Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:9][CH:10]=[C:11]([CH:13]=O)[CH:12]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].C(OP([CH2:23][C:24]1[CH:25]=[C:26]([C:34]([O:36][CH3:37])=[O:35])[C:27](=[CH:32][CH:33]=1)[C:28]([O:30][CH3:31])=[O:29])(OCC)=O)C.CC(C)([O-])C.[K+]>>[CH2:1]([C:3]1([C:8]2[S:9][CH:10]=[C:11](/[CH:13]=[CH:23]/[C:24]3[CH:25]=[C:26]([C:34]([O:36][CH3:37])=[O:35])[C:27](=[CH:32][CH:33]=3)[C:28]([O:30][CH3:31])=[O:29])[CH:12]=2)[O:4][CH2:5][CH2:6][O:7]1)[CH3:2]
Reactant: CCC1(c2cc(C=O)cs2)OCCO1
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)c(C(=O)OC)c1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCC1(c2cc(/C=C/c3ccc(C(=O)OC)c(C(=O)OC)c3)cs2)OCCO1

Procedure:
In a manner similar to that of Example 8(a), by reaction of 4.6 g (21.6 mmol) of 2-(2-ethyl-[1,3]dioxolan-2-yl)thiophene-4-carbaldehyde with 8.9 g (26 mmol) of dimethyl 4-(diethoxyphosphorylmethyl)-phthalate and 2.9 g (26 mmol) of potassium tert-butoxide, the desired product is obtained in the form of a yellow oil (m=7 g; Y=87%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][N:8]=2)[CH2:2]1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[F:27][C:26]([F:29])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([C:7]3[C:11]4=[C:12]5[CH:18]=[CH:17][NH:16][C:13]5=[N:14][CH:15]=[C:10]4[NH:9][N:8]=3)[CH2:2]2)=[N:21][CH:22]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: c1cc2c(ncc3[nH]nc(C4CCCNC4)c32)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(F)c1ccc(N2CCCC(c3n[nH]c4cnc5[nH]ccc5c34)C2)nc1
Temperature: 130 °C
Yield: 24.4 %

Procedure:
A mixture of 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.16 g, 0.65 mmol, Example #26, Step E) and 2-chloro-5-(trifluoromethyl)pyridine (0.031 g, 0.17 mmol) with DIEA (0.09 mL, 0.51 mmol) in EtOH (2 mL) was heated at about 130° C. for about 1 h in a microwave reactor (250 psi maximum pressure, 1 min ramp, 300 max watts). The crude material was purified by silica gel chromatography eluting with a 5-100% EtOAc in heptane gradient to give 1-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.016 g, 24%): LC/MS (Table 2, Method a) Rt=2.32 min; m/z: 387 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][CH:12]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].CO>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][C:12]=2[CH:20]([CH3:21])[C:19]([O:23][CH3:24])=[O:22])=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)co1
Reactant: C=CC(=O)OC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC#N
Solvent: O
Product: COC(=O)C(C)c1oc(=O)[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
4-(4-chlorophenyl)-2-oxo-4-oxazoline (5.00 g) was suspended in acetonitrile (15 ml) in a reaction vessel, and the gas in the reaction vessel was substituted for nitrogen gas. The obtained suspension was cooled and conc. sulfuric acid (7.53 g) was added dropwise at 2-10° C. Then methyl acrylate (4.41 g) was added dropwise at 2-3° C. The obtained mixture was stirred at 20-30° C. for 1.5 h and methanol (15 ml) was added dropwise at 22-25° C. After cooling, water was added dropwise at 5-8° C. The precipitated crystals were collected by filtration, washed with water (25 ml), 1% aqueous sodium hydrogencarbonate (25 ml), water (25 ml) and diisopropyl ether (25 ml), and dried under reduced pressure at 40° C. for 7 h to give the title compound (5.72 g, yield 79.4%) as pale-red white crystals.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=1.[K+].[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH-:31])(=[O:30])=[O:29])=[N:26][CH:27]=1)([CH3:21])[CH3:20]>CN(C=O)C>[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH:31][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=2)(=[O:30])=[O:29])=[N:26][CH:27]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)ncnc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(C)C)cn1
Yield: 64.4 %

