Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[C:9]([C:19](=[O:21])[CH3:20])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:22])[C:6]=2[C:5]=1[C:23](=[O:25])[CH3:24])([O-])=O.[O:26]1[CH2:30]CCC1.[C-]#N.[Na+].[OH2:34]>>[C:30]([C:17]1[CH:4]=[C:5]([C:23](=[O:25])[CH3:24])[C:6]2[C:7](=[O:22])[C:8]3[C:13]([C:14](=[O:18])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][C:9]=3[C:19](=[O:21])[CH3:20])([OH:26])=[O:34]
Reactant: C1CCOC1
Reactant: CC(=O)c1cccc2c1C(=O)c1c(ccc([N+](=O)[O-])c1C(C)=O)C2=O
Reactant: O
Agent: [C-]#N
Agent: [Na+]
Product: CC(=O)c1cccc2c1C(=O)c1c(C(C)=O)cc(C(=O)O)cc1C2=O
Temperature: 50 °C
Yield: 44 %

Procedure:
Mono-nitro 1,8-diacetylanthraquinone (1 g; M.W. 397; 2.52 mmoles) was added to 10 ml of a mixture tetrahydrofuran: water=20:80 by volume. The mixture was heated to 50° C. under constant stirring followed by addition of NaCN (1.4 g; M.W. 49; 28.57 moles). The reaction mixture was maintained overnight at 50° C. under constant agitation. The resulting mixture was filtered and washed with water. The bright yellow-greenish crystals were dried at 50° C. 3-carboxy-1,8-diacetylanthraquinone was obtained in a 44% yield.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[C:13]([CH3:15])[C:12](I)=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:32]=[O:33].[ClH:35]>C1(C)C=CC=CC=1>[ClH:35].[CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[C:10]([CH3:17])=[CH:11][C:12]([CH:32]=[O:33])=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1I
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C=O
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a 1-liter 3-necked round-bottomed flask equipped with an overhead stirrer, temperature control and an addition funnel was added dibenzyl-(4-iodo-2,5-dimethylphenyl)amine (15 g, 35 mmol). Toluene (300 mL) was added and the resulting mixture was stirred for about 15 minutes. The reaction flask was purged with dry nitrogen and cooled to about −20° C. and 1.6 M n-butyllithium in hexanes (33 mL, 53 mmol) was added dropwise via the addition funnel. During the addition, the internal temperature of the reaction mixture was maintained below −10° C. When the addition was complete, the resulting mixture was stirred at about −15° C. for 15 minutes. N,N-Dimethylformamide (10 mL, 129 mmol) was then added dropwise while maintaining the internal reaction temperature below 0° C. The resulting mixture was then stirred at −20° C. to 0° C. for about 1 hour. Aqueous 1 M hydrochloric acid (200 mL) was then added over a 5 minute period and the resulting mixture was stirred for 15 minutes. The layers were then separated and the organic layer was washed with dilute brine (100 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to provide 4-dibenzylamino-2,5-dimethylbenzaldehyde hydrochloride (11.5 g, 90% yield, 95% purity) as thick oil that solidified upon standing. The product contained about 3 to 5% of the des-iodo by-product. 1H NMR (300 MHz, CDCl3) δ 2.42 (s, 3H), 2.50 (s, 3H), 4.25 (s, 4H), 6.82 (s, 1H), 7.10-7.30 (m, 10H), 7.62 (s, 1H), 10.15 (s, 1H); MS [M+H+] found 330.3.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH2:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[O:26][CH3:27])(=O)=O>>[CH3:27][O:26][C:19]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=1[CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: COc1ccc(OC)c(COS(C)(=O)=O)c1
Reactant: O=Cc1cccc2[nH]ccc12
Product: COc1ccc(OC)c(Cn2ccc3c(C=O)cccc32)c1

