Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[S:2]1([C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[NH:5]1)(=[O:4])=[O:3].[C:14]1([N:20]2[C:24](=[S:25])[N:23]([CH2:26]Cl)[N:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:14]1([N:20]2[C:24](=[S:25])[N:23]([CH2:26][N:5]3[C:6](=[O:7])[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:2]3(=[O:3])=[O:4])[N:22]=[N:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: S=c1n(CCl)nnn1-c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1Cn1nnn(-c2ccccc2)c1=S
Temperature: 0 °C
Yield: 58 %

Procedure:
A solution of 4.53 g (0.022 mol) of the sodium salt of saccharin and 5 g (0.022 mol) of 1-phenyl-4-chloromethyl-tetrazolin-5-thione in 50 ml of DMF was heated at 130° for four hours, then cooled and poured into ice water. The solid which separated was collected, washed with water, dried and chromatographed on silica gel, eluting with MDC, to give 4.8 g (58%) of 2-(1-phenyl-5-thioxotetrazolin-4-ylmethyl) saccharin, mp 140°-142° C.
Reaction SMILES: C(OC(N1CC[CH:10]([N:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=4)[N:26]=3)[CH:20]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9]1)=O)(C)(C)C.CS([Cl:45])(=O)=O>>[Cl:45][C:36]1[CH:35]=[C:34]([CH2:33][CH2:32][NH:31][C:27]2[N:26]=[C:25]([C:21]3[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=3)[CH2:18][N:13]([CH2:10][CH3:9])[S:14]([CH3:17])(=[O:16])=[O:15])[CH:30]=[CH:29][N:28]=2)[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(NCCc4ccc(O)cc4)n3)c2)S(C)(=O)=O)C1
Reactant: CS(=O)(=O)Cl
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)S(C)(=O)=O

Procedure:
Compound 94 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 461. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (s, 1H) 7.5 (d, 2H) 7.3 (m, 1H) 7.2 (s, 1H) 7.1 (d, 1H) 7.0 (d, 1H) 6.9 (d, 1H) 4.4 (s, 2H) 3.5 (m, 2H) 3.2 (m, 2H) 3.0 (s, 3H) 2.8 (m, 2H) 1.0 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([C:13](=[O:38])[C:14]1[CH:19]=[C:18]([CH2:20][C:21]2[C:22](=[O:33])[C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[C:25](=[O:28])[C:26]=2[CH3:27])[CH:17]=[CH:16][C:15]=1[O:34]C(=O)C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][N:2]([C:13](=[O:38])[C:14]1[CH:19]=[C:18]([CH2:20][C:21]2[C:22](=[O:33])[C:23]([O:31][CH3:32])=[C:24]([O:29][CH3:30])[C:25](=[O:28])[C:26]=2[CH3:27])[CH:17]=[CH:16][C:15]=1[OH:34])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([F:11])([F:12])[F:10])=[CH:7][CH:8]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N(C)c3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)N(C)c3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Yield: 58.8 %

Procedure:
N-Methyl-N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline (0.138 g, 0.260 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:2) to obtain the titled compound (0.075 g, 0.153 mmol, 59%).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:17]([CH:18]=[N:19][C:20]=2[C:23]([OH:25])=[O:24])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[CH2:14]1)=[O:12])=O)(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH2:8][C@H:9]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:32]=1[F:39])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:17]([CH:18]=[N:19][C:20]=2[C:23]([OH:25])=[O:24])[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[CH2:14]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1Cc2ccccc2-n2cnc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CC(=O)N1Cc2ccccc2-n2cnc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of (R)-5-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)butyryl]-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid (35 mg, 0.06 mmol) in dry DCM (5 mL), was added trifluoroacetic acid (6.18 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After the completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were evaporated in vacuo to afford a gummy solid was crystallised from hexane to afford trifluoroacetic acid salt of 5-[(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid (28 mg, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:27]C1CC2C(=CC=C(O)C=2)OC1C1C=CC=CC=1>>[CH3:27][CH:15]1[CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:12]=2)[O:17][CH:16]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC1Cc2cc(O)ccc2OC1c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: CC1Cc2cc(Oc3ccc([N+](=O)[O-])cn3)ccc2OC1c1ccccc1