Procedure:
A solution of 2.71 g of 4,6-dichloro-5-(o-methoxyphenoxy)-pyrimidine (Example 10b) and 5.0 g of 5-isopropyl pyridine-2-sulfonamide potassium salt (Example 1e) in 50 ml of DMF was stirred at room temperature for 20 h. The solvent was removed in vacuo, the residue was taken up in 200 ml of 10% aqueous acetic acid and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The crude product was crysallised from a mixture of 2-propanol and diethyl ether. The crystals were collected, washed with cold 2-propanol and diethyl ether and dried to give 2.8 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as white crystals. LC-MS: tR=4.99 min, [M+1]+=435.25, [M−1]−=433.28.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:11](C(OC(C)(C)C)=O)[NH2:12].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([O:6][CH2:7][C:8]([NH:11][NH2:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)COC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NNC(=O)COC1CCCC1
Reaction time: 18 h
Yield: 94.7 %

Procedure:
2.60 g of cyclopentyloxyacetic acid (18.03 mmol, 1.0 eq.) are placed in 50 mL of dichloromethane at room temperature with stirring. 2.86 g of tert-butyl hydrazinecarboxylate (21.64 mmol, 1.2 eq.), 2.437 g of hydroxybenzotriazole (18.03 mmol, 1.0 eq.), 4.148 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.64 mmol, 1.2 eq.) and 4.08 mL of diisopropylethylamine (23.44 mmol, 1.3 eq.) are successively added with stirring. After 18 hours, the reaction medium is diluted with dichloromethane and washed twice with water. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue is dissolved in 60 mL of dichloromethane. 15 mL of trifluoroacetic acid (201.93 mmol, 11.20 eq.) are added. The reaction medium is stirred for 2 hours and concentrated under vacuum. The residue is chromatographed on silica gel, eluting with a dichloromethane/methanol/aqueous ammonia gradient ranging from 99/1/0.1 to 95/5/0.5. 2.7 g of cyclopentyloxyacetic acid hydrazide are obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:11]([NH:13][C@H:14]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([NH:46][C@H:47]([C:54]([NH:56][C@H:57]([C:67]([O:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:68])[CH2:58][CH2:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:55])[CH2:48][O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:45])[CH2:38][O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:35])[C@@H:27]([CH3:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:24])[CH2:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3].[NH:76]([C:111]([O:113][C:114]([CH3:117])([CH3:116])[CH3:115])=[O:112])[C@H:77]([C:84]([NH:86][C@H:87]([C:96]([NH:98][C@H:99]([C:101](ON1C(=O)CCC1=O)=[O:102])[CH3:100])=[O:97])[CH2:88][C:89](=[O:95])[O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:85])[CH2:78][O:79][C:80]([CH3:83])([CH3:82])[CH3:81].CCN(CC)CC.O>CN(C=O)C>[NH:76]([C:111]([O:113][C:114]([CH3:115])([CH3:117])[CH3:116])=[O:112])[C@H:77]([C:84]([NH:86][C@H:87]([C:96]([NH:98][C@H:99]([C:101]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:11]([NH:13][C@H:14]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([NH:46][C@H:47]([C:54]([NH:56][C@H:57]([C:67]([O:69][C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1)=[O:68])[CH2:58][CH2:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:55])[CH2:48][O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:45])[CH2:38][O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:35])[C@@H:27]([CH3:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:24])[CH2:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:12])[CH:8]([CH3:9])[CH3:10])=[O:5])[CH3:3])=[O:102])[CH3:100])=[O:97])[CH2:88][C:89](=[O:95])[O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:85])[CH2:78][O:79][C:80]([CH3:81])([CH3:82])[CH3:83]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C
Reactant: C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C
Reaction time: 17 h