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 2,5-dimethoxybenzyl methanesulfonate instead of the benzyl bromide used in Example 1 to give 940 mg of 1-(2,5-dimethoxybenzyl)indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 64%.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[F:9][C:10]1[CH:27]=[CH:26][C:13]([CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[CH2:20][CH2:19]3)=[CH:12][CH:11]=1.Cl>>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[C:20](=[N:1][OH:2])[CH2:19]3)=[CH:26][CH:27]=1
Reactant: O=C1CCc2cc(OCc3ccc(F)cc3)ccc21
Reactant: CC(C)CCON=O
Agent: Cl
Product: O=C1C(=NO)Cc2cc(OCc3ccc(F)cc3)ccc21
Reaction time: 0.5 h

Procedure:
Isoamyl nitrite (4.05 mL, 29.2 mmol) was added to a suspension of 5-(4-fluoro-benzyloxy)-indan-1-one (15 g, 58.5 mmol) in methyl cellulose (210 mL) and HCl (conc) (15.6 mL, 187 mmol) at room temperature. After some minutes (−10) a solid appears and another portion of the isoamyl nitrite (4.05 mL, 29.2 mol) was added. The mixture was stirred for further 30 minutes, poured on ice water and the product was filtrated, washed well with water and diluted EtOH and dried at the pump (15.2 g, 91%). MS: m/e =284.1 (M−H).
Reaction SMILES: [ClH:1].Cl.NC1CCN([CH2:10][CH:11](C2(O)CCCCC2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[C:14]([Cl:30])[CH:13]=2)CC1.[Cl:38]C1C=[C:41]([CH:57](C2(O)CCCCC2)[C:58]([N:60]2[CH2:65][CH2:64][CH:63]([NH:66]C(=O)OC(C)(C)C)[CH2:62][CH2:61]2)=O)[CH:42]=[CH:43][C:44]=1[O:45]CC1C=CC2C(=CC=CC=2)C=1>>[ClH:30].[ClH:38].[NH2:66][CH:63]1[CH2:62][CH2:61][N:60]([CH:58]2[CH2:57][CH2:41][CH2:42][CH2:43][C:44]2([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[C:14]([Cl:1])[CH:13]=2)[OH:45])[CH2:65][CH2:64]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)C(c2ccc(OCc3ccc4ccccc4c3)c(Cl)c2)C2(O)CCCCC2)CC1
Reactant: NC1CCN(CC(c2ccc(OCc3ccc4ccccc4c3)c(Cl)c2)C2(O)CCCCC2)CC1
Agent: Cl
Product: NC1CCN(C2CCCCC2(O)CCc2ccc(OCc3ccc4ccccc4c3)c(Cl)c2)CC1

Procedure:
In an analogous manner to Example 1, step 2 1-{2-(4-aminopiperidin-1-yl)-1-[3-chloro-4-(2-naphthylmethoxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl {1-[[3-chloro-4-(2-naphthylmethoxy)phenyl](1-hydroxycyclohexyl)acetyl]piperidin-4-yl}carbamate. MS (ESI) m/z 493; HRMS: calcd for C30H37ClN2O2+H+, 493.26163; found (ESI, [M+H]+), 493.2599.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)(O)[O-].[K+].O>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.O1CCOCC1>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 90 %

Procedure:
4-Chloro-2-methoxy-1-nitro-benzene (1.12 g, 5.96 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.84 g, 5.95 mmol), tetrakis(triphenylphosphine)palladium(0) (380 mg, 0.33 mmol), a 2 M solution of potassium bicarbonate in water (7.45 mL, 14.9 mmol), and 1,4-dioxane (18 mL) were combined in a sealed tube, and the mixture was stirred and heated at 80° C. overnight. HPLC indicated the complete conversion of the starting material. The product, 4-(3-methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was isolated by flash chromatography (Silicagel, EtOAc/Hexanes 25-50%) in 90% yield.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[O:22][C:23]=3[CH3:24])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.ClCCl.CO>O>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:20][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2ccc(-c3nc(-c4ccc(C(F)(F)F)cc4)oc3C)cc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(O)cc2)cc1
Temperature: 0 °C
Reaction time: 10 h
Yield: 90.6 %