Procedure:
2-(3-Methyl-2-phenylchroman-6-yloxy)-5nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 600 mg of 3-methyl-2-phenylchroman-6-ol. The product was purified by column chromatography using heptane-2-propanol (20:1) as an eluant. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.8 Hz), 8.59 (dd, 1H, J 9.1, 2.8 Hz), 7.43-7.36 (m, 5H), 7.19 (d, 1H, J 9.1 Hz), 7.00 (d, 1H, J 2.6 Hz), 6.95 (dd, 1H, J 8.7, 2.6 Hz), 6.86 (d, 1H, J 8.7 Hz), 4.73 (d, 1H, J 9.3Hz), 2.85 (dd, 1H, J −16.7, 5.0 Hz), 2.64 (dd, 1H, J −16.5, 10.9 Hz), 2.18 (m, 1H), 0.77 (d, 3H, J 6.7 Hz).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1.[NH4+].[Cl-]>O1CCCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1COC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)COC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.6 mol/L in hexanes, 1.33 mL) was added to a solution of 1,4-dibromobenzene (0.50 g) in tetrahydrofuran (5 mL) cooled to −78° C. The solution was stirred at this temperature for 30 min prior to the dropwise addition of 3-oxetanone (0.15 g) dissolved in tetrahydrofuran (2 mL). The solution was warmed in the cooling bath to room temperature overnight. Aqueous NH4Cl solution was then added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent was evaporated. The residue was purified by HPLC on reversed phase (acetonitrile/water) to give the title compound. Yield: 0.19 g (39% of theory); Mass spectrum (ESI−): m/z=273/275 (Br) [M+HCOO]−.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:17][OH:18])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])C1C=CC=CC=1>CO.[C].[Pd]>[CH3:15][N:14]([CH3:16])[C:12](=[O:13])[C@H:11]([CH2:17][OH:18])[NH2:10]
Reactant: CN(C)C(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)[C@@H](N)CO
Yield: 101.4 %

Procedure:
A solution of (S)-benzyl[1-(dimethylamino)-3-hydroxy-1-oxopropan-2-yl]carbamate (3.20 g) and 10% palladium carbon (320 mg) in methanol (30 mL) was stirred at room temperature for 5 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.61 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:24][CH2:23][C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1cccnc1
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3cccnc3)c21
Yield: 45.9 %

Procedure:
The title compound (cis/trans=22/78) was prepared as a pale yellow powder in 45.9% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=20/80) and 3-pyridinemethanol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:5]=[C:4]([CH3:12])[N:3]=1.[BrH:13].BrBr>C(O)(=O)C>[Br:13][CH:9]([CH3:10])[C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:12])=[CH:5][CH:6]=1)=[O:11]
Reactant: Br
Reactant: CCC(=O)c1ccc(C)nc1C
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)C(C)Br)c(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution 1-(2,6-dimethl-pyridine-3-yl)-propan-1-one (0.3 g, 1.8 mmol) in 30% by weight solution of hydrogen bromide in acetic acid (3 ml) was added dropwise (0.29 g, 1.8 mmol) of Bromine. The reaction was allowed to warm to room temperature with stirring for 2h. The mixture was then concentrated in vacuo and the resulting crude material neutralized using saturated sodium carbonate solution. The mixture was extracted twice with dichloromethane and the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Yield: 400 mg (92%). 1H NMR (300 MHz, CDCl3), •1.88 (d, CH3, 3H), 2.64 (s, CH3, 3H), 2.76 (s, CH3, 3H), 5.12 (q, CH, 1H), 7.14 (d, Ar, 1 H,), 7.93 (d, Ar, 1 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]O)=O.[C:12]1(C=O)C2C=CC=CC=2C=1.[F-].[K+]>C(Cl)Cl>[OH:7][CH:5]1[C:4]2=[CH:9][CH:10]=[CH:11][CH:2]=[C:3]2[CH2:12]1
Reactant: O=CC1=Cc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: OC1Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Chloroperoxybenzoic acid (0.66 g) was added to a solution of benzocyclobutene aldehyde (0.2 g) in methylene chloride (10 mL) at 0° C. The mixture was stirred for 30 minutes at 0° C. and then warmed to room temperature. Stirring was continued for 12 hours at room temperature. Potassium floride (0.3 g) was added and stirring continued for an additional two hours. The reaction mixture was filtered, washed with sodium bisulfite solution and the solvent was removed by flash column chromatography. Liquid chromatographic analysis found a yield to hydroxy benzocyclobutene of approximately 55 percent and no benzocyclobutene carboxylic acid, with the balance comprising unidentified materials characterized as undesired product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: CO
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)c(F)c1
Temperature: 80 °C
Yield: 97 %

