Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.B([C:11]1[CH:16]=[CH:15][C:14]([N:17]([C:34](=[O:43])/[CH:35]=[CH:36]/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:18][C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]2)=[O:20])=[CH:13][CH:12]=1)(O)O.[C:44]1([OH:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>ClCCl>[O:50]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([C:34](=[O:43])/[CH:35]=[CH:36]/[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:18][C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]2)=[O:20])=[CH:13][CH:12]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(B(O)O)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
Triethylamine (0.13 mL, 0.91 mmol) was added to [(S)-1-(2-{(4-borono-phenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamic acid, tert-butyl ester 5 (90 mg, 0.18 mmol), copper[II]acetate, 4 Å sieve (powdered) and phenol (26 mg, 0.27 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with dichloromethane and washed with 10% hydrochloric acid, 1M NaOH (×2) and brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/petrol (2:1), to give the title compound as a white powder (60 mg) which was used directly in the next stage.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH:38]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25]>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: COC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 29.0 g of methoxymethyl-triphenylphosphonium-chloride in 200 ml of t-butyl methyl ether was treated with 9.7 g of potassium t-butylate at -10° C. within 3 minutes while gassing with argon in a sulphonation flask provided with a mechanical stirrer. The orange suspension was stirred at about 0° C. for 1 hour, then treated dropwise at -10° C. within 10 minutes with a solution of 12.0 g of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde in 90 ml of t-butyl methyl ether and stirred at 0° C. for a further 45 minutes. The mixture was subsequently partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and evaporated. In order to separate triphenylphosphine oxide, the residue was dissolved in ethyl acetate and the solution was diluted with petroleum ether, filtered and evaporated. Chromatographic separation of the yellowish, crystalline residue (16.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 10.1 g (74%) of p-[trans-4-(2-methoxyvinyl)cyclohexyl]benzonitrile as white crystals.
Reaction SMILES: [N:1]([CH:4]([C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH2:15][CH3:16])[O:14][CH2:13][CH2:12][O:11]1)=[N+]=[N-].[N-]=[N+]=[N-]>>[CH2:15]([C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([NH2:1])[C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:18]=2)[O:11][CH2:12][CH2:13][O:14]1)[CH3:16]
Reactant: CCC1(CCCCCC(N=[N+]=[N-])c2cnc(-c3ccccc3)s2)OCCO1
Agent: [N-]=[N+]=[N-]
Product: CCC1(CCCCCC(N)c2cnc(-c3ccccc3)s2)OCCO1

Procedure:
5-[1-azido-6-(2-ethyl-1,3-dioxolan-2-yl)hexyl]-2-phenyl-1,3-thiazole from alcohol (N2) was prepared according to the procedure used in Example 89 Step 2. 1H NMR (300 MHz, CDCl3) δ: 8.00-7.90 (2H, d, J=7.5 Hz), 7.57 (1H, s), 7.45-7.35 (3H, m), 5.10 (1H, t, J=7.3 Hz), 3.95 (4H, s), 1.89-1.78 (2H, m), 1.65-1.55 (4H, m), 1.45-1.25 (6H, m), 0.90-0.80 (3H, m). MS (ES) C20H26N4O2S requires: 386, found: 387 (M+H)+. The azide was then reduced according to the Example 89 Step 3 to afford the desired amine (N3). 1H NMR (300 MHz, CDCl3) δ: 7.95 (2H, d, J=7.5 Hz), 7.57 (1H, s), 7.45-7.35 (3H, m), 4.95 (1H, t, J=7.3 Hz), 3.95 (4H, s), 1.89-1.78 (2H, m), 1.65-1.55 (4H, m), 1.45-1.25 (6H, m), 0.90-0.80 (3H, m). MS (ES) C20H28N2O2S requires: 360, found: 361 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11]1.[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH2:37][CH3:38])[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH2:37][CH3:38])[C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:11]1)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)C(=O)OCCN1CCC[C@@H](Nc2cc(F)ccc2N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
