Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]2([CH3:38])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27]C(=O)OC(C)(C)C)=[CH:26][C:20]=4[S:19](=[O:36])(=[O:35])[N:18]=3)[C:7]2=[O:37])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:8]3[C:7](=[O:37])[C:6]([CH2:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)([CH3:38])[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:18][S:19](=[O:36])(=[O:35])[C:20]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC3CC3)C1=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 157F (1.06 g, 2.00 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (10 mL) at room temperature for 1 hour. After concentrating in. vacuo, the resulting oil was partitioned between ethyl acetate and aqueous NaHCO3, the organic layer was removed and the aqueous layer extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in. vacuo to yield a solid that was used without further purification. 1H NMR (300 MHz, DMSO-d6): δ ppm −0.25 (m, 2 H) 0.25 (m, 2 H) 0.46 (m, 2 H) 0.80 (m, 1 H) 1.57 (s, 3 H) 2.15 (m, 1 H) 2.32 (m, 1 H) 6.99 (m, 2 H) 7.44 (d, J=8.82 Hz, 1 H) 7.54 (m, 1 H) 7.77 (d, J=4.04 Hz, 2 H) 8.15 (d, J=7.72 Hz, 1 H) 13.55 (s, 1 H). MS (ESI+) m/z-438 (M+H)+, 455 (M+NH4)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si](C)(C)C)=[CH:12][N:11]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:9][CH2:8][CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[N:11][CH:12]=1)#[CH:17]
Reactant: C[Si](C)(C)C#Cc1ccc(NCCN2CCOCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc(NCCN2CCOCC2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(2-morpholinoethyl)-5-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (2.0 g, 6.60 mmol) was dissolved in methanol (30 mL) before it was cooled to 0° C. and potassium carbonate (1.0 g, 7.26 mmol) added. The reaction mixture was stirred for 1 h at ambient temperature, then diluted with 50 mL EtOAc, washed with 20 mL saturated, aqueous NaHCO3, and dried over anhydrous Na2SO4 to give the title compound. MS (ES+): 232 (M+H).
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[CH:20]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([S:26]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)(=[O:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: O
Product: O=S(=O)(NC1CCN(CCc2c[nH]c3ccccc23)CC1)C1CCCCC1

Procedure:
Using an analogous procedure to Example 1 3-[2-(4-amino-1-piperidyl)ethyl]indole monohydrate may be reacted with cyclohexanesulphonyl chloride to give the title compound.
Reaction SMILES: C(O[C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH:27]1([S:33]([Cl:36])(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[ClH:36].[NH2:16][C@H:15]([C:24](=[O:26])[N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[CH2:14][CH2:13][CH2:12][N:11]([CH3:9])[S:33]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)(=[O:35])=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)C1CCCCC1
Product: CN(CCC[C@H](N)C(=O)N1CCCC1)S(=O)(=O)C1CCCCC1
Product: Cl

Procedure:
Starting from (S)-N5-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-ornithine, cyclohexanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 68.
Reaction SMILES: [C:1]1([C:7]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[OH:27])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1.O>C1COCC1>[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39]1[CH:46]=[CH:45][C:42]([CH2:43][O:27][C@@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@@H:21]2[NH:20][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:41][CH:40]=1
Reactant: O[C@@H]1CCCC[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(C(N[C@H]2CCCC[C@H]2OCc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
Cis-2-triphenylmethylaminocyclohexanol (1.52 g; 4.25 mmol) is added to a solution of sodium hydride (256 mg; 60%; 6.4 mmol) in 20 ml dry THF and refluxed overnight. The solution is cooled, 4-(benzoxazol-2-yl)benzyl bromide (1.3 g; 4.5 mmol) is added in one portion and refluxed for 5 hrs. This is then poured into water and extracted with 2×100 ml CH2Cl2, dried (Na2SO4), concentrated to dryness and flash chromatographed using 4:1 8:1; hexane:EtOAc to obtain Cis-1-[4-(benzoxazol-2-yl)benzyloxy]-2-triphenylmethylaminocyclohexane which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:4](=[O:5])[C:3]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=2[F:1])=[CH:17][CH:16]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1cc([N+](=O)[O-])ccc1F
Reaction time: 144 h

Procedure:
A mixture of 2-fluoro-5-nitro-benzoyl chloride (1.1 g, 5.4 mmol) in 20 mL DCM was added dropwise to 4-bromoaniline (929 mg, 5.4 mmol), 0.905 mL TEA in 20 mL DCM. The mixture was stirred for 6 days, successively washed with satd. NaHCO3-solution and 2 M aq. HCl solution and dried with Na2SO4. After filtration and concentration i. vac. the subtitle compound was obtained. Yield: 1.57 g (86%). MS [M+H]+=339 (Br-isotope pattern); TLC: Rt=0.96 (silica gel, DCM:EtOH 9:1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl>[O:21]1[CH2:22][CH2:23][N:18]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[CH2:19][CH2:20]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a stirred suspension of 4-(bromomethyl)benzonitrile (4.00 g, 20 mmol) in DCM (50 ml), at room temperature, triethylamine (4.12 g, 41 mmol) and morpholine (2.67 g, 31 mmol) were added. The reaction mixture was stirred overnight at room temperature. The solution was then diluted with DCM (100 ml) and washed with NaHCO3 saturated aqueous solution (50 ml), the organic phase was separated, dried over magnesium sulphate and solvents evaporated under reduced pressure. The product was purified by column chromatography using a 80 g silica gel cartridge and the following gradient: Solvent A: DCM, Solvent B: MeOH, 1 min hold at 100% A followed by 12 min ramp to 2.5% B and then 5 min hold at 2.5% B. The desired fractions were combined and concentrated to dryness under reduced pressure to obtain the desired product as a white solid (3 g, 14.8 mmol, Yield 72%).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:10]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCBr
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCOc1ccccc1O
Yield: 47696.8 %

Procedure:
A mixture of 740 mL of methyl ethyl ketone, 120 g (1.09 mol) of catechol, 178 g (1.09 mmol) of 1-bromohexane, and 211 g (1.53 mol, 1.4 eq.) of potassium carbonate was refluxed for 25 hours. After being cooled, the mixture was filtered and the solvent was evaporated. The residue of 202 g was purified by silica-gel column chromatography and was then distilled. As a result, 101 g of a transparent liquid was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:33])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH3:6])=[O:4].[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(O)(=O)C>[C:34]([NH:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:33])[NH:23][C:24]3[C:29]\2=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)/[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)[CH3:6])=[O:4])(=[O:36])[CH3:35]
Reactant: CN(C(=O)CN)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NCC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 31 from (Z)-3-{1-[4-(N-aminomethylcarbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone and acetic anhydride in glacial acetic acid.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH2:10]([O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:7]([C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)=[O:9])[CH:17]=1)[CH3:11]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1csc(Cl)n1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2csc(Cl)n2)c1

Procedure:
Carboxylic acid (79)(220 mg, 1.34 mmol) was coupled to aniline (60)(257 mg, 1.34 mmol) using Method C to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:9][C:8]2=O.[CH2:32]([NH:34][CH3:35])[CH3:33]>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[CH3:15])[N:11]=[C:10]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:9]=[C:8]2[N:34]([CH2:32][CH3:33])[CH3:35]
Reactant: CCNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(C)c(Oc3c(C)cccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(2,6-dimethylphenoxy)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-ethyl-N-methylamine in step E. MS (ESI/CI): predicted mass C25H24N5O3, 431.2.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)C(C)C)(C)C.Cl[S:15]([C:18]1[CH:19]=[C:20]([C:24]2[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:36]([O:38][CH3:39])=[O:37])[CH:30]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16]>ClCCl>[CH3:2][N:3]([CH3:4])[S:15]([C:18]1[CH:19]=[C:20]([C:24]2[C:33]([CH3:34])([CH3:35])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:36]([O:38][CH3:39])=[O:37])[CH:30]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)(=[O:16])=[O:17]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N(C)C)c1)=N2
Yield: 25 %

Procedure:
To a stirred solution of dimethylamine hydrochloride (82 mg, 1.0 mmol) and N,N-diisopropylethyl amine (388 mg, 3.0 mmol) in dichloromethane (4 mL) was added a solution of methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (394 mg, crude product) in dichloromethane (4 mL). The mixture was purified on preparative Thin layer chromatography to afford 100 mg of methyl 2-(3-(N,N-dimethylsulfamoyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate, which was used directly.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH2:19]([S:23]([C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:28][CH:27]=1)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([S:23]([C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][N:34]([C:7]([C:6]3[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=3[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:33][CH2:32]2)=[N:28][CH:27]=1)(=[O:25])=[O:24])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CCCCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)s1
Yield: 54 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(butane-1-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 54%). MS (m/e): 530.3 (M+H+, 35%), 547.5 (M+NH4+, 100%).
Reaction SMILES: C(OC(=O)NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1)(C)(C)C.[O:40]=[C:41]1[CH2:46][O:45][C:44]2[N:47]=[C:48]([C:57]3[CH:62]=[CH:61][C:60]([C:63]4([NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71])[CH2:66][CH2:65][CH2:64]4)=[CH:59][CH:58]=3)[C:49]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:50][C:43]=2[NH:42]1.[F:75][CH:76]([F:79])[CH2:77]I>>[C:70]([O:69][C:68](=[O:74])[NH:67][C:63]1([C:60]2[CH:61]=[CH:62][C:57]([C:48]3[C:49]([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)=[CH:50][C:43]4[N:42]([CH2:77][CH:76]([F:79])[F:75])[C:41](=[O:40])[CH2:46][O:45][C:44]=4[N:47]=3)=[CH:58][CH:59]=2)[CH2:64][CH2:65][CH2:66]1)([CH3:71])([CH3:73])[CH3:72]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: FC(F)CI
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC(F)F)C(=O)CO4)cc2)CCC1