Procedure:
Boron tribromide (1.0 M, 3.91 mL, 3.91 mmol) was added dropwise into a cold (−78° C.) mixture of 4-(4′-methoxy-biphenyl-4-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (1.6 g, 3.91 mmol), and dichloromethane (20 mL). The reaction mixture was allowed to come gradually to room temperature and stirred for 10 hours. Then, the mixture was cooled to 0° C. and methyl alcohol (5 mL) was added dropwise. After stirring for 10 minutes the mixture was poured into water and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and crystallization from ethyl ether/hexanes gave an off-white solid (1.4 g, 90% yield): mp 189–191; MS m/e 396 (M+H)+;
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[CH3:44][NH:45][CH3:46]>>[CH3:44][N:45]([CH3:46])[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1ccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3ccccn3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (30 mg, 0.055 mmol) was dissolved in a solution of dimethylamine in tetrahydrofuran (2M, 545 μl, 1.091 mmol), and the reaction mixture stirred at room temperature overnight. The solvent was removed in vacuo to give a yellow oil, which was purified by chromatography on silica gel (gradient: 10-100% ethyl acetate in isohexane) to afford (R)-(6-((6-(dimethylamino)pyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (25 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.38 min, m+H=559.3; 1H NMR (400 MHz, CDCl3): δ 8.62 (1H, ddd, J=4.8, 1.8, 0.9 Hz), 8.43 (1H, d, J=2.5 Hz), 7.88 (1H, dt, J=8.0, 1.1 Hz), 7.81 (1H, td, J=7.7, 1.8 Hz), 7.60 (1H, dd, J=9.1, 2.5 Hz), 7.46-7.40 (3H, m), 7.28 (1H, s), 7.20-7.12 (2H, m), 6.47 (1H, d, J=2.2 Hz), 6.39 (1H, dd, J=9.1, 0.8 Hz), 5.47 (1H, dd, J=12.0, 2.2 Hz), 4.29 (1H, d, J=16.9 Hz), 3.84-3.79 (1H, m), 3.14 (6H, s), 2.92-2.75 (2H, m), 2.70 (1H, d, J=12.0 Hz), 2.51-2.44 (2H, m).
Reaction SMILES: [O:1]=[C:2]([N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[C:35]([O:37]CC1C=CC=CC=1)=[O:36])[CH:3]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:26]=[N:27][NH:28][N:29]=3)=[CH:18][C:13]=2[N:12]=[CH:11]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>CO>[O:1]=[C:2]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C:35]([OH:37])=[O:36])[CH:3]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:26]=[N:27][NH:28][N:29]=3)=[CH:18][C:13]=2[N:12]=[CH:11]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCC(C(=O)N1CCCC1C(=O)OCc1ccccc1)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Solvent: CO
Product: CCCCCCC(C(=O)N1CCC[C@H]1C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.5 %

Procedure:
Benzyl 1-[1-oxo-2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazole-1-yl]octyl]-2-pyrrolidinecarboxylate (0.388 mmoles, 230 mg) was dissolved in 5.0 ml methanol/3.0 ml 2N NaOH and stirred at room temperature for 16 hours. The ethanol was removed in vacuo. The aqueous layer washed with ether. The DH was adjusted to 3.5 using 2N HCl with cooling. The precipitate was filtered and dried to yield 75 mg of 1-[1-Oxo-2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazole-1-yl]octyl]-L-proline. (MS)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH2:12]([O:19][CH2:20][C@H:21]([C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH3:25])[CH2:22]O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C.CCCCCC>[CH2:12]([O:19][CH2:20][C@@H:21]([CH2:22][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:11])[C@H:24]([O:26][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:28])[CH3:29])[CH3:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)COCc1ccccc1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](COCc1ccccc1)Cn1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.3 %