To an ice-cooled mixture of 2,2-dimethylpropionic acid 2-[(R)-3-(2-amino-5-fluorophenylamino)piperidin-1-yl]ethyl ester (500 mg, 1.48 mmol), (S)-2-tert-butoxycarbonylaminobutyric acid (331 mg, 1.63 mmol) and HOAt (202 mg, 1.48 mmol) in DCM (30 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (341 mg, 1.78 mmol). The reaction mixture was stirred in the ice bath for 1 h, then diluted with DCM, washed with 2M Na2CO3, then water. The organic fraction was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 50-80% EtOAc in cyclohexane) affording the title compound as a pink gum (0.734 g, 95%). LCMS (Method B): RT 2.56 min [M+H]+ 523.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])C)[CH:7]=1.[H-].[Na+].[CH3:15][O:16][C:17]([C:19]1OC(Cl)=[N:21][CH:20]=1)=[O:18]>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[O:11][C:9]([NH:8][C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=2[CH3:12])=[N:21][CH:20]=1)=[O:18]
Reactant: CC(=O)Nc1cc(N)ccc1C
Reactant: COC(=O)c1cnc(Cl)o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(Nc2cc(N)ccc2C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A solution of N-(5-Amino-2-methyl-phenyl)-acetamide (0.51 g, 3.1 mmol) in THF (12 mL) was added to a suspension of NaH (186 mg, 4.65 mmol, 60% dispersion in mineral oil) in THF (12 mL) at 0° C. under an atmosphere of argon. The mixture was stirred for 30 min. at room temperature and cooled to 0° C. A solution of 2-chloro-oxazole-5-carboxylic acid methyl ester (0.5 g, 3.1 mmol) in THF (12 mL) was added dropwise to the mixture. After 30 min., at 0° C., the reaction was poured into ice water (30 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and filtered. After removal of solvent the residue was silica gel column chromatographed (CH2Cl2/Ethanol:99/1) to give 0.54 g of 2-(5-Amino-2-methyl-phenylamino)-oxazole-5-carboxylic acid methyl ester (71%) as a Colorless syrup.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:11]1[NH:15][N:14]=[C:13]([C:16](O)=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20])[CH:8]([CH3:10])[CH3:9].C[N:23](C)C=O>ClCCl>[CH2:7]([C:11]1[NH:15][N:14]=[C:13]([C:16]([NH2:23])=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20])[CH:8]([CH3:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: CC(C)Cc1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)Cc1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (10 ml, 115 mmol) was added dropwise to a suspension of 5-isobutyl-4-nitro-1H-pyrazol-3-carboxylic acid (5.6 g, 26 mmol) in dichloromethane (70 ml) containing dimethylformamide (0.1 ml) under nitrogen at 0° C. The reaction was stirred at 0° C. for 0.5 hours, allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed under reduced pressure, the residue was azeotroped with dichloromethane (3×50 ml) and the residue was dissolved in toluene (100 ml). Ammonia gas was bubbled into the solution for 2 hours and the reaction was stirred under nitrogen at room temperature for 18 hours, concentrated under reduced pressure and the residue was suspended in methanol (250 ml). After filtration, the filtrates were concentrated under reduced pressure, the residue was dissolved in ethyl acetate (400 ml) and washed with water (50 ml). The organic phase was filtered, the filtrate was dried over MgSO4 and concentrated under reduced pressure. The filtered solid and residue from the filtrates were combined to give 5-isobutyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (4.8 g) as an off-white solid. 