Procedure:
A solution of H-Ala-Val-Asp(OtBu)-Thr(tBu)-Ser(tBu)-Ser(tBu)-Glu(OtBu)-OC6H5 0.708 mmol) in DMF (34 mL) was cooled to 0° and Boc-Ser(tBu)-Asp(OtBu)-Ala-OSu 510 mg, 0.85 mmol, 1.2 eq) added. Stirring proceeded at 0° for 30 min and 25° for 17 h while the pH was maintained at ~8 by addition of Et3N. Water (150 mL) was added with stirring and the product was collected by filtration and dried in vacuo. The solid was washed with CH3OH (2×20 mL) and dried in vacuo. Yield: 586 mg (53.3%); mp >250°; [α]D25 -23.06° (c 1, TFE); Rf 0.51 (CHCl3 :MeOH:AcOH; 80-2-0.4); Rf 0.72 (CHCl3 :MeOH:AcOH; 80-5-2). Anal. calc. for C76H131N10O23 (1552.93): C, 58.78; H, 8.50; N, 9.01. Found: C, 58.65; H, 8.32; N, 8.93.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([NH2:13])[CH:3]=1.[C:14](Cl)(=[O:16])[CH3:15]>N1C=CC=CC=1.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][C:14](=[O:16])[CH3:15])[CH:3]=1
Reactant: CCOc1nc(N)cc(N)c1C#N
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOc1nc(NC(C)=O)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To 50 mg (0.28 mmol) of 4,6-diamino-2-ethoxy-nicotinonitrile dissolved in 1 mL of pyridine was added 60 μL (0.84 mmol) of acetyl chloride. The mixture was stirred at ambient temperature for 2 hours then diluted with 7 mL of water. The precipitate was filtered and washed with 5 mL of water. The supernatant was extracted with ethyl acetate (3×5 mL), then the combined ethyl acetate layers were back extracted with brine (1×5 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to a solid. This was combined with the precipitated product, dissolved in methanol/ethyl acetate, and concentrated. Most of the remaining pyridine was removed by coevaporation with toluene under reduced pressure. The product was purified via silica gel chromatography, eluting with 50% ethyl acetate/hexanes to provide 31 mg (50%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.73 (s, 1H), 7.17 (s, 1H), 6.88 (s, 2H), 4.32 (q, 2H, J=7.1 Hz), 2.07 (s, 3H), 1.29 (t, 3H, J=7.1 Hz); MS (ESI) m/e=221 (M+H)+, m/e=219 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH:7](Br)[C:6]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4].[C:15](#[N:17])C>[C-]#N.C([N+](CC)(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH:7]([C:15]#[N:17])[C:6]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4]
Reactant: CC#N
Reactant: COC(=O)C1=C(C(=O)OC)C(Br)CC1
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Product: COC(=O)C1=C(C(=O)OC)C(C#N)CC1
Yield: 25 %

Procedure:
3-Bromo-cyclopent-1-ene-1,2-dicarboxylic acid dimethyl ester was dissolved in acetonitril under inert conditions. Tetraethylammoniumcyanide (1.1 eq) was added in one portion. The mixture was stirred under inert gas until the reaction was finished (2 h monitored by TLC). The solvent was removed in vacuum and the residue was purified by flash chromatographie using a hexane/ethylacetat gradient to give 3-Cyano-cyclopent-1-ene-1,2-dicarboxylic acid dimethyl ester in 25% yield.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]#[N:17])=[CH:3][CH:2]=1.CO>C1COCC1>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH2:16][NH2:17])=[CH:3][CH:2]=1
Reactant: N#CCOc1cccc2[nH]c3ccccc3c12
Solvent: CO
Solvent: C1CCOC1
Product: NCCOc1cccc2[nH]c3ccccc3c12
Temperature: 85 °C
Yield: 52.9 %

Procedure:
To a mixture of (9H-carbazol-4-yloxy)acetonitrile (1.13 g, 5.1 mmol) in dry THF (50 mL) is added borane-methyl sulfide complex (1.4 mL, 15.3 mmol). The mixture is heated at 85° C. for 6 h. Methanol is added slowly until gas evolution ceased. The solvents are removed under reduced pressure. Methanol (20 mL) is added then removed under reduced pressure. Methanol (50 mL) and concentrated hydrochloric acid are added and the mixture heated at 65° C. overnight. The mixture is neutralized with saturated potassium carbonate and partitioned between water and CH2Cl2. The layers are separated and the organic layer washed twice with water (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography, silica gel (200 mL), using CH3OH/CH2Cl2 (4/96) gave 0.61 g (53%) of the title compound; IR (drift) 3082, 1608, 1585, 1456, 1443, 1346, 1336, 1303, 1252, 1222, 1098, 911, 782, 750, 719 cm−1. 1H NMR (DMSO-d6) δ3.05, 4.13, 6.65, 7.03, 7.12, 7.24, 7.31, 7.41, 8.12; Anal. Calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found: C, 73.90; H, 6.32; N, 12.14.
Reaction SMILES: C(C1C=CC=CC=1)(=O)C.C(NCCCCCCNCC1C=CC=CC=1)C1C=CC=CC=1.C([N:39]([CH2:75][C:76]([C:78]1[CH:83]=[CH:82][C:81]([O:84]CC2C=CC=CC=2)=[C:80]([NH:92][C:93]([NH2:95])=[O:94])[CH:79]=1)=[O:77])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46](CC1C=CC=CC=1)[CH2:47][C:48](=[O:67])[C:49]1[CH:54]=[CH:53][C:52]([O:55]CC2C=CC=CC=2)=[C:51]([NH:63][C:64]([NH2:66])=[O:65])[CH:50]=1)C1C=CC=CC=1>CC(C)=O>[OH:55][C:52]1[CH:53]=[CH:54][C:49]([CH:48]([OH:67])[CH2:47][NH:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][NH:39][CH2:75][CH:76]([OH:77])[C:78]2[CH:83]=[CH:82][C:81]([OH:84])=[C:80]([NH:92][C:93]([NH2:95])=[O:94])[CH:79]=2)=[CH:50][C:51]=1[NH:63][C:64]([NH2:66])=[O:65]
Reactant: NC(=O)Nc1cc(C(=O)CN(CCCCCCN(CC(=O)c2ccc(OCc3ccccc3)c(NC(N)=O)c2)Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: c1ccc(CNCCCCCCNCc2ccccc2)cc1
Solvent: CC(C)=O
Solvent: CC(=O)c1ccccc1
Product: NC(=O)Nc1cc(C(O)CNCCCCCCNCC(O)c2ccc(O)c(NC(N)=O)c2)ccc1O