Procedure:
Following the procedure for tert-butyl(1-(4-(1-(2-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate, tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol) was reacted with 1,1-difluoro-2-iodoethane (122 mg, 0.636 mmol) to afford the title compound (85 mg. 1H NMR (500 MHz, CDCl3): 7.42 (1H, s), 7.24-7.30 (7H, m), 7.17-7.19 (2H, m), 6.11 (1H, tt), 5.05 (1H, br), 4.92 (s, 2H), 4.28 (dt, 2H), 2.44-2.49 (m, 4H), 2.05 (m, 1H), 1.81 (m, 1H), 1.2-1.43 (br, 9H).
Reaction SMILES: [Br:1][CH:2]([Br:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CC(C)=O>[BrH:1].[Br:12][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:15]1[NH:16][CH:17]=[CH:18][N+:14]=1[CH3:13]
Reactant: Cn1ccnc1
Reactant: CCCCCCCCCC(Br)Br
Solvent: CC(C)=O
Product: Br
Product: C[n+]1cc[nH]c1CCCCCCCCCCBr
Temperature: 55 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
A dry 250 mL Schlenk flask was equipped with a magnetic stir bar, dropping funnel, and sealed with a rubber septum. Dibromodecane (73.0 g, 0.24 mol) was dissolved in acetone (50 ml) and added to the flask. The mixture was heated to 55° C. in an oil bath, and 1-methylimidazole (4.0 g, 48.7 mmol) was added over 90 minutes via dropping funnel through the top of the flask under nitrogen flow. After addition, the reaction was allowed to stir at 55° C. for 6 hours. The reaction was cooled and solvent was removed in vacuo. The residue was diluted with 150 mL of hexanes and 60 mL of ethyl acetate and placed in a separatory funnel. The bottom layer was removed and purified by column chromatography over silica (dichloromethane/methanol, 9:1 v/v). Yield: 68%.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17]Br)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[C:19]([NH2:28])(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH2:22].C([O-])(=O)C.[Na+]>O>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]([NH2:28])=[O:27])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: NC(=O)c1ccccc1N
Reactant: Oc1ccc(N2CCN(CCBr)CC2)cc1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1ccccc1NCCN1CCN(c2ccc(O)cc2)CC1
Yield: 40 %

Procedure:
A mixture of 61 g 1-(p-hydroxyphenyl)-4-(2-bromoethyl)piperazine dihydrobromide, 18.5 g anthranilamide, 33.5 g sodium acetate, and 250 ml water was refluxed 16 hours, cooled, filtered and the solid washed with water and isopropanol. The solid was suspended in water and made alkaline with Na2CO3. The solid was filtered, suspended in 75% ethanol and added dilute HCl until acidic. The solution was cooled and the solid filtered and recrystallized from 1200 ml water to give 18.5 g product, m.285.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([OH:7])[CH:5]([OH:8])[CH:4]([CH3:9])[O:3]1.[OH-].[Na+]>[Ag].O>[CH3:1][CH:2]1[C:6](=[O:7])[CH:5]([OH:8])[CH:4]([CH3:9])[O:3]1
Reactant: CC1OC(C)C(O)C1O
Agent: [Ag]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1OC(C)C(O)C1=O
Temperature: 20 °C