1H NMR (400 MHz, DMSO-D6): δ=13.61-13.81 (1H, brs), 7.80-7.96 (1H, brs), 7.50-7.66 (1H, brs), 2.70-2.76 (2H, d), 1.90-2.01 (1H, m), 0.83-0.88 (6H, d) ppm. LRMS (electrospray): m/z [M+Na]+ 235, [2M+Na]+ 447, [M−H]+ 211, [2M−H]+ 423. Anal. Found C, 45.12; H, 5.68; N, 26.31. C8H12N4O3 requires C, 45.28; H, 5.70; N, 26.40%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH3:12])=[O:10].[N+](C1C=C(S(O[CH2:26][C@@H:27]2[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O>[CH3:12][NH:11][C:9](=[O:10])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:26][C@@H:27]1[CH2:29][O:28]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CNC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CNC(=O)Cc1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
A mixture of 2-(2-hydroxyphenyl)-N-methylacetamide (1.00 g, 6.1 mmol) prepared according to a known procedure (Bernd, Peschke, Eur. J. Med. Chem., 2000, 35, 599-618), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.58 g, 6.1 mmol) and cesium carbonate (2.37 g, 7.3 mmol) in 1-methylpyrrolidin-2-one (15 ml) was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate, the combined organic layers were dried with sodium sulphate, volatiles were removed in vacuo. The residue was purified by recrystillaziation from ethyl acetate/heptane; (390 mg) of the subtitle compound was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:22][O:23]/[N:24]=[C:25](/[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1)\[CH2:26]Br.Cl>CS(C)=O>[CH2:34]([C:31]1[CH:32]=[CH:33][C:28]([C:25](=[N:24][O:23][CH3:22])[CH2:26][O:1][C:2]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]3[S:11][C:10](=[O:12])[NH:9][C:8]3=[O:13])=[CH:4][CH:3]=2)=[N:29][CH:30]=1)[CH3:35]
Reactant: CCc1ccc(/C(CBr)=N/OC)nc1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1ccc(C(COc2ccc(CC3SC(=O)NC3=O)cc2)=NOC)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (210 mg, 0.941 mmol) in DMSO was added potassium tert-Butoxide (227 mg, 2.02 mmol) in a single portion. Stirred at RT for 15 minutes. Added a solution of (1Z)-2-bromo-1-(5-ethylpyridin-2-yl)ethanone O-methyloxime (242 mg, 0.941 mmol; Supplier=Kalexsyn; Lot=1003-TTP-186) in DMSO (2 ml). Added 1M HCl until pH of mixture was about 3. Extracted with EtOAc. The extract was washed with water, dried (Na2SO4), filtered and evaporated in vacuo to give an off-white foam. 278 mg. 1H-NMR (DMSO-d6): δ12.05 (brs, 1H), 8.47 (d, J=1.7 Hz, 1H), 7.77 (m, 1H), 7.70 m, 1H), 7.14 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 5.17 (s, 2H), 4.87 (dd, J=8.9, 4.4 Hz, 1H), 4.01 (s, 3H), 3.30 (dd, J=14.2, 4.5 Hz, 1H), 3.06 (dd, J=14.1, 9.1 Hz, 1H), 2.64 (q, J=7.7 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H). HPLC: 3.103 min., 82 area % and 3.379 min., 18 area % @254 nm; 3.109 min., 91 area % and 3.379 min., 9 area % @ 254 nm. MS (ESI—) for C20H21N3O4S m/z 400.3 (M+H)+: m/z 398.3 (M−H)−
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)=[O:23])=[CH:4][CH2:3]1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][O:20][C:14]1([C:12]2[CH:11]=[CH:10][C:9]([NH:21][C:22]([C:24]3[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=3)=[O:23])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:31])([CH3:1])[CH2:3][CH:4]=3)[CH:13]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CN(C)CCO
Reactant: CC1(C)CC=C(c2cc(C3(O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCOC1(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Temperature: 50 °C
Yield: 20.3 %

Procedure:
To a suspension of 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (48.0 mg, 0.114 mmol)(prepared in Example 1, step (h)) in 1 mL of DCM was added 2-dimethylamino-ethanol (0.114 mL, 1.14 mmol), TFA (0.130 mL, 1.17 mmol), and the mixture heated to 50° C. for 8 h. The mixture was concentrated and the title compound purified by RP-HPLC on a C18 column eluting with a linear gradient of 30-50% CH3CN in 0.1% TFA/H2O over 12 min to give 14 mg (20%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.21 (d, J=8.6 Hz, 1H), 7.91 (s, 1H), 7.35 (dd, J=8.6, 2.2 Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 5.67 (m, 1H), 3.83-3.66 (m, 4H), 3.30-3.15 (m, 4H), 2.76 (s, 6H), 2.26-2.20 (m, 2H), 2.12-1.94 (m, 6H), 1.51 (t, J=6.3 Hz, 2H), 1.00 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C28H37N5O3, 492.3 (M+H). found 492.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][C:11]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:10][C:9]3=[O:21])[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC1(c2ccccc2)CCN(c2nccc(Cl)n2)C(=O)O1
Reactant: OB(O)c1cccc(F)c1
Product: CC1(c2ccccc2)CCN(c2nccc(-c3cccc(F)c3)n2)C(=O)O1

Procedure:
The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 3-fluorophenylboronic acid. LC-MS Method 3, tR=1.215 min, m/z=749. 1H NMR (CDCl3) 1.80 (s, 3H), 2.48-2.53 (m, 1H), 2.62-2.71 (m, 1H), 3.58-3.67 (m, 1H), 4.30-4.40 (m, 1H), 7.30-7.65 (m, 10H), 7.80-7.90 (m, 2H), 8.90-8.95 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)\[C:11](=[N:13]\[OH:14])\[NH2:12])[N:6]=1.C1N=CN([C:26](N2C=NC=C2)=[O:27])C=1>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)\[C:11]2[NH:12][C:26](=[O:27])[O:14][N:13]=2)[N:6]=1
Reactant: NC(=N\O)/C(=N\OCc1csc(N)n1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Nc1nc(CO/N=C(/c2ccccc2)c2noc(=O)[nH]2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution of (1Z,2Z)-2-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}-N′-hydroxy-2-phenylethanimidamide (3 g, 10.29 mmol, 1 eq.) in DMF (50 ml) was added CDI (1.66 g, 10.29 mmol, 1 eq.) and stirring at room temperature was allowed for 30 min before heated to 80° C. for 6 h. The reaction was quenched by addition of water and extracted with EtOAc (3×50 ml). The organics were combined, washed with aq. sat. NaCl, dried over MgSO4 and concentrated. The residue was triturated in MeCN and a white solid was isolated by filtration giving 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-1,2,4-oxadiazol-5(4H)-one (2.89 g, 50% purity, 43% yield).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH2:8])([CH3:3])[CH3:2].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)OCCCN
Product: CC(C)OCCCNc1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
42 ml of 3-isopropoxypropylamine was added to 21 g (0.15 mol) of 1-fluoro-4-nitrobenzene. As the reaction is exothermic, the temperature was maintained at 90° C. by cooling slightly. After 30 minutes, the reaction was complete. The medium was poured onto ice, and an oil appeared. This oil was extracted with ethyl acetate, and the organic phase is washed with water and dried over sodium sulfate. After the oil was evaporated to dryness, 35 g of a yellow oil were obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](C1C=CC(B(O)O)=CC=1)([OH:23])=[O:22]>>[O:20]=[C:19]1[C:13]2[C:14]3[C:15](=[C:7]([C:1]4[CH:2]=[CH:3][C:4]([C:21]([OH:23])=[O:22])=[CH:5][CH:6]=4)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:16][CH2:17][NH:18]1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (530 mg, 2.00 mmol) and 4-carboxyphenylboronic acid (365 mg, 2.20 mmol) were coupled to yield 4-(6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzoic acid, 340 mg (56%) as a pale yellow solid: m.p. 345.5-346.5° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 3.10 (m, 2H), 3.40 (m, 2H), 7.25 (t, J=7.8 Hz, 1H), 7.59 (dd, J=8.1, 0.9 Hz, 1H), 7.70 (dd, J=7.5, 0.6 Hz, 1H), 7.78 (m, 2H), 8.10 (m, 3H), 11.73 (br S, 1H), 13.00 (br s, 1H). MS (electrospray, MH+) 307. Anal. (C18H14N2O3.0.9 H2O) C, H, N.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:15][C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:29])[C:18]=2[CH:17]=1>C(OCC)C>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:19]1([OH:29])[C:18]2[CH:17]=[C:16]([Br:15])[CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: Brc1ccccc1-c1ccccc1
