Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]([CH3:7])[C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].C([Li])CCC.[Fe:15].[Fe].O1CCCC1>CCCCCC.O1CCCC1>[CH3:9][C:3]1[CH-:4][C:5]([CH3:8])=[C:6]([CH3:7])[C:2]=1[CH3:1].[CH-:4]1[C:5]([CH3:8])=[C:6]([CH3:7])[C:2]([CH3:1])=[C:3]1[CH3:9].[Fe+2:15]
Reactant: CC1=CC(C)=C(C)C1C
Reactant: [Fe]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1[cH-]c(C)c(C)c1C
Product: [Fe+2]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
25.00 g (204.6 mmol) of 1,2,4,5-tetramethyl-cyclopenta-1,3-diene was charged into a reaction vessel and dissolved in approximately 200 ml of hexane while under positive nitrogen pressure. The solution was cooled with an ice bath to approximately 0 degrees centigrade, whereupon 84 ml (210 mmol) of 2.5M n-butyllithium was charged into the reaction vessel via syringe. Next, the reaction mixture was allowed to warm to room temperature while being agitated overnight. In a separate vessel, 1.95 g (35 mmol) of Fe in approximately 100 ml of tetrahydrofuran (THF) was purged with nitrogen and then cooled to 0 degrees centigrade. 11.56 g (70 mmol) of FeCl3 was charged into the Fe/THF mixture in 3 equal portions, whereupon the mixture was heated to reflux for approximately 2 hours under a nitrogen atmosphere. The FeCl2-2THF was then cooled to room temperature, and transferred to the LiMe4Cp suspension via cannula. The complete mixture was heated to reflux for 2 hours. After cooling, the reaction was quenched by the addition of approximately 300 ml of water and a small amount of zinc powder. The reaction mixture was charged into a separatory funnel, whereby the organic layer was isolated and collected. The aqueous layer was extracted with Et2O. Next, the organic layers were combined, washed with a saturated brine solution, dried over MgSO4, and filtered. The solvents were then removed by rotary evaporation to give an orange solid which was washed with MeOH and collected on a vacuum frit. Additional product was recovered by reducing the volume of the MeOH solution and cooling in a freezer overnight. The total yield was approximately 22 g of octamethylferrocene.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.Cl.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1.[OH-].[Na+]>>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:10]([NH2:11])=[C:9]([N:8]=[N:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]([NH2:13])=[N:35]2)=[CH:30][CH:29]=1
Reactant: NNc1ccc(Br)cc1
Reactant: N#CC(C#N)=NNc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Nc1ccccc1
Solvent: N#CCC#N
Product: Nc1nn(-c2ccc(Br)cc2)c(N)c1N=Nc1ccccc1
Temperature: 25 °C

Procedure:
1-(4-bromophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and 4-bromophenylhydrazine hydrochloride (112 mg, 0.5 mmol) with the addition of 0.5 mL of 5% sodium hydroxide solution. Solids had not formed after heating the reaction at 75° C. for 3 hrs, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in methanol and then precipitated by the addition of water. The resulting solid was isolated by filtration and dried to yield 49 mg (27%) of the compound as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26])[CH3:37]
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Reactant: CCOC(=O)CCCCCBr
Product: CCOC(=O)CCCCCOc1cccc(C#CCCCCOC2CCCCO2)c1/C=C/C(=O)OC
Yield: 93.3 %

Procedure:
Using the procedure of example 122, rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester (example 121), was alkylated with ethyl 6-bromohexanoate giving the title compound as a pale-yellow oil, in 93.3% yield.
Reaction SMILES: C(N)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[BH3-]C#N.[Na+].[C:23]([Si:27]([CH3:80])([CH3:79])[O:28][C@@H:29]1[C@@:33]([CH:53]([NH:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[NH:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([CH2:34][O:35][Si:36]([C:49]([CH3:52])([CH3:51])[CH3:50])([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:32][C@@H:31]([N:70]2[CH:78]=[C:76](C)[C:74](=[O:75])[NH:73][C:71]2=[O:72])[CH2:30]1)([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[C:23]([Si:27]([CH3:80])([CH3:79])[O:28][C@@H:29]1[C@@:33]([CH:53]([NH:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[NH:62][CH2:63][C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)([CH2:34][O:35][Si:36]([C:49]([CH3:52])([CH3:51])[CH3:50])([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:32][C@@H:31]([N:70]2[CH:78]=[CH:76][C:74](=[O:75])[NH:73][C:71]2=[O:72])[CH2:30]1)([CH3:24])([CH3:25])[CH3:26]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)(C(NCc3ccccc3)NCc3ccccc3)O2)c(=O)[nH]c1=O
Agent: NC(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@]1(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(NCc1ccccc1)NCc1ccccc1

Procedure:
3′-O-[(tertbutyl)dimethylsilyl]-5′-O-[(tertbutyl)diphenylsilyl]-4′-C-formyl-2-deoxyuridine (10) (Yang et al; Tetrahedron Letters 1992, 33, 37–40.) (0.15 g, 0.25 mmol) was treated with Ph2CHNH2 (0.07 g, 0.37 mmol, 0.064 mL), glacial acetic acid (0.015 g, 0.26 mmol, 0.015 mL) and NaBH3CN (0.023 g, 0.37 mmol) in acetonitrile (1 mL) according to the procedure used for the preparation of compound (2). The title compound (11) was obtained as clear, viscous oil (0.13 g, 69%). δH(300 MHz, CDCl3) 8.02(1H, s, br, N3—H), 7.81(1H, d, H-6), 7.69–7.18(20H, m, Ph2CHNH, tBuSiPh2), 6.32(1H, dd, H-1′), 5.30(1H, d, H-5), 4.67(1H, s, Ph2CHNH), 4.61(1H, dd, H-3′), 4.02(1H, d, H-5′), 3.87(1H, d, H-5′), 2.69(1H, d, 4′-C—CH2), 2.53(1H, d, 4′-C—CH2), 2.37(1H, m, H-2′), 2.17(1H, m, H-2′), 1.10(9H, s, tBuSiPh2), 0.75(9H, s, tBuSiMe2), 0.01(6H, s, tBuSiMe2); ES +ve m/z 776(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C@H:9]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([N:29]2[CH2:58][CH2:57][C:32]3([CH2:36][C@@H:35]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[N:34]([C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:48])[CH2:33]3)[CH2:31][CH2:30]2)[N:3]=1.[CH3:59][C:60](O)([C:65]([F:68])([F:67])[F:66])[C:61]([F:64])([F:63])[F:62].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[N:3]=[C:4]([N:29]2[CH2:58][CH2:57][C:32]3([CH2:36][C@@H:35]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:38])[N:34]([C:47]([O:49][CH2:50][C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)=[O:48])[CH2:33]3)[CH2:31][CH2:30]2)[CH:5]=[C:6]([O:8][C@H:9]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([O:20][C:60]([CH3:59])([C:65]([F:68])([F:67])[F:66])[C:61]([F:64])([F:63])[F:62])=[O:19])=[CH:16][C:15]=2[N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)[C:10]([F:12])([F:11])[F:13])[N:7]=1
Reactant: CC(O)(C(F)(F)F)C(F)(F)F
Reactant: Cc1ccn(-c2cc(C(=O)O)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCc3ccccc3)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccn(-c2cc(C(=O)OC(C)(C(F)(F)F)C(F)(F)F)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCc3ccccc3)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[(1R)-1-[2-amino-6-[(2S)-2,3-bis(benzyloxycarbonyl)-3,8-diazaspiro[4.5]decan-8-yl]pyrimidin-4-yl]oxy-2,2,2-trifluoro-ethyl]-3-(3-methylpyrazol-1-yl)benzoic acid (80 mg, 0.1 mmol) in CH2Cl2 (4 mL) was added DMAP (73 mg, 0.6 mmol), (CF3)2MeCOH (108 mg, 0.6 mmol), followed by EDCI (114 mg, 0.6 mmol). The reaction mixture was stirred at RT for 12 h, diluted with CH2Cl2 and washed with water. The aqueous solution was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided dibenzyl (2S)-8-[2-amino-6-[(1R)-2,2,2-trifluoro-1-[2-(3-methylpyrazol-1-yl)-4-[2,2,2-trifluoro-1-methyl-1-(trifluoromethyl)ethoxy]carbonyl-phenyl]ethoxy]pyrimidin-4-yl]-3,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[F:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][NH:23][C:22](=[O:25])[C:21]=2[CH:26]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][N:23]=[C:22]([O:25][C@@H:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:1])([CH3:15])[C@H:3]3[OH:14])[C:21]=2[CH:26]=1
Reactant: O=c1[nH]oc2ccc(F)cc12
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Oc2noc3ccc(F)cc23)[C@@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-fluoro-benzo[d]isoxazol-3-one as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(Cl)Cl>O>[Cl:15][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:3][CH:4]=[CH:5][N:6]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: C1CNCCN1
Reactant: Clc1ccc(-c2nccnc2Cl)cc1Cl
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(-c2nccnc2N2CCNCC2)cc1Cl
Temperature: 25 °C

Procedure:
Combine 2-chloro-3-(3,4-dichloro-phenyl)-pyrazine (0.124 g, 0.477 mmol) and piperazine (1.40 gm; 16.3 mmol) and heat the mixture for 2 hr. at 120° C. Cool to room temperature, and add DCM (50 mL) and water (50 mL). Separate the layers and extract the aqueous layer with DCM (2×25 mL). Combine the organic layers, wash with brine, dry (MgSO4) and concentrate. Purify via chromatography on silica gel eluting 0-15% methanol in DCM to give the title preparation (0.118 gm, 80%). MS (ES+) m/z: 310 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=[O:29])[CH:23]=1>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:28]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[OH:29])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(O)c2cccnc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 35 %

Procedure:
Dissolve 4-(tert-butyldimethylsilyloxymethyl)bromobenzene (1 g, 3.319 mmol, prepared by following the procedure described in J. Am. Chem. Soc. 1995, 117, 704-714) in anhydrous THF (20 mL). Cool the solution to −78° C., add n-BuLi (4.149 mL, 6.638 mmol, 1.6M solution in hexane) and stir at this temperature for 1.5 h. Warm to −60° C., stir for an additional 30 min and add 3-pyridine carboxaldehyde. Allow the reaction mixture to warm gradually to room temperature and stir overnight. Add brine and extract with EtOAc. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and EtOAc to give the desired intermediate (380 mg, 35%). MS (ES+) m/z: 330 (M+H)*.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][C:7]=2[N:15]2[C:18]3([CH2:21][O:20][CH2:19]3)[CH2:17][CH2:16]2)[CH2:3][CH2:2]1.C1(N(C2N=C(C)ON=2)C)CC1.[CH:33]1([CH2:36][C@H:37]([NH2:44])[C:38]2[N:42]=[C:41]([CH3:43])[O:40][N:39]=2)[CH2:35]C1>>[CH:36]1([CH:37]([NH:44][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[C:18]4([CH2:19][O:20][CH2:21]4)[CH2:17][CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[N:11]=2)=[O:13])[C:38]2[N:42]=[C:41]([CH3:43])[O:40][N:39]=2)[CH2:33][CH2:35]1
Reactant: O=C(O)c1ccc(N2CCC23COC3)c(OCC2CC2)n1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Agent: Cc1nc(N(C)C2CC2)no1
Product: Cc1nc(C(NC(=O)c2ccc(N3CCC34COC4)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(cyclopropylmethoxy)-5-(6-oxa-1-azaspiro[3.3]heptan-1-yl)picolinic acid (Example 234 b) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can e.g. be prepared in a similar manner than (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e) as starting materials. MS (EI): m/e=426.0 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:47])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[C:34]1=[O:46])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])=[O:7].[CH:48](=O)[C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:47])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[C:34]1=[O:46])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)[NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])=[O:7]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NNC[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H]([C@@H](C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(OC)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H]([C@@H](C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Yield: 58.3 %

Procedure:
A solution of Example 283A (50 mg, 0.45 mmol) in 1,2-dichloroethane (1 mL) and treated with p-anisaldehyde (16 mg, 1.5 equivalents), acetic acid (5 μL, 2 equivalents), and sodium triacetoxy borohydride (32 mg, 2 equivalents) at 25° C. for 16 hrs. The mixture was quenched with 10% NaHCO3 (2 mL) and CHCl3. The organic layer was separated, dried over sodium sulfate, filtered and the solvents were evaporated. The residue was purified using 5% methanol/CHCl3 to give 53 mg (90%) of the title compound.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][N:14]([CH3:18])[CH2:15]CO>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH2:13][N:14]([CH3:18])[CH3:15])=[O:8])=[CH:11][CH:12]=1
Reactant: CN(C)CCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Na]
Product: CN(C)CCOC(=O)c1ccc(O)cc1
Temperature: 110 °C

Procedure:
In a first step, 1 g (43 mmol) of sodium was dissolved in 20 ml of 2-(dimethylamino)ethanol. An amount of 3.0 g (22 mmol) of methyl 4-hydroxybenzoate was added and heated to 110° C. for 24 hours and then cooled to room temperature. The solvent was removed under reduced pressure and using a column chromatography (silica gel, chloroform-methanol), a white solid of 2-(dimethylamino)-ethyl 4-hydroxybenzoate was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@H:13]2[CH2:25][CH:26]=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:30][N:31]([CH3:33])[NH2:32].C(OCC)(=O)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:19])[CH3:20])[CH2:14][C@H:13]2[CH2:25][CH2:26][NH:32][N:31]([CH3:33])[CH3:30])=[O:11])=[CH:28][CH:29]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CC=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CN(C)N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)NCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-formylmethyl-4-t-butyldimethylsilyloxypyrrolidine (423 mg) was dissolved in 2 ml of ethanol, and 65 mg of N,N-dimethylhydrazine was added thereto, followed by stirring at room temperature for 15 minutes. To the reaction mixture was added ethyl acetate, and the mixture was washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel thin layer chromatography to obtain (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-dimethylhydrazinoethyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [C:1](=[O:4])([O-])[OH:2].[K+:5].[C:6]([O:22][C:23]([C:26]([C:29]([O:32][C:33](C(F)=O)([C:35]([F:38])([F:37])[F:36])[F:34])([F:31])[F:30])([F:28])[F:27])([F:25])[F:24])([C:15]([S:18]([F:21])(=[O:20])=[O:19])([F:17])[F:16])([C:8]([S:11]([F:14])(=[O:13])=[O:12])([F:10])[F:9])[F:7]>C(COC)OC>[C:6]([O:22][C:23]([C:26]([C:29]([O:32][C:33]([C:1]([O:2][K:5])=[O:4])([C:35]([F:38])([F:37])[F:36])[F:34])([F:31])[F:30])([F:28])[F:27])([F:25])[F:24])([C:15]([S:18]([F:21])(=[O:20])=[O:19])([F:17])[F:16])([C:8]([S:11]([F:14])(=[O:13])=[O:12])([F:10])[F:9])[F:7]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)OC(F)(C(F)(F)S(=O)(=O)F)C(F)(F)S(=O)(=O)F)C(F)(F)F
Reactant: [K+]
Reactant: O=C([O-])O
Solvent: COCCOC
Product: O=C(O[K])C(F)(OC(F)(F)C(F)(F)C(F)(F)OC(F)(C(F)(F)S(=O)(=O)F)C(F)(F)S(=O)(=O)F)C(F)(F)F
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Potassium hydrogen carbonate (6.03 g) was charged into a flask together with monoglyme (59 mL), and (FSO2CF2)2CFOCF2CF2CF2OCF(CF3)COF (35.6 g) obtained in Example 3 was added dropwise thereto with stirring under cooling with ice. Vacuum drying was carried out for 30 minutes and then vacuum drying was further carried out at 120° C. for 48 hours to obtain (FSO2CF2)2CFOCF2CF2CF2OCF(CF3)COOK (21.1 g). The obtained (FSO2CF2)2CFOCF2CF2CF2OCF(CF3)COOK was heated at 200° C. under 400 Pa (absolute pressure), and generated gas was collected in a trap cooled with liquid nitrogen to obtain a liquid (8.35 g). The liquid was analyzed by NMR and GC and as a result, formation of the title compound (NMR yield: 25%, GC purity: 87%) was confirmed. Further, as another component, formation of (FSO2CF2)2CFOCF2CF2CF2OCFHCF3 was confirmed.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[NH2:13])=[CH:5][CH:4]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].CN1CCOCC1>C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[NH:13][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1nccc2ccc(C(F)(F)F)cc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Nc1nccc2ccc(C(F)(F)F)cc12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 7-(trifluoromethyl)isoquinolin-1-amine (410 mg, 1.9 mmol), from above step E, and benzyl chloroformate (0.33 mL, 2.3 mmol) in DCM was treated with N-methylmorpholine (0.23 mL, 2.1 mmol) and stirred at room temperature for 18 h. Reaction mixture was diluted with DCM and washed with water and dried over Na2SO4. DCM was removed under vacuum and the residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:20]=[CH:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1>O1CCCC1>[CH3:12][C:10]([CH3:11])([CH3:13])[C:9]([NH:8][C:6]1[N:7]=[C:2]([F:1])[C:3]([CH:21]([OH:20])[CH2:22][CH2:23][CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:28][CH2:29]2)=[CH:4][CH:5]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC=O)CC1
Reactant: CC(C)(C)C(=O)Nc1cccc(F)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCC(O)c2ccc(NC(=O)C(C)(C)C)nc2F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To a solution of N-(6-fluoro-2-pyridinyl)-2,2-dimethylpropanamide (Turner, James A., J. Org. Chem., 1983, 48, 3401–3408, 1.15 g, 5.87 mmol) in tetrahydrofuran (15 ml) was added dropwise a solution of n-butyllitium (8.1 ml, 12.9 mmol) at −78° C. over 10 min., and the mixture was stirred at 0° C. for 1 h. After cooling to −78° C., a solution of 1,1-dimethylethyl 4-(3-oxopropyl)-1-piperidinecarboxylate (Keenan, Richard M. et. al, J. Med. Chem., 1999, 42, 545–559, 1.70 g, 7.04 mmol) in tetrahydrofuran (5 ml) was added to the mixture. After stirring for 0.5 h, the mixture was allowed to warm up to room temperature and stirred for further 2 h. The mixture was quenched with water (20 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml) and dried over magnesium sulfate. Removal of solvent gave brown oily residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (2:1) to afford 0.86 g (34%) of the title compound as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1]N(C)C=O.[CH3:6][O:7][C:8]1[CH:22]=[CH:21][C:11]([CH2:12][S:13][CH2:14][CH2:15][C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)=[CH:10][CH:9]=1.[H-].[Na+].CI>O>[CH3:1][N:20]1[CH:19]=[CH:18][N:17]=[C:16]1[CH2:15][CH2:14][S:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:22][CH:21]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(CSCCc2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1ccc(CSCCc2nccn2C)cc1
Reaction time: 0.17 h

