Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1O.[NH:13]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[N:15]=[CH:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[CH3:21][O:20][C:18]([C:16]1[N:15]([CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][C:2]2([CH3:12])[CH3:1])[CH:14]=[N:13][CH:17]=1)=[O:19]
Reactant: CC1(C)Cc2ccccc2C1O
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2ccccc2CC1(C)C
Temperature: 0 °C

Procedure:
To a solution of 2,2-dimethyl-indan-1-ol (3.5 g, 21.6 mmol) in THF (160 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 4.1 g, 32.3 mmol), and triphenylphosphine (9.09 g, 34.5 mmol). The reaction is cooled to 0° C. and diisopropyl azodicarboxylate (6.67 mL, 34.5 mmol) is added. After one hour the reaction is diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:1) to provide 3-(2,2-dimethyl-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester. HRMS: (ESI) m/z 271.1440 [(M+H)+: Calcd for C16H19N2O2: 271.1447]; 1H NMR (400 MHz, CDCl3) δ ppm 2.60-3.08 (m, 2 H), 3.92 (s, 3 H), 6.25 (s, 1 H), 7.03 (s, 1 H), 7.15-7.46 (m, 4 H), 7.80 (d, J=1.0 Hz, 1 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(2,2-dimethyl-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:13](=[O:21])[CH:12](C(OCC)=O)[C:11]3=[O:27])=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:13](=[O:21])[CH2:12][C:11]3=[O:27])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C1C(=O)C(c2ccccc2)N(c2ccc3[nH]cnc3c2)C1=O
Agent: Cl
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccccc1

Procedure:
The compound was synthesized starting from ethyl 1-(1H-benzo[d]imidazol-5-yl)-2,4-dioxo-5-phenylpyrrolidine-3-carboxylate (which may be prepared in accordance with the procedure described for Intermediate 5; 0.1 g, 0.196 mmol) and 5 N aqueous hydrochloric acid (6 ml) according to the method described in Method 1, step 3.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.C([Li])(C)(C)C.CN(C)[CH:20]=[O:21].P(=O)(O)(O)O>CCOCC.CCCCCC>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([CH:20]=[O:21])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Combine hexane washed potassium hydride (1.3 g, 10.7 mmol) and ether (20 ml). Cool to about 0° C. and add a solution of 6-bromo-1H-indole (2.1 g, 10.7 mmol) in ether (5 ml). After 15 min, cool to about −78° C. and add a solution of t-butyllithium, 1.4 M solution in hexane (14.0 ml, 10.7 mmol). After 10 min, add dimethylformamide (1.7 ml, 20.0 mmol) in ether (5 ml). Slowly, warm to room temperature and then pour into a ice cold solution of 1M phosphoric acid and extract with EtOAc. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrated to give a residue. Chromatograph the residue eluting with 9:1 hexane:EtOAc to give the title compound.
Reaction SMILES: O.Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[O:13])=[CH:5][CH:4]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([O-:29])=[O:28].[F-].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:11]([S:22]([CH3:25])(=[O:24])=[O:23])([CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:33]2[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=2)=[CH:4][CH:5]=1)[C:12]([NH:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)=[O:13]
Reactant: CC(CCc1ccc(Br)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: CC(CCc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 90 °C
Yield: 182.2 %

Procedure:
Water (1.0 mL) was added to a solution of (+/−)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.35 g, 0.806 mmol), which may be prepared as in Preparation 2, Step 4, in 1,4-dioxane (5.0 mL). (4-nitrophenyl)boronic acid (209 mg, 1.01 mmol), cesium fluoride (0.49 mg, 3.22 mmol) and tetrakis(triphenylphosphine)palladium (0.094 g, 0.810 mmol) were added and the solution was heated to 90° C. After 4 hours the reaction was concentrated in vacuo and the resulting residue was triturated with ethyl acetate. The suspension was filtered through celite. The filtrate was washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification on Biotage flash 40S (hexanes/ethyl 6:4-1:1) afforded the title compound as a yellow solid (700 mg, 50%). LCMS m/z 475.2 (M−1).
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:31])[C:10]2[N:11]=[CH:12][N:13]([C:29]=2[N:30]=1)[C@@H:14]1[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:32][O:33][C:34]1[CH:55]=[CH:54][C:37]([C:38](Cl)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:36][CH:35]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:31])[C:10]2[N:11]=[CH:12][N:13]([C:29]=2[N:30]=1)[C@@H:14]1[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:23])[CH3:22])[C@@H:16]([O:17][C:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:37]2[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:55][CH:54]=2)[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(O[C@H]2C[C@H](n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)O[C@@H]2CO[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 40 °C
Yield: 698.5 %