Reactant: O=C1c2ccccc2-c2ccc(Br)cc21
Agent: [Mg]
Solvent: CCOCC
Product: OC1(c2ccccc2-c2ccccc2)c2ccccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
1.26 g (0.052 mol) of magnesium was put in a 100 mL three-necked flask to which a dropping funnel and a Dimroth condenser were connected, and the flask was evacuated. The magnesium was activated by 30 minutes of heating and stirring. After cooling to room temperature, the flask was placed under a nitrogen gas flow. 5 mL of diethyl ether and several drops of dibromoethane were added, and 11.65 g (0.050 mol) of 2-bromobiphenyl dissolved in 15 mL of diethyl ether was slowly delivered from the dropping funnel by drops into the mixture. After the dropping was complete, the mixture was refluxed for 3 hours and made into a Grignard reagent. 11.7 g (0.045 mol) of 2-bromo-9-fluorenone and 40 mL of diethyl ether were put in a 200 mL three-necked flask to which a dropping funnel and a Dimroth condenser were connected. To this reaction solution, the synthesized Grignard reagent was slowly delivered by drops from the dropping funnel. After the dropping was complete, the mixture was refluxed for 2 hours, and then stirred at room temperature for about 12 hours. After the reaction was complete, the solution was washed twice with saturated ammonia chloride solution. An aqueous layer was extracted twice with ethyl acetate and combined with an organic layer, and the solution was washed with a saturated saline solution. After drying with magnesium sulfate, suction filtration and concentration were conducted, and a solid of 9-(biphenyl-2-yl)-2-bromo-9-fluorenol was obtained, weighing 18.76 g in a yield of 90%.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][N:7]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(C2OCCO2)cn1
Reaction time: 0.67 h
Yield: 58.6 %

Procedure:
A mixture of 6-bromo-pyridine-3-carbaldehyde (8.0 g, 43 mmol) described in Manufacturing Example 210-1-1, ethylene glycol (5.3 g, 86 mmol), p-toluenesulfonic acid (820 mg, 4.3 mmol), and toluene (110 mL) was stirred for 40 minutes under reflux. (The water produced in this reaction was removed with a Dean-Stark trap.) The reaction solution was concentrated under a reduced pressure, and the residue was partitioned into ethyl acetate and water. The organic layer was separated and passed through a glass filter provided with NH silica gel (eluted with ethyl acetate). The eluate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=8:1) to obtain the title compound (5.8 g, 59%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21][NH2:22]>C(O)C.N1C=CC=CC=1>[CH3:12][C:11]1([CH3:13])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[NH:22][CH3:21]
Reactant: CN
Reactant: CC1(C)C(Cl)=Nc2ccccc2C1(O)c1ccccc1
Solvent: CCO
Solvent: c1ccncc1
Product: CNC1=Nc2ccccc2C(O)(c2ccccc2)C1(C)C
Reaction time: 4 h

Procedure:
2-Chloro-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (1.43g., 0.005 mole) was dissolved in a mixture of a 33% w/v solution of methylamine in ethanol (40 ml.) and pyridine (0.79g.). The solution was stirred for four hours, after which the methylamine and ethanol were evaporated off to leave a residue, which was recrystallised twice from isopropyl alcohol to give the title compound (0.96g., m.p. 192° - 194° C).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:34])([F:33])[O:21][C:22]1[CH:23]=[C:24](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:33])([F:34])[F:19])[CH:23]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(OC(F)(F)F)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(OC(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid.