Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[O-].[Na+].O=[C:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:14]([O:16]CC)=O.[NH2:19][C:20]([NH2:22])=[S:21].Cl>CCO>[SH:21][C:20]1[N:19]=[C:14]([OH:16])[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:6]=2[N:22]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C1CCCCCCC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(S)nc2c1CCCCCC2
Yield: 63.2 %

Procedure:
700 mg of NaOEt (10 mmol; 1.0 equiv) was added to 6 mL of abs. EtOH. To this solution was added, with stirring, 2 g of ethyl 2-keto-cyclooctylcarboxylate (10 mmol; 1.0 equiv) and 1 g of thiourea (13 mmol; 1.3 equiv). The mixture was refluxed for 6 hours. After cooling, the mixture was poured onto ice and acidified with hydrochloric acid. 1.33 g of 2-mercapto-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine-4-ol (63% yield) was obtained as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:15])[N:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[Br:14])=[O:4].[OH-].[Na+]>C(O)C>[Br:14][C:9]1[C:8]2[C:13](=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:15])[N:7]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1c2cccc(Br)c2nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc2c(Br)cccc2c1C(=O)O
Temperature: 55 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A mixture of 7-bromo-2-methyl-2H-indazole-3-carboxylic acid methyl ester (35a; 0.215 g, 0.799 mmol), 8 mL of a 2 M aqueous NaOH solution, and 6 mL of ethanol was stirred at 55° C. overnight, then concentrated to remove ethanol. The remaining aqueous layer was acidified with a 10% aqueous HCl solution and extracted with three 20 mL portions of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford crude 7-bromo-2-methyl-2H-indazole-3-carboxylic acid (35e; 0.193 g; 94%) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Cl)Cl.C[Si](C=[N+]=[N-])(C)C.CCOCC>CO>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-(t-butoxycarbonyl)azetidine-3-carboxylic acid (2.03 g, 10.09 mmol) was dissolved in MeOH (10 ml) and DCM (10 mL) and then cooled to 0° C. A 2M solution of trimethylsilyldiazomethane in ether (7.57 ml, 15.1 mmol) was then added drop-wise over 5 minutes. The solution was stirred for 10 minutes at 0° C. and then warmed to room temperature over 30 minutes. The solution was concentrated under reduced pressure to remove volatiles to afford crude 119, which was used directly in the next step without further purification. 1H NMR: 1.44 (s, 9H), 3.35 (m, 1H), 3.75 (s, 3H), 4.10 (d, 4H, J=7.6 Hz).
Reaction SMILES: [Na].[CH2:2]([C:9]#[N:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11][C:12]([CH3:16])=[CH:13][CH:14]=O>CO>[CH3:11][C:12]([CH3:16])=[CH:13][CH:14]=[C:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]#[N:10]
Reactant: N#CCc1ccccc1
Reactant: CC(C)=CC=O
Agent: [Na]
Solvent: CO
Product: CC(C)=CC=C(C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
Sodium (9.2 g, 0.4 mol) is dissolved in methanol (130 ml) and benzylcyanide (46.8 g, 0.40 mol) is added, followed by the careful addition of a solution of 3-methyl-2-butenal (40.3 g, 0.48) in methanol (100 ml). The resulting suspension is stirred for 20 h at room temperature and then worked up following the procedure described in Example 2. The crude product is crystallized twice from hexane to yield 5-methyl-2-phenyl-hexa-2,4-diene nitrile (44.9 g, 61%), m.p. 66-67° C.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[C:7]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[F:3][C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[C:7]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([NH:27][C:34]([CH:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[O:35])[CH2:25][CH2:26]3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3ccc(F)c4occc34)CC2)CC1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3ccc(F)c4occc34)CC2)CC1)C1CCOCC1

Procedure:
The title compound, off-white solid (87 mg, 76%), MS (ISP) m/z=457.4 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(7-fluoro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate C) (104 mg, 0.25 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:27]OS(C)(=O)=O)[C:13](=[O:26])[N:14]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[C:42]([O:41][C:39]([N:33]1[CH2:38][CH2:37][N:36]([CH2:27][C:12]2[C:13](=[O:26])[N:14]([CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[N:15]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[CH:11]=2)[CH2:35][CH2:34]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 72.6 %