Procedure:
To 4-bromo-3-fluorobenzoic acid (2.00 g, 9.13 mmol) in methanol (12 ml) was added sulfuric acid (500 μl) and heated to 80° C. for 18 h then cooled to room temperature and concentrated. The residue was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and then concentrated to afford (2.07 g, 97%) of methyl 4-bromo-3-fluorobenzoate, which was used without further purification. 1H NMR (400 MHz, CD3OD): 7.80-7.73 (m, 3H), 3.91 (s, 3H). MS (EI) for C8H6BrFO2: 234 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]1([S:23](Cl)(=[O:25])=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:25])=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cccc3ccccc23)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 1-naphthylsulfonyl chloride according to METHOD A, giving a crude product that was purified by flash column chromatography on silica gel eluting with 2% methanol in DCM. This gave the pure title compound (3.93 g, 89%). MS (Ionspray, [M+H]+) m/z 376; Anal. Calcd. (found) for C17H16N2O4S2: C, 54.2 (54.02)%; H, 4.3 (3.9)%; N, 7.4 (7.1)%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CCN(C(C)C)C(C)C.Br[C:19]1[C:28]2[C:23](=C[CH:25]=[C:26](OC)[N:27]=2)[N:22]=[CH:21]C=1N>CN(C)C=O>[CH3:19][C@@H:28]1[CH2:23][N:22]([CH3:21])[CH2:25][CH2:26][N:27]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: COc1ccc2ncc(N)c(Br)c2n1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C)CCN1c1cc(N)ncn1
Temperature: 220 °C
Yield: 23.8 %

Procedure:
A mixture of 6-chloro-4-pyrimidinamine (200 mg, 1.544 mmol), Hunig's base (1.2 ml, 6.95 mmol) and (3R)-1,3-dimethylpiperazine (Ref.: WO2009061879 (A1)) (433 mg, 2.316 mmol) in N,N-dimethylformamide (DMF) (2 ml) was heated to 220° C. via a microwave reactor for 15 min. The reaction mixture was purified by RP-HPLC to yield 6-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (76 mg, 0.367 mmol, 24% yield). MS (ES+) m/z 208.0 (MH+).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[S:42][CH:43]=[CH:44][N:45]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:41]2[S:42][CH:43]=[CH:44][N:45]=2)=[O:40])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1nccs1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3nccs3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N-methylthiazole-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CCOC(C)=O.O>[N:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[NH:23][C:19]=1[N:15]1[CH2:16][CH2:17][N:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:13][CH2:14]1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc2c(N3CCN(c4nc5ccccc5[nH]4)CC3)ccnc2c1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (247 mg, 1.0 mmol) and 2-chlorobenzimidazole (46 mg, 0.3 mmol) are heated at 150° C. for 1 h. The mixture is dissolved in EtOAc-water. The organic layer is separated, dried (MgSO4), and concentrated. Column chromatography of the residue with hexane-EtOAc furnishes the title product as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-])=O)=[CH:8][C:7]=1[CH3:16]>[Pd].C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[CH:8][C:7]=1[CH3:16]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1Br
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(C)cc(N)cc2C)cc1Br
Reaction time: 3 h
Yield: 94 %

Procedure:
A mixture of the title product of Step A (5.0 g) and 10% palladium on carbon (0.6 g) in ethyl acetate (100 ml) was hydrogenated at 50 psi for 3 h. The reaction was filtered through Celite and concentrated to afford the title compound of Step B as a yellow solid (4.3 g). MS (APCI+) Calc: 321; Found 322 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[N:21]=[N:20][CH:19]=3)[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.[OH-].[Na+].O.Cl>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[N:21]=[N:20][CH:19]=3)[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2cnnn2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3cnnn3C)c2)nc1
Reaction time: 16 h
Yield: 117 %