Procedure:
To a dimethylformamide (15 ml) solution of 2-[2-(p-methoxybenzylthio)ethyl]imidazole (1.5 g) was added 60% sodium hydride (0.29 g) in mineral oil at 0° C. To the mixture was added, 15 minutes later, methyl iodide (0.41 ml) at -20° C., followed by stirring for 10 minutes. The reaction mixture was poured into water (60 ml), which was subjected to extraction with methylene chloride (20 ml×three times). The organic layer was washed with water (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to a silica gel chromatography (3 cm×15 cm), eluting with methanol-methylene chloride (5:95). The desired fraction was concentrated under reduced pressure to afford 1-methyl-2-[2-(p-methoxybenzylthio)ethyl]imidazole (1.6 g) as a colorless oily product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[S:6][CH:7]=1.[H-].[Na+].[CH3:15]I.O>O1CCCC1>[CH3:15][O:1][CH2:2][C:3]1[C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[S:6][CH:7]=1
Reactant: Cc1cccc2c(CO)csc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1csc2c(C)cccc12
Temperature: 50 °C

Procedure:
400 mg of 3-hydroxymethyl-7-methyl-benzo[b]thiophene are dissolved in tetrahydrofuran, mixed with 82 mg of NaH (80%) and after addition of 48 mg of methyl iodide heated for half an hour at 50° C. The reaction mixture is mixed with water, repeatedly extracted and the organic phase washed, dried and concentrated on a rotary evaporator. The residue is chromatographed over silica-gel (eluant: toluene/glacial acetic acid=95:5) to yield the title compound as an oil.