Procedure:
A vertical tubular reactor of 2 cm internal diameter, at the top of which 28 g of silver crystals (8 g of particles with diameters from 0.75 to 1 mm, 14 g of particles with diameters of from 0.4 to 0.75 mm and 6 g of particles with diameters of from 0.2 to 0.4 mm) were arranged, as a 2 cm thick bed, above a silver gauze screen, was fed, per hour, with a gaseous mixture, at 175° C., of 18.7 liters of 2,5-dimethyl-3,4-dihydroxy-tetrahydrofuran (=110 g), 72 liters of air and 100 liters of nitrogen. The catalyst temperature was 535° C. and the residence time over the catalyst about 0.04 second. After having passed over the catalyst, the gas mixture was immediately cooled to 20° C. by passing it into water. The resulting solution was brought to pH 8 with 10% strength NaOH solution. The water was then stripped off at 20 mbar and the residue was distilled at 1.3 mbar. This gave, at 61°-66° C., 35 g of a distillate containing about 80% of 2,5-dimethyl-4-hydroxy-tetrahydrofuran-3-one, and, at 109°-120° C., 60 g of unconverted 2,5-dimethyl-3,4-dihydroxy-tetrahydrofuran. The conversion was about 45% and the yield, based thereon, about 70%.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([C@@H:10]([CH2:21][NH:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[O:11]CC2C=CC(OC)=CC=2)[O:7][C@H:6]1[N:40]1[CH:45]=[CH:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])(=[O:3])[CH3:2].C(Cl)Cl.FC(F)(F)C(O)=O>C(Cl)Cl.CCOCC>[C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([C@@H:10]([CH2:21][NH:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:11])[O:7][C@H:6]1[N:40]1[CH:45]=[CH:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCC(=O)NC[C@@H](OCc1ccc(OC)cc1)[C@@H]1C[C@@H](OC(C)=O)[C@H](n2ccc(=O)[nH]c2=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC(=O)NC[C@@H](O)[C@@H]1C[C@@H](OC(C)=O)[C@H](n2ccc(=O)[nH]c2=O)O1
Reaction time: 1 h
Yield: 24 %

Procedure:
240 mg of the product of Stage A dissolved in 2 ml of methylene chloride is added to 7.5 ml of a mixture of methylene chloride/trifluoroacetic acid (9/1) under a nitrogen atmosphere. The solution obtained is agitated for 1 hour followed by evaporating and drying. A product is obtained which is taken up in ether then in pentane followed by evaporation again. The product obtained is chromatographed and 47 mg of sought product is obtained.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH2:24]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH2:25][CH3:26]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:31][C:30]4[CH:32]=[CH:33][C:27]([CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=4)=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CCCc1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCCc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 28 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-propylaniline (46.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-propylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (19.1 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.Cl.[O-:13][C:14]#[N:15].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:14]([NH2:15])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN)c1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1cccc(CCNC(N)=O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a solution of 2-(3-methoxy-phenyl)-ethylamine (1) (50.0 g, 331 mmol) and concentrated HCl (27.6 mL) in water (350 mL), potassium cyanate (28.2 g, 348 mmol) was added and stirred at 50° C. for 2 hours, then at room temperature for 2 days. Formed precipitate was collected by filtration. The solid was washed with water and dried under reduced pressure to give the title compound (53.4 g, 83%). MS (ESI) (M+H)+ 195.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[O:16][CH:15]([CH3:17])[CH2:14][NH:13][CH2:12]1>>[CH3:17][CH:15]1[O:16][CH:11]([CH3:10])[CH2:12][N:13]([C:2]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=2)[CH2:14]1
Reactant: N#Cc1ccc(F)cc1
Reactant: CC1CNCC(C)O1
Product: CC1CN(c2ccc(CN)cc2)CC(C)O1

Procedure:
4-Fluorobenzonitrile and 2,6-dimethylmorpholine were processed as described in Examples 66A and 66B to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([O:20]CC)=[O:19])[CH2:13][C:12]([F:15])([F:14])[C:11]2([F:17])[F:16])=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([OH:20])=[O:19])[CH2:13][C:12]([F:15])([F:14])[C:11]2([F:16])[F:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(OCC)cc2)CC(F)(F)C1(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(C2(C(=O)O)CC(F)(F)C2(F)F)cc1
Temperature: 0 °C

Procedure:
Ethyl 1-(4-ethoxyphenyl)-2,2,3,3-tetrafluorocyclobutane carboxylate (14.5 g) was dissolved in ethanol (100 ml) and a 10% w/w solution of sodium hydroxide in water (100 ml) was added and the mixture refluxed for 2.5 hours. The mixture was cooled, added to ice water and extracted with diethyl ether. The aqueous layer was acidified and the precipitate was filtered off, washed with water, dried and crystallised from 60°-80° petroleum ether to give the acid mp 112°-113° C. Yield 11.2 g (85%).