Procedure:
Following the procedures of Example 14, the above prepared acetophenone and N,N'-dibenzyl-hexamethylenediamine are refluxed in acetone for 12 hours and the resulting N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-ureidophenyl)-2-oxoethyl]-hexamethylenediamine is hydrogenated to yield N,N'-bis[2-(4-hydroxy-3-ureidophenyl)-2-hyroxyethyl]-hexamethylenediamine.
Reaction SMILES: [CH3:1][N:2]1[C:20](=O)[C:19](=O)[N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[N:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>O1CCOCC1>[CH3:1][N:2]1[CH2:20][CH2:19][N:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[N:15][C:7]=3[CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1
Reactant: CN1CC2c3ccccc3Cc3ncccc3N2C(=O)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN2c3cccnc3Cc3ccccc3C2C1
Temperature: 15 °C

Procedure:
1.46 g (0.005 mol) 2-methyl-3,4-dioxo-1,2,3,4,10,14b-hexahydro-benzo[c]pyrazino[1,2-a]pyrido[2,3-f]azepine is added cautiously to a suspension of 0.4 g LiAlH4 in 25 ml dry dioxan under nitrogen at 25° C. The reaction mixture is boiled under reflux for 2 hours, after which it is cooled to 15° C. 5 ml water is then added, and the inorganic salts are filtered off and rinsed with dioxan. The filtrate is evaporated to dryness, giving a yellow oil. Melting point maleate salt: 163°-164° C (dec.).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])O1.Cl[C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([N+:41]([O-:43])=[O:42])[CH:32]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.COCCOC.O>[C:24]([O:23][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([N+:41]([O-:43])=[O:42])[CH:32]=1)=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Water (3.0 mL), sodium carbonate (1.1 g), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (1.5 g), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (30 mg) were added to an ethylene glycol dimethyl ether (10 mL) solution of methyl 4-chloro-2-nitrobenzoate (0.90 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 1.5 g of methyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].[CH3:10]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH3:10])=[O:4]
Reactant: C=CCC(C)(C)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C=CCC(C)(C)C(=O)OC

Procedure:
2,2-Dimethyl-4-pentenoic acid (15 g, 0.117 mol) was mixed with 70 mL anhydrous methanol and 50 mL toluene. Concentrated sulfuric acid (0.1 mL ) was added. The solution was refluxed for 24 h. Solvents were then removed. The crude product was distilled under reduced pressure to gave 6 g pure product. 1H NMR (CDCl3): δ 1.28 (s, 6H, —CMe2—); 2.37 (d, 2H, CH2═CHCH2—); 3.77 (s, 3H, —CO2Me); 5.15 (m, 2H, CH2═CH—); 5.84 (m, 1H, CH2═CH—)
Reaction SMILES: CS(C)=O.C(Cl)(=O)C([Cl:8])=O.C1(S([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]2[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])(=O)=O)C2C(=CC=CC=2)C=CC=1.CCN(CC)CC>C(Cl)Cl>[ClH:8].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)CCCC1CCCCN1S(=O)(=O)c1cccc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)CCCC1CCCCN1
Product: Cl
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 98.1 %

