Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=C[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5]C=1.[NH2-].[Li+].[CH3:11][O:12][C:13]([CH3:19])([O:15]CC#C)[CH3:14].BrCC>CCCCCC>[CH3:11][O:12][C:13]([CH3:19])([O:15][CH2:5][C:6]#[C:7][CH2:8][CH3:3])[CH3:14]
Reactant: C#CCOC(C)(C)OC
Reactant: C=Cc1ccccc1
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCC
Solvent: CCBr
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 96.9 %

Procedure:
883 mg (126 mmol) of granulated lithium were added within 5 minutes to 107 g (6.30 mol) of liquid ammonia at −38° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 14.6 g (140 mmol) of styrene were added portion wise within 20 minutes. The end of the formation of lithium amide could be recognized by the discoloration of the reaction mixture. 9.9 g (70 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne (90.8% GC) were added with a dropping funnel to the reaction mixture at −38° C. within 20 minutes. The reaction mixture was held at −38° C. for about 1 hour. 14 g (126 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 20 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 16 hours. 70 ml of water were added to the reaction mixture at 22° C., and the mixture was stirred until all salt was dissolved. The organic layer was separated and dried over 2 g of anhydrous magnesium sulfate. The solution was concentrated under reduced pressure (40° C., 40 mbar) and the crude product was analyzed by GC. 10.6 g of 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne were obtained with a purity of 84.4% (yield 81.8%, based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[NH2:5].[CH3:42][O:43][C:44]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])=[O:45].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NN>CN1CCOCC1.CN(C=O)C.CN1CCOCC1.CN(C=O)C>[OH:1][C@H:2]([C@@H:13]([NH:21][C:22](=[O:41])[C@H:23]([CH2:37][C:38](=[O:40])[NH2:39])[NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][N:4]([CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[NH:5][C:51](=[O:52])[C@H:47]([CH:48]([CH3:49])[CH3:50])[NH:46][C:44]([O:43][CH3:42])=[O:45]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)CC1CCCCC1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)NN(CC1CCCCC1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under a nitrogen atmosphere, 100 mg (0.178 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]hydrazine (Example 71e) i)) and 34 mg (0.196 mmol) of N-methoxycarbonyl-(L)-valine (Example 73b) are dissolved in 1.75 ml of a 0.3M solution of NMM in DMF, 74 mg (0.196 mmol) of HBTU are added and the mixture is stirred at RT. Since, after 3 days, there is still unreacted hydrazine present, a further 0.3 equivalents in each case of N-methoxycarbonyl-(L)-valine and HBTU in 0.48 ml of 0.3M NMM/DMF is added. After 18 h the reaction mixture is concentrated by evaporation under HV, the residue is dissolved in methylene chloride and washed with saturated NaHCO3 solution, water and brine, the aqueous phases are extracted twice with methylene chloride, and the organic phases are dried with Na2SO4 and concentrated by evaporation. Column chromatography (SiO2, methylene chloride/methanol 15:1) and digestion from DIPE yields the title compound: TLC Rf (A')=0.17; tRet (V)=14.6 min; FAB-MS (M+H)+ =718.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]3[C@H:14]([CH2:15][CH2:16][OH:17])[O:13][CH2:12][CH2:11][C:10]=3[CH:18]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].CS(OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1)(=O)=O>>[CH3:19][S:20]([O:17][CH2:16][CH2:15][C@H:14]1[C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:18][C:10]=2[CH2:11][CH2:12][O:13]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCC[C@@H]1OCCc2cc(-n3cccn3)ccc21
Agent: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Product: CS(=O)(=O)OCC[C@@H]1OCCc2cc(-n3cccn3)ccc21

Procedure:
Prepared from 2-[(1S)-6-(1H-pyrazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethanol and methanesulfonyl chloride, as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate.
Reaction SMILES: CON=[CH:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[O:8][C@@H:7]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:6]1.CC=[O:34]>CO>[CH:4]([C@@H:5]1[C@@H:9]([CH2:10][O:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[O:8][C@@H:7]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:6]1)=[O:34]
Reactant: CON=C[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CON1C(=O)c2ccccc2C1=O
Reactant: CC=O
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](C=O)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O