Procedure:
To a solution of methyl 3-(5-methylpyridin-2-yl)-5-(1-methyl-1H-1,2,3-triazol-5-yl)benzoate (85 mg, 0.276 mmol) in THF (5 mL) was added 1 M aqueous sodium hydroxide (0.827 mL, 0.827 mmol) and water (4 mL). After 16 h, the reaction was acidified to pH 1 by 1 M HCl. The solution was concentrated and dried under vacuum to give the hydrochloride salt of title compound (95 mg). MS 295.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](=O)[NH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[S:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[C:6]2[C:7]([Cl:15])=[N:8][CH:9]=[C:10]([CH3:11])[C:5]=2[S:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c[nH]c(=O)c2c(Br)csc12
Product: Cc1cnc(Cl)c2c(Br)csc12
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of Example 277B (10.25 g, 42.1 mmol) in POCl3 (50 mL) was stirred at reflux for 2 hours, cooled to room temperature, diluted with ice water, and stirred vigorously resulting in a precipitate which was collected by filtration. The filter cake was further purified by silica gel chromatography on silica gel with dichloromethane to provide 7.14 g (64% yield) of the desired product. MS (ESI(+)) m/e 261.9, 263.9 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[CH:17]N(C)C)[CH:15]=O)=[CH:10][CH:9]=1>[Na]>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:17]=[C:3]([C:1]#[N:2])[C:4](=[O:5])[NH:6][CH:15]=2)=[CH:10][CH:9]=1
Reactant: N#CCC(N)=O
Reactant: CN(C)C=C(C=O)c1ccc(Cl)cc1
Agent: [Na]
Product: N#Cc1cc(-c2ccc(Cl)cc2)c[nH]c1=O

Procedure:
Sodium (7 grams in 300 ml methanol) was stirred while a methanolic solution of 2-cyanoacetamide (16 grams) and 2-(4-chlorophenyl)-3-(dimethylamino)acrolein (37 grams) was added. The mixture was refluxed for 1 hour and the resulting precipitate was filtered, washed with ethanol, dissolved in hot water, and then acidified. The resulting precipitate was filtered, washed with water, and identified as the desired product, m.p. 278°-280° C.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:7]([CH:8]3[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: Fc1ncccc1C1CCCOCC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1ccc(Oc2ncccc2C2CCCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 140 °C
Reaction time: 96 h

Procedure:
2-Fluoro-3-(oxepan-4-yl)pyridine (0.10 g, 0.51 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.37 g, 1.54 mmol), and cesium carbonate (0.50 g, 1.54 mmol) were mixed in NMP (1.5 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 140° C. for 96 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (EtOAc/hexanes) to give (1H-benzo[d]imidazol-2-yl)(4-(3-(oxepan-4-yl)pyridin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 414.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:20])[CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)NCCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g of 3,4-dihydro-2H-1,4-benzoxazine, 1.03 ml of triethylamine, 27 ml of tetrahydrofuran and then 1.5 g of para-nitrophenyl chloroformate are introduced into a 100 ml round-bottomed flask. The reaction mixture is stirred at ambient temperature for three hours and then filtered. The solvent is evaporated under reduced pressure and the residue is taken up in dichloromethane and washed with a 2N aqueous hydrochloric acid solution and then twice with water. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure to result in 2.1 g of 4-nitrophenyl 2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:14])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6]([NH:39][CH:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)=[O:8])=[C:4]([F:14])[CH:3]=1
Reactant: CCOc1cc(C(=O)O)c(F)cc1N
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1N
Yield: 87.3 %

Procedure:
4-amino-5-ethoxy-2-fluorobenzoic acid (Intermediate 171; 190 mg, 0.95 mmol), HATU (545 mg, 1.43 mmol) and 4-amino-1-methylpiperidine (Fluorochem; 164 mg, 1.43 mmol) were stirred in DMF (3 mL) and diisopropylethylamine (0.58 ml, 2.86 mmol) added. The mixture was stirred over night and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (3% ammonia in methanol/DCM) to yield the title compound as a white crystalline solid (245 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[NH2:27][CH:8]([C:6]1[C:5]([O:11][CH3:12])=[C:4]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[C:3]([CH3:20])=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1N1CCC(O)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1c(C(C)N)cc(Cl)c(C)c1N1CCC(O)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-3-(4-hydroxypiperidin-1-yl)-2-methoxy-4-methylphenyl]ethanone (15 mg, 0.050 mmol), ammonium acetate (39 mg, 0.50 mmol) and sodium cyanoborohydride (6 mg, 0.1 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (7 mg, 50%). LCMS calculated for C15H24ClN2O2 (M+H)+: m/z=299.1. found: 299.1.