Procedure:
A solution of DMSO (21.24 ml, 299 mmol) in CH2Cl2 (600 ml) was added dropwise to a solution of oxalyl chloride (15.0 ml, 171 mmol) in CH2Cl2 (300 ml) at an internal temperature below −65° C. in the course of 30 min. A solution of 3 (46.7 g, 142 mmol) in CH2Cl2 (300 ml) was added dropwise in the course of 15 min, the temperature remaining below −65° C. The reaction mixture was stirred at −78° C. for a further 45 min and Et3N (99.0 ml, 712 mmol) was then added. After the reaction mixture had been stirred at −78° C. for 45 min, the reaction mixture was warmed to room temperature, while stirring, and was then stirred for a further hour. The reaction mixture was washed with H2O and sat. NaCl solution, dried over Na2SO4 and concentrated. The residue was dissolved in ether, the solution was filtered, the filtrate was concentrated and the residue was recrystallized (Et2O/heptane) to obtain 4 (30.9 g, 67%). The mother liquor was concentrated and the residue was recrystallized (Et2O/heptane) and gave additional product 4 (2.27 g, 5%).
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[C@H:10]([OH:11])[C:9]([CH3:13])([CH3:12])[O:8][C:7]2[CH:14]=[CH:15][C:16]([N+:18]([O-])=O)=[CH:17][C:6]1=2)([CH3:3])[CH3:2].C(OCC)C.[S:26](=O)(=[O:29])([OH:28])[OH:27]>C(O)C.Cl>[S:26]([O:11][C@@H:10]1[C:9]([CH3:13])([CH3:12])[O:8][C:7]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:6]=2[C@H:5]1[NH:4][CH:1]([CH3:3])[CH3:2])([OH:29])(=[O:28])=[O:27]
Reactant: O=S(=O)(O)O
Reactant: CC(C)N[C@@H]1c2cc([N+](=O)[O-])ccc2OC(C)(C)[C@H]1O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CC(C)N[C@@H]1c2cc(N)ccc2OC(C)(C)[C@H]1OS(=O)(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trans-4-Isopropylamino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran-3-ol (3.54 g.) was added to a solution of stannous chloride (7.90 g.) in ethanol (36 ml.) and concentrated hydrochloric acid (60 ml.) and stirred for 3 hours at ambient temperature. After dilution, work-up via diethyl ether gave a gum (3.25 g.). Purification of this gum (2.00 g.) by application to silica gel plates and development with ethyl acetate/60°-80° petroleum ether mixture gave an amorphous solid (1.01 g.) which was dissolved in dilute sulphuric acid and evaporated to dryness to yield trans-4-isopropylamino-3,4-dihydro-2,2-dimethyl-6-amino-2H-benzo[b]pyran-3-ol sulphate as a light brown solid m.p. 180° - 190°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[CH2:10]2)(=[O:3])[CH3:2].C1N=[CH:36][N:35](C(N2C=NC=C2)=O)[CH:34]=1.CNC>C1COCC1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[C:12](=[O:14])[N:11]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([N:35]([CH3:36])[CH3:34])=[O:18])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)C)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 47.8 %

Procedure:
3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide was prepared by the procedure of example 13 from 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.1 g, 0.22 mmol), CDI (0.05 g, 0.33 mmol) and dimethylamine (0.33 ml, 0.66 mmol) in THF (10 ml) to give as 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide white solid (0.05 g, 50% yield): mp 141–143° C.; 1HNMR (CDCl3): δ 1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 2.93 (s, 3H, NCH3), 3.04 (dd, J=5, 15 Hz, 1H, CH2), 3.10 (s, 3H, NCH3), 3.60 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.0 Hz, 2H, OCH2CH3), 4.33 (d, J=18 Hz, 1H, CH2N), 4.44 (d, J=18 Hz, 1H, CH2N), 5.59 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, CF2H), 7.04 (m, 4H, Ar), 7.45 (t, J=7.5 Hz, 1H, Ar), 8.45(d, J=7.5 Hz, 1H, Ar), 10.35 (s, 1H, NHCO). 13CNMR (DMSO-d6): δ 14.5, 24.8, 35.5, 35.9, 37.2, 49.0, 53.8, 64.7, 111.9, 113.4, 113.5, 116.0, 116.8, 117.5, 117.8, 119.1, 119.1, 120.1, 122.6, 133.0, 137.7, 138.2, 139.7, 138.2, 139.6, 139.7, 141.5, 150.6, 168.9, 169.2, 169.5; Anal. Calcd. for C24H27F2N3O5: C, 60.62; H, 5.72; N, 8.84. Found: C, 59.90; H, 5.46; N, 8.66.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.CO.O.[N:18]#[C:19]Br>C1COCC1>[C:9]1([C:1]2[CH:6]=[CH:5][C:4]3[NH:7][C:19]([NH2:18])=[N:8][C:3]=3[CH:2]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CBr
Reactant: Nc1ccc(-c2ccccc2)cc1N
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc2cc(-c3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of biphenyl-3,4-diamine (0.99 mmol) in THF:MeOH:water (5 mL:10 mL:10 mL) was added cyanogen bromide (5M solution in acetonitrile, 1.06 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was partitioned between EtOAc and aqueous sodium hydroxide and the aqueous layer re-extracted with EtOAc.