Procedure:
3'-Deoxy-3'-C-[(methoxyimino)methyl]-5'-O-phthalimidothymidine upon treated with CH3CHO in MeOH regenerated the 3'-C-formyl group. The product on purification by silica gel column chromatography furnished the title compound as homogeneous material in 81% overall yield for 3 steps. 1H NMR (CDCl3) δ 9.95 (s, 1, CH=O); 8.62 (br s, 1, NH); 7.71-7.90 (m, 5, aromatic H, H-6); 6.06 (t, 1, H-1', J1'2' =6.61 Hz, J1'2' =6.6 Hz); 4.36-4.73 (m, 3, H-4', H5',5"); 3.78 (m, 1, H-3'); 2.20-2.90 (m, 2, H-2'2"); 1.98 (s, 3, C5CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][CH:4]=1.[Br-:9].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>CO.O>[Br:9][C:4]1[CH:5]=[N:6][N:7]([CH3:8])[C:3]=1[O:2][CH3:1]
Reactant: COc1ccnn1C
Reactant: [Br-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: COc1c(Br)cnn1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A solution of 5-methoxy-1-methyl-1H-pyrazole (0.500 g, 4.46 mmol) in MeOH (50.0 mL) was cooled to 0° C. and charged with pyridinium tribromide (1.43 g, 4.46 mmol) in portions. The solution was stirred for 1 h at 0° C. then for an additional 16 h at rt. The reaction mixture was charged with sat. NaHCO3 (2.5 mL) and diluted with H2O and extracted with CHCl3 (3×). The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo resulting in 647 mg, 76% yield of the title compound as a red oil. This material was used in the next step without further purification. 1H NMR (400 MHz, CD3OD): δ=3.66 (s, 3H), 4.07 (s, 3H), 7.30 (s, 1H). MS (ES+): m/z 190.98, 192.99 (49.5/50.5) [MH+]. HPLC: tR=3.33 min (polar—5 min, ZQ3).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>>[NH:18]([C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[CH:4][N:3]=1)[NH2:19]
Reactant: NN
Reactant: COc1ccc(F)c(-c2cnc(Cl)cn2)c1
Solvent: O
Product: COc1ccc(F)c(-c2cnc(NN)cn2)c1

Procedure:
An ethanolic solution of 2-chloro-5-(2-fluoro-5-methoxyphenyl) pyrazine and hydrazine monohydrate (10 equiv.) was refluxed under a N2 atmosphere for 6 h. The ethanol was removed under reduced pressure and the residue was partitioned between 5% HCl and CH2Cl2. The CH2Cl2 layer was extracted several times with 5% HCl and the combined aqueous portions were washed (1×) with CH2Cl2. The aqueous solution was made basic with 10N NaOH and then extracted (4×) with CH2Cl2. The combined CH2Cl2 portions were washed (1×) with brine, dried (Na2SO4), treated with decolorizing charcoal and filtered through celite. Evaporation of the solvent under reduced pressure yielded 2-hydrazino-5-(2-fluoro-5-methoxyphenyl)-pyrazine as a beige oil.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:17]=2)=[CH:5][CH:4]=1.N>CO.C(Cl)Cl>[CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:19][CH:20]=3)[C@@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CN(C)c1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)cc1
Yield: 77 %

Procedure:
1-(4-Dimethylamino-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 2.70 mmol scale, to give 0.93 g (77%) of the desired product as a viscous oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C28H39F3N3O2, 449.3; m/z found, 450.5 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([NH2:10])=[N:6][O:7][C:8]=1[CH3:9].[CH2:11]([C:13]1[S:21][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[C:14]=1[S:22](Cl)(=[O:24])=[O:23])[CH3:12]>C1COCC1>[Cl:3][C:4]1[C:5]([NH:10][S:22]([C:14]2[C:15]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[S:21][C:13]=2[CH2:11][CH3:12])(=[O:24])=[O:23])=[N:6][O:7][C:8]=1[CH3:9]
Reactant: Cc1onc(N)c1Cl
Reactant: CCc1sc2ncccc2c1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1sc2ncccc2c1S(=O)(=O)Nc1noc(C)c1Cl
Yield: 35.2 %

