Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:35]1[C:47]2[CH:46]([CH2:48][O:49][C:50]([NH:52][CH:53]([CH2:57][CH2:58][CH2:59][CH2:60][N:61]([CH2:88][C:89]3[N:90]([CH2:94][C:95]([N:97]([CH2:106][C:107]([O:109][C:110]([CH3:113])([CH3:112])[CH3:111])=[O:108])[CH2:98][C:99](=[O:105])[O:100][C:101]([CH3:104])([CH3:103])[CH3:102])=[O:96])[CH:91]=[CH:92][N:93]=3)[CH2:62][C:63]3[N:64]([CH2:68][C:69](=[O:87])[N:70]([CH2:79][C:80](=[O:86])[O:81][C:82]([CH3:85])([CH3:84])[CH3:83])[CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[CH:65]=[CH:66][N:67]=3)[C:54](O)=[O:55])=[O:51])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:110]([O:109][C:107](=[O:108])[CH2:106][N:97]([CH2:98][C:99](=[O:105])[O:100][C:101]([CH3:104])([CH3:103])[CH3:102])[C:95](=[O:96])[CH2:94][N:90]1[CH:91]=[CH:92][N:93]=[C:89]1[CH2:88][N:61]([CH2:62][C:63]1[N:64]([CH2:68][C:69](=[O:87])[N:70]([CH2:79][C:80](=[O:86])[O:81][C:82]([CH3:83])([CH3:84])[CH3:85])[CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:75])([CH3:76])[CH3:77])[CH:65]=[CH:66][N:67]=1)[CH2:60][CH2:59][CH2:58][CH2:57][C@@H:53]([C:54](=[O:55])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:52][C:50](=[O:51])[O:49][CH2:48][CH:46]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:47]1=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH3:111])([CH3:112])[CH3:113]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CCCCN(Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (97 mg, 0.20 mmol), 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (132 mg, 0.12 mmol), EDCI (38 mg, 0.20 mmol), HOBt (26 mg, 0.20) and DIPEA (0.30 mL) in DCM (5.0 mL) was stirred at rt for 2 days. The reaction mixture was purified by biotage eluting with 1% MeOH in DCM to afford (5S,12S,16S)-tri-tert-butyl 5-(4-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-1-(9H-fluoren-9-yl)-3,6,14-trioxo-2-oxa-4,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylate (impure) as an oil.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:23][CH2:24][CH3:25]
Reactant: C#CCCCCCCCCCC
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCCCCCCCC=C[Sn](CCCC)(CCCC)CCCC
Temperature: 50 °C
Yield: 95.8 %

Procedure:
A solution of 1-dodecyne (50.0 g), tributyltinhydride (109.4 g), and azobisisobutyronitrile (100 mg) was stirred at 95° C. for 3 hrs. The reaction mixture was cooled to 50° C. and evaporated. The residue was filtered through a column of silica, using hexane as the eluent. The appropriate fractions were collected and evaporated. The residue was dried under vacuum to give 131.7 g (96.0%) of tri-n-butyl-1-dodecenylstannane.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccccc3[N+](=O)[O-])c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.9 %

Procedure:
2-Nitroaniline (0.222 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. 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 (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.140 g, 0.283 mmol, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(2-aminoethyl)morpholine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a light yellow rigid foam: 1H NMR (CDCl3) δ 10.41 (1H, m), 8.57 (1H, s), 7.15 (2H, dd, J=8.5, 6 Hz), 7.03 (3H, m), 4.92 (2H, s), 4.12 (2H, s), 3.99 (4H, m), 3.89 (2H, q, J=6 Hz), 3.72 (2H, m), 3.50 (2H, m), 3.46 (2H, m), 3.35 (2H, t, J=6 Hz), 2.93 (2H, br), 1.70 (2H, m), 1.61 (2H, m), 1.53 (2H, m); HRMS calcd for C29H34FN5O5+H+: 552.2622. Found: 552.2618 .
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[C:12](=[O:18])[N:11]([CH2:19][CH2:20][N:21]4[CH:25]=[C:24]([C:26]([O:28]CC)=[O:27])[CH:23]=[N:22]4)[CH:8]3[N:9]=2)=[C:5]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)[N:4]=[CH:3]1.[OH-].[Li+]>O1CCCC1.CO>[NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[C:12](=[O:18])[N:11]([CH2:19][CH2:20][N:21]4[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[N:22]4)[CH:8]3[N:9]=2)=[C:5]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)[N:4]=[CH:3]1
Reactant: CCOC(=O)c1cnn(CCN2C(=O)N(CC3CC3)N3C4=C(c5ccco5)N=CN(N)C4=NC23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NN1C=NC(c2ccco2)=C2C1=NC1N(CCn3cc(C(=O)O)cn3)C(=O)N(CC3CC3)N21
Temperature: 26 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
A mixture of ethyl 1-[2-[5-amino-1-(cyclopropylmethyl)-8-(2-furyl)-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl]pyrazole-4-carboxylate obtained in step 1 (0.055 g, 0.115 mmol) was dissolved in solution of tetrahydrofuran (6 ml) and methanol (4 ml). To this reaction mixture a solution of lithium hydroxide (0.013 g, 0.576 mmol, in 2 ml water) was added and stirred at 25-27° C. for 16 hours. The reaction mixture was concentrated and acidified with saturated solution of citric acid to get PH˜2-3 and solid obtained was filtered off and washed with water (10 ml) followed by diethyl ether (15 ml). It was dried to obtain 1-[2-[5-amino-1-(cyclopropylmethyl)-8-(2-furyl)-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl]pyrazole-4-carboxylic acid (0.025 g, 49%) as an off white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:26][C:25]([C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:14][C:13]=2[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Reactant: C=CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1=Cc2cc(OCc3ccccc3)ccc2OC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5-Benzyloxy-2-hydroxybenzaldehyde (2.01 g, 8.80 mmol) is dissolved in 30 ml of DMF and treated successively with potassium carbonate (1.22 g, 8.80 mmol) and tert-butyl acrylate (1.22 g, 13.2 mmol). The mixture is heated at 100° C. for 1 hour. The temperature is gradually raised to 135° C. over a period of 2 hours, and held at 135° C. for 1 hour. The resultant dark mixture is cooled and evaporated to remove most of DMF. The residue is partitioned between ether and water, and the aqueous phase is discarded. The organic layer is dried (MgSO4), evaporated and purified by silica gel chromatography (6% ethyl acetate/hexane) to give tert-butyl 6-benzyloxy-2H-1-benzopyran-3-carboxylate as a yellow crystalline solid, m.p. 64°-67° C.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][NH:6][CH2:5][CH:4]1[C:8]1[NH:13][C:12](=[O:14])[C:11]2=[CH:15][N:16]=[C:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:10]2[N:9]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.[BH3-]C#N.[Na+]>ClCCCl.C(O)(=O)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:6]2[CH2:7][CH:3]([CH3:2])[CH:4]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[CH:15][N:16]=[C:17]([CH:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH2:5]2)=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC1CNCC1c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1CN(Cc2ccc(F)cc2)CC1c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
To a solution of compound 9 (80 mg, 0.263 mmol) and 4-fluorobenzaldehyde (326 mg, 2.63 mmol) in 1,2-dichloroethane (15 mL) was added 2 drops of acetic acid. The resulting solution was stirred at room temperature for one hour. Then NaBH3CN (178 mg, 2.63 mmol) was added to the reaction in portions. The resulting mixture was stirred at room temperature for 16 hours. LC-MS showed that the starting material was almost consumed. The reaction mixture was quenched with water (40 mL), and extracted with CH2Cl2 (30 mL×3). The combined organic phases were washed with brine (30 mL), and dried over Na2SO4. After filtered, the filtrate was concentrated in vacuum. The residue was purified by preparative TLC to afford the desired product (20 mg, 21% yield) as a white solid. LC-MS: m/z 412.2 [M+1]+. 1H NMR (400 MHz, CD3OD-d4): δ 8.27 (s, 1H), 7.61 (s, 1H), 7.35˜7.31 (m, 2H), 7.02˜6.98 (m, 2H), 3.96˜3.93 (m, 2H), 3.79˜3.70 (m, 2H), 3.51˜3.39 (m, 3H), 3.15˜3.11 (m, 1H), 3.05˜2.95 (m, 2H), 2.84˜2.79 (m, 1H), 2.61˜2.57 (m, 1H), 2.33˜2.29 (m, 1H), 1.93˜1.87 (m, 2H), 1.80˜1.77 (m, 2H), 1.09 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].N1C=CC=CC=1>ClCCl>[CH3:15][O:14][N:13]([CH3:12])[C:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:8]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 10.00 g of p-toluoyl chloride in 300 ml of dichloromethane, 6.94 g of N,O-dimethylhydroxyamine hydrochloride was added. The reaction solution was ice-cooled and 11.5 ml of pyridine was added dropwise. After the completion of dropwise addition, the mixture was stirred at room temperature for one hour and the solvent was evaporated under reduced pressure. The residue was combined with water, extracted with diethyl ether and then washed in turn with 10% hydrochloric acid, water and an aqueous saturated sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 10.40 g of the desired compound as a colorless oily substance.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:33])=[C:17]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4([C:30]#[N:31])[CH2:29][CH2:28]4)[CH:22]=3)[CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:33])=[C:17]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4([C:30]#[N:31])[CH2:28][CH2:29]4)[CH:22]=3)[CH:18]=1)[N:10]=2
Reactant: N#C[S-]
Reactant: Cc1ccc(Oc2ccc(N)cn2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Potassium thiocyanate (506 mg, 5.2 mmol) was suspended in acetic acid (10 mL), and the mixture was stirred at room temperature for 10 min. A solution of N-{5-[(5-aminopyridin-2-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (500 mg, 1.3 mmol) in acetic acid (10 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 15 min. A solution of bromine (230 mg, 1.43 mmol) in acetic acid (7.0 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 4 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and washing solution were combined, and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (200 mL), and the suspension was washed with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (350 mg, 61%) as a pale-yellow amorphous substance. The amorphous substance was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][N:4]([CH2:13][CH2:14][CH2:15][NH2:16])[CH:3]3[CH2:2]1.C([O-])(O)=O.[Na+].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(Cl)Cl>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][N:4]([CH2:13][CH2:14][CH2:15][NH:16][C:22](=[O:24])[CH3:23])[CH:3]3[CH2:2]1
Reactant: NCCCN1CCc2cccc3c2C1CC3
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCCCN1CCc2cccc3c2C1CC3
Reaction time: 1.5 h
Yield: 86.6 %

Procedure:
3-(2,2a,4,5-Tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propylamine (516 mg, 2.39 mmol) was disolved in a vigorously stirred mixture of CH2Cl2 (2.7 ml) and NaHCO3 (sat. solution, 2.7 ml). After the addition of acetic anhydride (348.9 mg, 3.42 mmol), stirring was applied for 90 min at room temperature. Then, the layers were separated. Water (6 ml) was added to the bicarbonate layer and was extracted with CH2Cl2 (3×6 ml). The combined organic layers were dried with Na2SO4, filtered and evaporated too dryness to afford as slightly brown solid identified as the acetylated compound (535 mg, 87% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[CH3:20][C:21]([CH3:25])=[CH:22]CO.C[O-].[Na+]>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH:20]=[C:21]([CH3:25])[CH3:22])=[O:17]
Reactant: COC(=O)c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Reactant: CC(C)=CCO
Agent: C[O-]
Agent: [Na+]
Product: CC(C)=CCOC(=O)c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1N

Procedure:
12.0 parts by weight of methyl 5-amino-1-(2,4,6-trichlorophenyl)-pyrazole-4-carboxylate, 24.0 parts by weight of 3-methylbut-2-enol and 0.5 parts by weight of sodium methylate were refluxed for 2 hours (complete conversion), while dry nitrogen was passed over. The excess alcohol was removed under a reduced pressure of from 0.5 to 1.0 mbar/50° C., and the residue was dissolved in 100 ml of ether and precipitated with dry hydrogen chloride gas. The hydrochloride was filtered off with suction and stirred with saturated sodium bicarbonate solution, and the precipitate was filtered off with suction and dried under reduced pressure at 50° C. to give 10.6 g of 3-methylbut-2-enyl 5-amino-1-(2,4,6-trichlorophenyl)-pyrazole-4-carboxylate of melting point 102°-105° C. (active ingredient No.10).
Reaction SMILES: Cl[CH:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]([OH:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>C1C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:25]([CH:24]([O:32][CH:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCOC(=O)C(Cl)Sc1ccccc1
Reactant: CCCCCCC=CCC(O)CCCCCCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCC=CCC(CCCCCCC)OC(Sc1ccccc1)C(=O)OCC

Procedure:
Part B. The method of Speckamp et al., Tetrahedron Letters, v. 32, p. 1491 (1991), is employed here. Thus, a solution of ethyl 2-chloro-2-(phenylthio)acetate [prepared according to the method of Bohme et al., Liebigs Annalen der Chemie, p. 51 (1977)], 7-heptadecen-10-ol, andcatalytic zinc acetate dihydrate in benzene is heated to reflux under a Dean-Stark trap until the formation of hydrogen chloride is complete. Workup according to the listed reference affords ethyl 2-(1-heptyl-3-decen-1-oxy)-2-(phenylthio)acetate.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N+](=[C:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]1=[O:19])=[N-]>FC1C(F)=C(F)C(F)=C(F)C=1F.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[O:18][C:17]2[CH2:16][CH2:15][CH2:14][C:13](=[O:19])[C:12]=2[N:5]=1
Reactant: N#Cc1ccccc1F
Reactant: [N-]=[N+]=C1C(=O)CCCC1=O
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: Fc1c(F)c(F)c(F)c(F)c1F
Product: O=C1CCCc2oc(-c3ccccc3F)nc21
Temperature: 60 °C

Procedure:
A mixture of rhodium acetate (32 mg, 72 μmol) and 2-fluorobenzonitrile (2.31 ml; 22 mmol) in perfluorobenzene (5 ml) is treated at 60° C. dropwise by a solution of diazocyclohexanedione (obtained in Stage 66.1; 1 g; 7.24 mmol) in 5 ml of perfluorobenzene. The reaction medium is maintained at 60° C. until exhaustion of the release of nitrogen (1 hour; TLC on SiO2: 2% MeOH/CH2Cl2). After cooling down to ambient temperature and filtration, the solvent of the filtrate is evaporated. The residue is purified by chromatography (SiO2: AcOEt/heptane: 1/1) in order to produce a light yellow powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([NH:18][C:19]([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[O:20])=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=1[N:44]=[C:45]=[O:46]>O1CCCC1>[S:23]1[CH:24]=[CH:25][C:21]([C:19]([NH:18][C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:6]4[CH:5]=[CH:4][C:3]([NH:2][C:45]([NH:44][C:35]5[CH:36]=[C:37]([C:40]([F:41])([F:43])[F:42])[CH:38]=[CH:39][C:34]=5[F:33])=[O:46])=[CH:8][CH:7]=4)=[CH:10][CH:11]=3)[NH:15][N:14]=2)=[O:20])=[CH:22]1
Reactant: Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3c2)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3c2)cc1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 24 °C
Reaction time: 3.5 h

Procedure:
A solution of 1.72 g of 6-(4-aminophenyl)-3-[(thiophen-3-yl)carbonylamino]-1H-indazole hydrochloride and 0.65 mL of triethylamine in 70 mL of tetrahydrofuran is admixed slowly under an argon atmosphere with 0.67 mL of 2-fluoro-5-trifluoromethylphenyl isocyanate. The reaction mixture is stirred at 24° C. for 3.5 hours and then concentrated under reduced pressure. The residue is purified by flash chromatography on a silica column (60; 35-70 μM), eluting with a dichloromethane/methanol (97/3 by volume) mixture, to give 0.4 g of 1-(4-{3-[(thiophen-3-yl)carbonylamino]-1H-indazol-6-yl}phenyl)-3-(2-fluoro-5-trifluoromethylphenyl)urea, whose characteristics are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11](Cl)=[O:12].[NH2:14][CH:15]([CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([O:25][CH3:26])[CH2:21][CH2:20]1)[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:16]([CH:15]([NH:14][C:11](=[O:12])[CH2:10][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH3:9])[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([O:25][CH3:26])[CH2:21][CH2:20]1)#[N:17]
Reactant: CON1CCC(CC(N)C#N)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CON1CCC(CC(C#N)NC(=O)Cc2c(C)cc(C)cc2C)CC1
Reaction time: 0.5 h

Procedure:
At room temperature, (2,4,6-trimethyl-phenyl)-acetyl chloride (10.6 g, 54 mmol) was added dropwise to a mixture of 2-amino-3-(1-methoxy-piperidin-4-yl)-propionitrile (6.6 g, 36 mmol) and K2CO3 (9.9 g, 72 mmol) in 100 ml of THF. After the addition, the mixture was stirred for 0.5 h. The reaction mixture was diluted with 50 ml of water and extracted with EtOAc five times. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel Yield: 10.6 g of N-[1-cyano-2-(1-methoxy-piperidin-4-yl)-ethyl]-2-(2,4,6-trimethyl-phenyl)-acetamide as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14](OC([O-])=O)(=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([O:15][C:14]([N:12]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][C:11]1=[O:13])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C1CCC(c2ccc(F)cc2)N1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)CCC1c1ccc(F)cc1
Yield: 61.9 %

Procedure:
22.6 g (0.126 mol) of 5-(4-fluorophenyl)-pyrrolidin-2-one in 200 ml of toluene are boiled at reflux with 55 g (0.25 mol) of tert-butyl pyrocarbonate for 5 hours. After cooling the mixture, is washed repeatedly with water and the organic phase, is dried and concentrated under reduced pressure using a rotary evaporator. The residue is stirred with petroleum ether and the crystals are filtered off with suction. This gives 21.8 g (62% yield of theory) of 1-(tert-butyloxycarbonyl)-5-(4-fluorophenyl)-pyrrolidin-2-one of m.p. 117°.