Procedure:
N2-isobutyryl-5′-O-(tert-butyldimethylsilyl)-2′-deoxyguanosine (19.8 g) was dissolved in 100 ml of anhydrous pyridine. 4,4′-dimethoxytrityl chloride (1.66 g) was added to the resultant solution and 140 ml of anhydrous pyridine was further added, follow by stirring at 40° C. After the reaction completed, the reaction mixture was neutralized by sodium hydrogen carbonate and pyridine was distilled off. Extraction using chloroform was carried out and the extract was washed by a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. The extract was concentrated and purified by column chromatography (ethyl acetate/hexane) to obtain 25.8 g of the titled compound (yield: 78%).
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13].[N:16]#[C:17][NH2:18]>>[ClH:1].[CH2:6]([C:5]1[N:14]=[C:17]([NH2:18])[NH:16][CH:4]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13]
Reactant: C#CCCCCCCC(N)C(=O)OC
Reactant: N#CN
Agent: Cl
Product: C#CCCCCCCc1c[nH]c(N)n1
Yield: 53 %

Procedure:
2-Amino-dec-9-ynoic acid methyl ester hydrochloride (1.50 g, 6.42 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Oct-7-ynyl-1H-imidazol-2-ylamine hydrochloride (0.774 g, 53%) as a pale yellow solid (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (400 MHz, CD3OD) δ 6.09 (s, 1H), δ 2.19 (t, 2H), δ 1.95 (t, 1H), 1.93 (m, 2H), δ 1.39-1.11 (m, 8H) ppm; 13C NMR (75 MHz, CD3OD) δ 148.5, 131.0, 110.1, 83.9, 68.3, 28.6, 28.5, 28.4, 28.3, 25.7, 17.8 ppm; HRMS (ESI) calcd for C11H18N3 (M+) 192.1495. found 192.1495.
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:31])=[C:14]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][C:20]([OH:22])=O)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.[CH3:33][NH:34][O:35][CH3:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:31])=[C:14]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][C:20]([N:34]([CH3:33])[O:35][CH3:36])=[O:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O
Reactant: CNOC
Agent: Cl
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)OC)c1=O

Procedure:
This compound was prepared from [7-[(4-fluorophenyl)methyl]-4-hydroxy-3-({[2-(methyloxy)ethyl]amino}carbonyl)-2-oxo-1,5-naphthyridine-1(2H)-yl]acetic acid and N,O-dimethylhydroxylamine hydrochloride employing methods similar to those described in Example 558 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.17 (1H, br t, J=5 Hz), 8.53 (1H, s), 7.82 (1H, s), 7.32 (2H, t, J˜8 Hz), 7.12 (2H, t, J˜9 Hz), 5.19 (2H, s), 4.12 (2H, s), 3.83 (3H, s), 3.53-3.48 (4H, m), 3.26 (3H, s), 3.12 (3H, s); AP+ MS: 473 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:24])[CH2:14][NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:24])[CH2:14][NH:15][C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[CH2:9][CH2:8]2)=[CH:25][CH:26]=1
Reactant: COc1ccc(NCC(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1
Agent: BrB(Br)Br
Solvent: CCOCC
Product: O=C(CNc1ccc(O)cc1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-2-(4-methoxy-phenylamino)-ethanone (Example 219) and boron tribromide according to the method described in Example 192. Melting Point: 155-157° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:35])[CH:9]=2)=[N:6][CH:7]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:48].Cl>>[ClH:1].[ClH:48].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:27][NH:26][CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:35])[CH:9]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cn5)cc4=O)cc31)CNCC2
Yield: 54 %

Procedure:
tert-Butyl 7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (80 mg, 0.16 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (40 mg, 54%) as a white solid 1H NMR (500 MHz, CD3OD) δ 8.74 (d, J=2.4 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 8.02 (dd, J=8.7, 2.4 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.27 (dd, J=8.5, 1.8 Hz, 1H), 7.15 (dd, J=8.4, 1.8 Hz, 1H), 4.50 (s, 2H), 3.75 (s, 3H), 3.68 (t, J=6.5 Hz, 2H), 3.22 (t, J=6.5 Hz, 2H); ESI MS m/z 391 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.2 min.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]=O)=[N:20][CH:21]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(O)(=O)C>ClCCCl.CCOC(C)=O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:20][CH:21]=1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(Br)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Brc1ccc(CN2CCOCC2)nc1
Reaction time: 2 h
Yield: 38.7 %

Procedure:
Sodium triacetoxyborohydride (1.6 gm, 7.5 mmol) was added to a solution of 5-bromopicolinaldehyde (1.0 g, 5.4 mmol) and morpholine (0.54 g, 6.2 mmol) in 1,2-dichloroethane (10 mL) and this was left stirring for 2 hr. Acetic acid (0.35 mL, 6.2 mmol) was added and the reaction was left stirring over the weekend. It was diluted with EtOAc and washed with sat. aq. NaHCO3 followed by brine. This was concentrated, captured on a SCX column, washed with MeOH, and released with 2 N NH3 in MeOH to give 4-((5-bromopyridin-2-yl)methyl)morpholine (537 mg, 2.09 mmol, 39% yield) as a brown oil. MS (ESI) m/z 256.96 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.61 (1H, d, J=2.44 Hz), 7.77 (1H, dd, J=8.24, 2.44 Hz), 7.33 (1H, d, J=8.24 Hz), 3.67-3.77 (4H, m), 3.60 (2H, s), 2.42-2.57 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:15](=O)([O-])[O-].[K+].[K+].IC>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:15])=[O:6]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)c1ccc([N+](=O)[O-])cc1OC
Yield: 77.7 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine, 2-methoxy-4-nitrobenzoic acid (1 g, 5 mmol), potassium carbonate (1.4 g, 10 mmol) and iodomethane (0.47 mL, 7.5 mmol) gave methyl 2-methoxy-4-nitrobenzoate (820 mg, 77%) as a white solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:29]=4[F:38])[C:23]3=[O:39])[CH2:18][CH2:17]2)=[N:14][CH:15]=1>CC(O)=O>[Cl:1][C:12]1[C:13]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:30][C:29]=4[F:38])[C:23]3=[O:39])[CH2:18][CH2:17]2)=[N:14][CH:15]=[C:10]([Cl:9])[N:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)c(F)c1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(Cl)nc4Cl)CC3)C2=O)c(F)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
N-Chlorosuccinimide (0.016 g, 0.12 mmol) was added to a mixture of (S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (Example 4; 0.042 g, 0.090 mmol) in AcOH (0.3 mL). The mixture was stirred at 50° C. for 1.5 hour and then cooled to ambient temperature. The volatiles were removed by a stream of flowing nitrogen and the resulting residue was stirred in a mixture of saturated aqueous Na2SO3 (1.5 mL) and EtOAc (1.5 mL) for 15 minutes. The mixture was then partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (40 mL). The organic phase was washed successively with water (20 mL), water (20 mL) and brine (20 mL). The combined organic phases were dried over MgSO4, filtered and concentrated. The residue was purified on silica (eluting with 2:1 EtOAc/hexanes) to afford (S)-1-(1-(3,5-dichloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.024 g, 0.048 mmol, 53%) as a white solid. Mass spectrum (apci) m/z=502 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][N:6]1[CH:14]=[C:12]([CH3:13])[C:10](=[O:11])[NH:9][C:7]1=[O:8].Cl>[OH-].[Na+]>[N:6]1([CH2:5][CH2:4][C:3]([OH:15])=[O:2])[CH:14]=[C:12]([CH3:13])[C:10](=[O:11])[NH:9][C:7]1=[O:8]
Reactant: COC(=O)CCn1cc(C)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cn(CCC(=O)O)c(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
3-(1-Thyminyl)-propanoic acid methyl ester (1.0 g, 0.0047 mol) was suspended in 2 M sodium hydroxide (15 ml), boiled for 10 min. The pH was adjusted to 0.3 with conc. hydrochloric acid. The solution was extracted with ethyl acetate (10×25 ml). The organic phase was extracted with saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated to dryness, in vacuo, to give the title compound as a white solid (0.66 g, 71%). M.p. 118-121° C. Anal. for C8H10N2O4, found (calc.) C, 48.38; (48.49); H, 5.09; (5.09); N, 13.93; (14.14). The compound showed satisfactory 1H and 13C-NMR spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1>>[Cl:16][C:17]1[N:18]=[N:19][C:20]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:11]=[C:12]2[CH3:15])=[CH:21][CH:22]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccc(Cl)nn1

Procedure:
The title compound, MS: m/e=329.1 (M+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 3,6-dichloropyridazine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][O:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][C:19]=1[O:26][CH3:27]>C(O)C>[CH3:15][O:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:20][C:19]=1[O:26][CH3:27]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(CBr)cc1OC
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1ccc(CN2CCN(C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To 100 mL of ethanol were added 10.0 g of 1-methylpiperazine and 20.2 g of triethylamine. To the mixture cooled with ice, 25 mL of a solution of 24.6 g of 4-(bromomethyl)-2-methoxy-benzoic acid methyl ester in ethanol was added dropwise. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated. To the residue, 75 mL of water and 250 mL of methylene chloride were added, and the organic layer was separated. The obtained organic layer was dried over Na2SO4 and concentrated. The residue was purified by amino-silica gel column chromatography (heptane/AcOEt system) to give 22.4 g of the title compound (85% yield).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=12.[Cl:17][CH2:18][C:19](Cl)=[O:20]>O1CCOCC1>[Cl:17][CH2:18][C:19]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[NH:10][C:11](=[O:12])[C:5]2=[CH:4][S:3][C:2]([CH3:1])=[C:6]12)=[O:20]
Reactant: Cc1scc2c1Nc1ccccc1NC2=O
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Product: Cc1scc2c1N(C(=O)CCl)c1ccccc1NC2=O

Procedure:
8 g of 9,10-dihydro-3-methyl-4H-thieno[3,4-b][1,5]benzodiazepin-10-one and 5.6 ml of chloroacetyl chloride are boiled in 160 ml of dioxane (containing 8 g of ground potassium carbonate) under reflux for 8 hours. The thus-obtained suspension is concentrated to dryness; the resulting residue is taken up in toluene; the toluene mixture is washed with sodium bicarbonate solution and then with water, and the toluene solution is dried over sodium sulfate. Concentration of the dried toluene solution yields 4-chloroacetyl-9,10-dihydro-3-methyl-4H-thieno[3,4-b][1,5]benzodiazepin-10-one (m. 156° to 158° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([N+:32]([O-])=O)=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Sn](Cl)Cl>CCO>[NH2:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:10][CH2:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:35])[CH2:13][CH2:12]3)[C:18]=2[CH:31]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Yield: 62.1 %

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-nitrodibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (120 mg) in EtOH (15 ml) were added tin (II) chloride (190 mg), and the mixture was heated to reflux for 1 hour. The solvent was distilled off under reduced pressure. To the residue was added ethyl acetate and sodium aqueous to neutralize. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (95:5) to give the titled compound (70 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]([C:15]([O:17]C)=[O:16])[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>[OH-].[K+].Cl>[CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7]([C:15]([OH:17])=[O:16])[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1Sc2ccccc2-c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C1Sc2ccccc2-c2ccccc21
Yield: 77 %

Procedure:
6H-dibenzo[b,d]thiopyran-6-carboxylic acid, methyl ester (4.1 g; 0.016 mol) was dissolved in N/5 methanolic KOH (50 ml) and the solution was heated at reflux for 4 hours. The solution was cooled and poured in diluted HCl and extracted with chloroform. The extracts were dried over Na2SO4 and concentrated. The residue was solidified in n.pentane to give 6H-dibenzo[b,d]thiopyran-6-carboxylic acid; (3 g; yield 77%); m.p. 156°-159° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]2[CH:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=4)[N:23]=[CH:22][C:21]=3[O:32]CC3C=CC=CC=3)OC(=O)[O:16]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][CH:15]([OH:16])[CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[N:23]=[CH:22][C:21]=2[OH:32])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2ncc(OCc3ccccc3)c(C3OC(=O)OC3C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2ncc(O)c(CC(O)C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10% Palladium on activated carbon (976 mg, 0.91 mmol, 0.3 eq) is added at room temperature to a stirred solution of {trans-4-[5-(3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-yl)-2-oxo-[1,3]dioxolan-4-ylmethyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.70 g, 3.02 mmol, 1.0 eq) in methanol (200 mL), followed by several drops of triethylamine. The resulting mixture is stirred under hydrogen flow (1 bar) at room temperature for 1 hour. The catalyst is then removed by filtration and the solution is concentrated to afford {trans-4-[2-hydroxy-3-(3-hydroxy-6-methoxy-[1,5]naphthyridin-4-yl)-propyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (890 mg, 68% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:15][NH2:16]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([NH2:13])[NH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: NN
Reactant: COc1ccc(C(=O)CC#N)cc1F
Solvent: CCO
Product: COc1ccc(-c2cc(N)[nH]n2)cc1F

Procedure:
3-(3-Fluoro-4-methoxyphenyl)-3-oxopropanenitrile (2.13 g, 11 mmol) and hydrazine (0.38 mL, 12.13 mmol) were combined in absolute ethanol and the reaction mixture was heated to reflux overnight. Then, the solvent and excess hydrazine were evaporated to provide the title compound in quantitative yield.