Procedure:
To a cold (˜0° C., ice/water bath) mixture of 2-amino-6-chloropurine (2.2 g. 13.2 mmol), 4 (3.9 g, 12 mmol), triphenylphosphine (3.52 g, 13.4 mmol) in 50 ml of anhydrous THF was added with stirring 2.75 ml (13.9 mmol) of diisopropylazodicarboxylate. The reaction was stirred at room temperature for 5 hrs. The solvent was removed in vacuo and the residue chromatographed on silica eluting with a gradient of ethyl acetate (20-66%) in hexane. The product-containing fractions were pooled and concentrated to afford a semi-crystalline material, which was re-suspended in 20% ethyl acetate/hexane and filtered to remove insoluble hydrazine bis(isopropyl)carbamate. Concentration of the filtrate and drying in vacuo afforded 4.3 g (75%) of 24 as a white solid. 1H NMR, (DMSO-d6): δ 8.09 (s, 1H), 7.4-7.2 (m, 5H), 6.85 (s, 2H), 4.36 (s, 2H), 4.19 (m, 1H), 4.06 (m, 1H), 3.96 (m, 1H), 3.38 (m, 2H), 2.33 (m, 1H), 1.16 (d, J=6 Hz, 3H), 0.85 (s, 9H), 0.17 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C=O)C>[Cl:19][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([O:10][C:5]2[C:6]([Cl:9])=[CH:7][CH:8]=[C:3]([CH2:2][N:25]3[C:21](=[O:31])[C:22]4[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:24]3=[O:26])[C:4]=2[F:20])[CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN3C(=O)c4ccccc4C3=O)c2F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.7 %

Procedure:
3-{[3-(Bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.8 g, 4.8 mmol) was dissolved in DMF (50 mL) and potassium phthalimide (2.25 g, 12.0 mmol) was added. The reaction mixture was placed in an oil bath at 60° C. and stirred for 2-3 h. The reaction mixture was cooled to RT and the solvent was evaporated. Purification was accomplished by column chromatography (CH2Cl2/MeOH) to afford the title compound (1.9 g, 90%). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.70-7.98 (m, 6H), 7.39-7.49 (m, 2H), 7.35 (dd, 1H), 4.81 (s, 2H). MS: m/z 463.2 (M+23).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].Cl[CH:22]([F:24])[F:23]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:22]([F:24])[F:23])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: FC(F)Cl
Reactant: COCOc1c(Br)ccc(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1c(Br)ccc(OC(F)F)c1OC
Temperature: -45 °C
Yield: 30 %

Procedure:
To a stirring solution of 4-bromo-2-methoxy-3-(methoxymethoxy)phenol (700 mg, 2.66 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (734 mg, 5.32 mmol) cooled to −45° C. and chlorodifluoromethane (gas) was passed for 10 min and the resultant reaction mixture was heated to 80° C. for 2 h. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were dried over anhy. sodium sulphate and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-5% ethyl acetate in pet ether) afforded 1-Bromo-4-(difluoromethoxy)-3-methoxy-2-(methoxymethoxy)benzene as a liquid (250 mg, 30%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9]/[C:10](/[C:13]([CH3:15])=O)=[N:11]\[OH:12].Cl.[OH-].[Na+]>C(O)(=O)C>[CH3:9][C:10]1[N+:11]([O-:12])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][C:13]=1[CH3:15]
Reactant: CC(=O)/C(C)=N/O
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2)[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
500 g of benzaldehyde and 476 g of diacetylmonoxime were suspended in 1 L of acetic acid and cooled in an ice bath. At internal temperature of 7° C., hydrochloride gas is slowly blown in to be saturated. At room temperature, the mixture was stirred overnight. The reaction mixture was poured into 1.5 kg of ice, and neutralized with 25% sodium hydroxide solution. The crystalline precipitate was isolated by filtration and washed with 1 L of water and 1 L of diisopropylether. The obtained crystals were dissolved in 3 L of chloroform and insoluble matter was filtered off. The filtrate was dried with 200 g of anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. 3 L of IPE was added to the residue to be crystallized, the crystal was isolated by filtration, dried under reduced pressure at 50° C. for 1 hour, and 440 g of the subject compound was prepared.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][OH:30])[CH2:25][CH2:24]1>>[OH:30][CH2:29][CH:26]1[CH2:27][CH2:28][N:23]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:24][CH2:25]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: OCC1CCNCC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC(CO)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with piperidin-4-ylmethanol (1.2 equiv) to give 183 (15.9 mg, M+1 411.1)
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH:16]([O:30][CH2:31][CH3:32])[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)=[CH:5][CH:4]=1.[CH2:34]([O:36][C:37](Cl)=[O:38])[CH3:35].C(N(CC)CC)C>CN(C=O)C>[CH2:34]([O:36][C:37](=[O:38])[N:29]=[C:27]([NH2:28])[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:17](=[O:18])[CH:16]([C:12]2[C:13]([F:15])=[CH:14][C:9]([C:6]3[CH:7]=[N:8][C:3]([NH2:2])=[CH:4][CH:5]=3)=[CH:10][C:11]=2[F:33])[O:30][CH2:31][CH3:32])=[CH:22][CH:23]=1)[CH3:35]
Reactant: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)c1c(F)cc(-c2ccc(N)nc2)cc1F
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N=C(N)c1ccc(CNC(=O)C(OCC)c2c(F)cc(-c3ccc(N)nc3)cc2F)cc1

