(c3ccccc31)c1cccc(CN)c12

Procedure:
A solution of 9-aminomethyl-9,10-dihydro-9,10-methanoanthracene (235 mg) and acetic anhydride (217 mg) in ethanol (5.0 ml) was refluxed for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-acetyl-aminomethyl-9,10-dihydro-9,10-methanoanthracene. M.P. 184°-185.5° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH3:28])=[N:22][CH:21]=4)[C:17]([F:29])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3]1.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[F:29][C:17]1[C:18]([C:20]2[N:24]([CH:25]([CH3:26])[CH3:27])[C:23]([CH3:28])=[N:22][CH:21]=2)=[N:19][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:31](=[O:32])[CH2:30][OH:33])[CH2:3]3)=[CH:12][CH:11]=2)=[N:15][CH:16]=1
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](N)C4)cc3)ncc2F)n1C(C)C
Reactant: O=C(O)CO
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](NC(=O)CO)C4)cc3)ncc2F)n1C(C)C

Procedure:
The title compound was prepared (38 mg, 15%), using a procedure analogous to Example 154, starting from N-{4-[(3S)-3-aminopyrrolidin-1-yl]phenyl}-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 153; 220 mg, 0.556 mmol) and glycolic acid (51 mg, 0.667 mmol). NMR: 1.39 (d, 6H), 1.91-2.04 (m, 1H), 2.13-2.25 (m, 1H), 2.44 (s, 3H), 3.04-3.12 (m, 1H), 3.18-3.47 (m, 3H), 3.80 (d, 2H), 4.38-4.47 (m, 1H), 5.32 (t, 1H), 5.40-5.52 (m, 1H), 6.50 (d, 2H), 7.30 (s, 1H), 7.35 (d, 2H), 7.82 (d, 1H), 8.40 (d, 1H), 9.04 (s, 1H); m/z 454.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[C:8]1[N:17]=[C:16]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[OH-].[Na+]>O1CCCC1>[N:1]1([C:8]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CCN(CC)CCNc1nc(Cl)nc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC)CCNc1nc(N2CCCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
A solution of 6.4 g of pyrrolidine in 50 ml of tetrahydrofuran was added to 10 g of 2-chloro-4-(2-diethylaminoethylamino)quinazoline hydrochloride in 100 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for about one hour and then was heated for 5 hours. The reaction mixture was poured into ice-water, made alkaline by the addition of dilute aqueous sodium hydroxide solution, and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue, a gummy solid, was triturated with about 5 ml of hexane, and the resulting mixture was chilled overnight in a refrigerator. The mixture then was filtered and the solid obtained was recrystallized from aqueous ethanol to give 2 g of 2-pyrrolidinyl-4-(2-diethylaminoethylamino)quinazoline; m.p. 87°-90°. The following analytical data were obtained:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[C:15](=[O:17])=[O:16]>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:15]([OH:17])=[O:16]
Reactant: O=C=O
Reactant: Fc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 10.0 grams (0.076 mole) of 1,3,5-trifluorobenzene in 150 ml of anhydrous tetrahydrofuran, under an argon atmosphere, was cooled to -78° and 4.8 grams (0.076 mole) of n-butyllithium (as 48.7 ml of a 1.55 molar solution in hexane) was added dropwise during a 30-minute period. Upon completion of addition the reaction mixture was stirred at -78° for eight hours. A quantity of fresh, crushed dry ice, sufficient to cause the reaction mixture to become a thick slurry, was added to the reaction vessel. The reaction mixture was allowed to warm to ambient temperature as it was stirred for 26 hours. The tetrahydrofuran was removed from the reaction mixture under reduced pressure. The residue was washed into a separatory funnel with 100 ml of aqueous 2N sodium hydroxide and 200 ml of diethyl ether. The aqueous base layer was separated and the organic layer extracted with two 100 ml portions of aqueous 2N sodium hydroxide. The organic layer was discarded and the combined aqueous base layer and extracts were washed with 100 ml of diethyl ether, cooled, and acidified with concentrated hydrochloric acid. The mixture was saturated with sodium chloride and extracted with three portions of 150 ml each of diethyl ether. The combined ether extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue. The residue was recrystallized from toluene to give 10.2 grams of 2,4,6-trifluorobenzoic acid; mp 225°-227°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([OH:11])[CH:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(O)c1
Reactant: OCCc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c(OCCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.5 g (2.94 mmol) of 4-Fluoro-3-hydroxy-benzoic acid methyl ester was dissolved in 30 ml of anhydrous tetrahydrofuran. To this solution was added 0.506 g (3.23 mmol) of 2-(4-chloro-phenyl)-ethanol, 2.93 g (equivalent to 8.8 mmol PPh3) of triphenylphosphine derivatized polystyrene and 1.53 g (8.8 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with tetrahydrofuran. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate/n-heptane (1/5) and the insoluble residue was removed by filtration. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/5).