Procedure:
Following the procedure of Example 1(10), 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 72.6%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:13]C)=O)[CH:8]=2)[NH:3]1.O.[NH2:16][NH2:17]>CCO>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([NH:16][NH2:17])=[O:13])[CH:8]=2)[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 80 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
To a solution of methyl 2-oxoindoline-5-carboxylate (0.40 g, 4.8 mmol) in EtOH (8 ml) was added hydrazine monohydrate (2 ml), and the mixture was stirred for 6 h at 80° C. The mixture was cooled to room temperature, and the resulting precipitate was filtered and dried to afford 2-oxoindoline-5-carbohydrazide (0.25 g, 63%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:31]5[NH:35][C:34](=[O:36])[O:33][N:32]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]4[N:40]=[C:41]([CH3:43])[N:42]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl>O1CCCC1>[CH3:43][C:41]1[N:42]=[C:12]2[N:11]([CH:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][C:34](=[O:36])[O:33][N:32]=4)=[CH:23][CH:24]=3)=[C:14]([CH2:37][CH2:38][CH3:39])[N:13]2[N:40]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2nc(C)nn12
Temperature: 70 °C
Reaction time: 22 h
Yield: 44.1 %

Procedure:
A mixture of 4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.76 g), 6M hydrochloric acid (3 mL) and tetrahydrofuran (4 mL) was stirred at 70° C. for 22 hr. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized (ethyl acetate) to give the title compound as a colorless solid (0.31 g, 44%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:10](#[N:12])[CH3:11].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[NH2:12][C:10](=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH3:11]
Reactant: COC(=O)CC(=O)OC
Reactant: CC#N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)C(C(=O)OC)=C(C)N

Procedure:
To a stirred solution containing 4.36 mL (38.0 mmol) of dimethyl malonate and 2.00 mL (38.0 mmol) of acetonitrile in 20 mL of 1,2-dichloroethane were added 8.90 mL (76.0 mmol) of SnCl4. The reaction mixture was stirred at reflux for 2 h. The reaction mixture was then concentrated under diminished pressure and the residue was dissolved into 100 mL of acetone. Then, 70 mL of satd. aq. sodium carbonate were added and the mixture was stirred for 20 minutes. The mixture was poured into 200 mL of satd. aq. sodium bicarbonate and extracted with two 200-mL portions of DCM. The combined organic solution was washed with a 200-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was recrystallized in ethyl acetate/hexanes to afford the expected product as colorless crystals: yield 3.96 g (60%); mp: 81-82° C.; silica gel TLC Rf 0.5 (1:1 ethyl acetate-hexanes); 1H NMR (CDCl3) δ 2.10 (s, 3H), 3.66 (s, 3H), 3.69 (s, 3H), 5.29 (br s, 1H) and 8.94 (br s, 1H); 13C NMR (CDCl3) δ 22.0, 51.0, 51.6, 92.4, 164.0, 168.7 and 168.9; mass spectrum (APCI), m/z 174.0760 (M+H)+ (C7H12NO4 requires 174.0766).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=1>>[CH3:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[CH2:38][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: Cc1cccc(CBr)c1
Product: Cc1cccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-3-methylbenzene following the procedure of Example 478: MS (ESI) m/z 498.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.C[N+]1[CH:14]=[CH:13][N:12]([S:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])C=1.[C@H:24]1([NH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=C(N)C=3)[N:35]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>C(#N)C>[C@H:24]1([NH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:13]([NH:12][S:15]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)(=[O:16])=[O:17])[CH:14]=3)[N:35]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: C[n+]1ccn(S(=O)(=O)N2CCOCC2)c1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: O=S(=O)(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCOCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 45.8 %