Procedure:
Analogous to example 15.4, (RS)-(2-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-N-(4-carbamimidoyl-benzyl)-2-ethoxy-acetamide hydrochloride (example 271) was reacted with ethylchloroformate and triethylamine in DMF to give (RS)-[amino-[4-({2-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-2-ethoxy-acetylamino]-methyl)-phenyl]-methylene}-carbamic acid ethyl ester. Off-white solid. MS 512.1 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Br:1][C:2]1[S:6][C:5]([CH2:7][N:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: C1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Brc1ccc(CN2CCCCCC2)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
5-Bromo-2-thiophenecarbaldehyde (191 mg, 1 mmol) was diluted in a mixture of dichloromethane (6 mL) and N,N-dimethylformamide (2 mL), and cooled to 0° C. Hexahydro-1H-azepine (0.17 mL, 1.5 mmol, 1.5 eq) was added, followed by sodium triacetoxyborohydride (1.04 g, 4.9 mmol, 4.9 eq) and glacial acetic acid (2 drops). The mixture was stirred at 23° C. for 3 h. The reaction mixture was carefully quenched with saturated aqueous sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by isco combiflash, 40 g column, using a 0-70% ethyl acetate in hexanes gradient. The product fractions were concentrated to give the title compound as clear colorless oil (200 mg, 73%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:15])([F:14])[F:13])[C:9]([C:16]([O:18]CC)=[O:17])=[CH:8][C:7]=2[CH:21]=1)#[N:2].[OH-].[Na+]>C1COCC1.C(O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([F:15])([F:13])[F:14])[C:9]([C:16]([OH:18])=[O:17])=[CH:8][C:7]=2[CH:21]=1)#[N:2]
Reactant: CCOC(=O)C1=Cc2cc(C#N)ccc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the ester (Step 2) (0.077 g, 0.259 mmol) in THF-EtOH-H2O (7:2:1, 2 mL) in a 5 mL pear-shaped flask was added aqueous NaOH (0.13 mL, 2.5 N solution) in one portion. After stirring for 6 hours at room temperature the solution was partially concentrated in vacuo to remove most of the THF and EtOH. The resulting solution was diluted with H2O and washed with diethyl ether. The resulting aqueous phase was sparged with nitrogen to remove trace diethyl ether and was acidified with concentrated HCl yielding a sticky suspension. The suspension was extracted with diethyl ether and the ether was dried over MgSO4, filtered and concentrated in vacuo yielding a pale yellow oil. This oil was crystallized from methylene chloride-hexanes yielding the title compound (0.041 g, 59%) as a tan powder: mp 185.1–186.1° C. 1H NMR (acetone-d6/300 MHz) 7.99–7.94 (m, 2H), 7.83 (dd, 1H, J=8.5, 2.0 Hz), 7.25 (d, 1H, J=8.5 Hz), 5.99 (q, 1H, J=7.0 Hz). FABLRMS m/z 270 (M+H). EIHRMS m/z 269.0316 (M+, Calc'd 269.0300).