Procedure:
1-Methyl-3-(morpholine-4-sulfonyl)-3H-imidazol-1-ium trifluoromethanesulfonate (0.139 g, 0.36 mmol) and (R)—N2-indan-1-yl-quinoline-2,6-diamine (0.10 g, 0.36 mmol) were dissolved in acetonitrile (2 mL) and stirred for 16 h at 80° C. The solvent was removed and the residue subjected to column chromatography (silica gel, heptane, ethyl acetate 4:1/1:1) to yield morpholine-4-sulfonic acid [2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide (0.07 g, 45%) as a yellow solid; MS: m/e=425.7 (M+H+).
Reaction SMILES: C(O[C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:22]([O:24][C:25](=[O:37])[CH:26](C(OCC)=O)[C:27](OCC)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:6](=[O:21])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:27]=1[OH:28])=[O:37])[CH3:23]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)n1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(F)cc2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (4-fluoro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (2.0 eq.). ESI (m/z): 331 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH:8]([C:15]([NH2:17])=O)[C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>>[C:1]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH:8]([C:15](=[S:19])[NH2:17])[C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)(C)c1ccc2c(n1)C(C(N)=O)CCC2
Product: CC(C)(C)c1ccc2c(n1)C(C(N)=S)CCC2

Procedure:
The title compound was prepared from 2-t-butyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (4 g.) and P2S5 (3 g.) as described in Example 8 and was isolated as creamy needles after recrystallisation from n-hexane m.p. 126° C (650 mgs.). Found: C, 68.18; H, 8.25; N, 11.14%. C14H20N2S requires C,67.70; H, 8.12; N, 11.23%.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:25]4[CH:26]=[C:27]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:28]=[CH:29][CH:24]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(3,4-dichloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.8) (82 mg, 0.25 mmol) and 4-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (37 mg, 30%). MS (ISP) 483.5 [(M+H)+]; mp 200–202° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Fe]>[F:16][C:12]([F:17])([CH:13]([F:14])[F:15])[CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)C(F)F)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 55 °C
Yield: 56 %

Procedure:
Iron powder (1.3 g, 23.2 mol) was added to a solution of 1-nitro-4-(2,2,3,3-tetrafluoro-propoxy)-benzene (600 mg, 2.4 mmol) in acetic acid (4 ml) and heated at 50-60° C. for 1 hr. The reaction mixture was filtered hot over celite and washed with ethyl acetate. The filtrate was washed with water, 5% sodium hydroxide solution, brine and then dried over anhydrous sodium sulfate. The filtrate was evaporated to dryness to yield 4-(2,2,3,3-tetrafluoro-propoxy)-phenylamine (300 mg, 56.7%) as solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=O)(C)(C)C.[CH3:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[NH2:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([CH3:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:23][CH2:24]1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 4-methyl-3-nitrobenzaldehyde (0.25 mmol), methanol (1.2 mL), and acetic acid (0.050 mL) was added NaBH3CN (0.50 mmol) in methanol (1.0 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. The resulting material was dissolved into ethyl acetate/methanol=2/1 (2 mL), loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol=2/1 (6 mL), and concentrated. The residue was dissolved in methanol (1 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, washed with CH3OH (5 mL×2), and eluted off using 2 N NH3 in CH3OH (5 mL). Concentration afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-methyl-3-nitrobenzyl)piperidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([N:15]3[CH:20]4[CH2:21][CH2:22][CH:16]3[CH2:17][CH:18]([OH:23])[CH2:19]4)=[O:14])=[CH:12][C:7]=2[N:6]=[CH:5]1.CCN(C(C)C)C(C)C.[O:33]=[S:34]1(=[O:43])[CH2:39][CH2:38][N:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]1>C1COCC1>[OH:23][CH:18]1[CH2:19][CH:20]2[N:15]([C:13]([C:11]3[CH:10]=[CH:9][C:8]4[N:4]([CH2:3][CH2:2][NH:1][C:40]([N:37]5[CH2:38][CH2:39][S:34](=[O:43])(=[O:33])[CH2:35][CH2:36]5)=[O:41])[CH:5]=[N:6][C:7]=4[CH:12]=3)=[O:14])[CH:16]([CH2:22][CH2:21]2)[CH2:17]1
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Reactant: NCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.3 %

Procedure:
To a solution of [1-(2-aminoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-methanone (0.2 g, 0.636 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0° C. To this reaction mixture was added 1,1-dioxo-thiomorpholine-4-carbonyl chloride slowly and stirred for 2 h at ambient temperature. The solvents were evaporated and the residue purified by preparative HPLC to afford 1,1-dioxo-thiomorpholine-4-carboxylic acid {2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide (0.007 g, 2.3%). MS-ESI m/z 476 (M+1); 1H-NMR (300 MHz, CD3OD) δ 1.5 (t, 1H), 1.8 (m, 4H), 2.1 (brs, 3H), 2.8 (s, 4H), 3.6 (t, 2H), 3.8 (s, 4H), 4.2 (m, 2H), 4.5 (t, 2H), 4.7 (s, 1H), 7.5 (d, 1H), 7.7 (d, 1H), 7.85 (s, 1H), 8.3 (s, 1H). HPLC (VERYPOL.M): tr=6.24 min (97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2Br)CC1
Temperature: 80 °C
Yield: 62.2 %

Procedure:
To a stirred solution of 2-bromophenol (0.5 g, 0.00289 mole) in DMF (4 mL) was added potassium carbonate (0.478 g, 0.003468 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (0.888 g, 0.00318 mole). The reaction mixture was heated at 80° C. for 6 hours. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (2% ethyl acetate in hexane) to afford 0.64 g (68%) of 4-(2-bromo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 356.08 (M+1)+, 99.56%. A solution of 4-(2-bromo-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.64 g, 0.0018 mole) in dichloromethane (6.4 mL) was stirred at 0-5° C. To the cold solution was added TFA (3.2 mL) dropwise and stirring was continued at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with hexane to afford 0.64 g (96%) of 4-(2-bromo-phenoxy)-piperidine trifluoroacetate. LCMS: 370.02 (M+1)+, 91.37%. 1H NMR (CDCl3-D2O): δ 7.6-7.54 (d, 1H), 7.32-7.26 (d, 1H), 6.94-6.86 (d, 2H), 4.8-4.7 (bs, 1H), 3.5-3.4 (m, 2H), 3.3-3.2 (m, 2H), 2.2-2.1 (s, 4H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[SiH:5]1[N:9]([CH:10]([CH3:12])[CH3:11])[CH:8]=[CH:7][N:6]1[CH:13]([CH3:15])[CH3:14]>CCCCCC>[CH2:1]([NH:3][SiH:5]1[N:9]([CH:10]([CH3:11])[CH3:12])[CH:8]=[CH:7][N:6]1[CH:13]([CH3:15])[CH3:14])[CH3:2]
Reactant: CC(C)N1C=CN(C(C)C)[SiH]1Cl
Reactant: CCN
Solvent: CCCCCC
Product: CCN[SiH]1N(C(C)C)C=CN1C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
In an argon atmosphere, 6.80 g (151 mmol) of ethylamine was dissolved in 20 mL of hexane, and a solution obtained by dissolving 5.73 g (28.0 mmol) of Si(iPrNCHCHNiPr)(H)Cl in 5 mL of hexane was added thereto at −20° C. After stirring at room temperature for 4 hours, insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 74° C./4.3×102 Pa) to obtain 2-ethylamino-1,3-di-isopropyl-1,3-diaza-2-silacyclopent-4-ene (Si(iPrNCHCHNiPr)(H)NHEt) as a colorless liquid (yielded amount: 5.34 g, yield: 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.Cl.[NH2:14][C:15]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:14][C:15]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16]1
Reactant: COC(=O)C1(N)CC1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Product: COC(=O)C1(NCc2ccc(OC)c(OC)c2)CC1
Yield: 82 %

Procedure:
Prepared as in Example 12-1b from 3,4-dimethoxybenzaldehyde and methyl 1-aminocyclopropanecarboxylate hydrochloride. Yield 82%. MS 266 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:21][C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[F:13])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12]
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Br)cc(Oc2ccc(F)cc2F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
1-Bromo-5-fluoro-2-methyl-3-nitro-benzene (9.40 g, 41.45 mmol) was dissolved in 90 mL dry DMF, and 2,4-difluorophenol (5.93 g, 45.58 mmol) and potassium carbonate (6.70 g, 45.58 mmol) were added. The reaction mixture was placed under nitronge and heated to 120° C. with stirring for 18 hours. The reaction mixture was cooled and concentrated under reduced pressure, and the residue was partitioned between water and EtOAc. The organic phase was separated, washed with 1N aqueous NaOH and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-6% EtOAc in hexanes) to give 8.484 g of 1-bromo-5-(2,4-difluoro-phenoxy)-2-methyl-3-nitro-benzene.