Procedure:
N-(4-chloro-5-methyl-3-isoxazolyl)-2-ethylthieno[2,3-bjpyridine-3-sulfonamide was prepared according to Example 1 (C), using NaH (44 mg, 1.9 mmoles), THF (5 ml), 4-chloro-5-methyl-3-aminoisoxazole (82 mg, 0.62 mmoles) and 2-ethylthieno[2,3-b]pyridine-3-sulfonyl chloride (0.19 g, 0.71 mmoles). Flash chromatography (50% EtOAc/hexanes) followed by recrystallization from EtOAc/hexanes provided 78 mg (35%) of the title compound as a light yellow solid, m.p. 172°-174° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCN1CCN(C)CC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 6) and 1-methylpiperazine following the procedure outlined in Example 15 (modifications: 25° C., overnight). 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 10.09 (s, 1H), 8.82 (s, 1H), 8.59 (s, 2H), 7.88 (d, 1H), 7.06 (d, 1H), 4.99 (s, 1H), 3.98 (t, 2H), 3.91 (s, 3H), 3.75-2.90 (br, 10H), 2.77 (s, 3H), 2.22 (s, 6H), 1.77 (m, 2H), 1.69 (m, 2H), 1.44 (m, 2H), 1.36 (m, 2H); MS (ESI): 494.4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=2)[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: Cc1cccc(C=O)c1
Product: Cc1cccc(CNC2CC2)c1

Procedure:
Synthesized according to typical procedure J from 3-methylbenzaldehyde and cyclopropylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:12].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>C(OCC)(=O)C>[C:20]([O:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH3:1])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2ccccc2c1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(C)ccc2ccccc12
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A solution of 9.48 g (60 mmole) of 2-methyl-1-naphthol and 8.10 g (80 mmole) of triethylamine in 50 mL of ethyl acetate was cooled to below 5° C. in an ice-bath. 5.50 g (70 mmole) of acetyl chloride was added at a rate such that the temperature did not rise about 5° C. The reaction mixture was stirred for an additional one hour, diluted with 50 mL of ethyl acetate, and washed with water then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give an oily residue. Crystallization in hexane yielded 7.58 g (63% yield) of the title compound with a melting point of 81°-83° C. and an 1HNMR as follows: (300 MHz, DMSO-d6) δ 2.26 ) (s, 3H), 2.48 (s, 3H), 7.42 (d, 1H, J=9 Hz), 7.46-7.55 (m, 2H), 7.47-7.81 (m, 2H), 7.92 (d, 1H, J=9 Hz). The mass spectrum showed a molecular ion at m/z 200.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>C(O)C>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[N:17]1[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]1=[O:11]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: COc1ccccc1N
Solvent: CCO
Product: COc1ccccc1N1CCC(C(=O)O)C1=O
Yield: 101.2 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 2-methoxyaniline (0.495 mL; 4.41 mmol) in ethanol (3 mL). 1-(2-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.350 g (quantitative) was obtained as a grey solid.
Reaction SMILES: O1CCOCC1.C(OC([N:14]1[CH2:17][CH:16]([N:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([CH2:32][C:33]5[CH:34]=[C:35]6[C:40](=[CH:41][C:42]=5[F:43])[N:39]=[CH:38][CH:37]=[CH:36]6)=[CH:30][N:31]=4)[N:28]=3)[CH:20]=[N:19]2)[CH2:15]1)=O)(C)(C)C.Cl>CCOC(C)=O.C([O-])(O)=O.[Na+]>[NH:14]1[CH2:15][CH:16]([N:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]4[N:27]([C:29]([CH2:32][C:33]5[CH:34]=[C:35]6[C:40](=[CH:41][C:42]=5[F:43])[N:39]=[CH:38][CH:37]=[CH:36]6)=[CH:30][N:31]=4)[N:28]=3)[CH:20]=[N:19]2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CNC4)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dioxane (5 mL) was charged in a flask. 3-{4-[3-(7-Fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-pyrazol-1-yl}-azetidine-1-carboxylic acid tert-butyl ester (Stage 146.2, 100 mg, 0.200 mmol) and HCl in dioxane (4 M solution, 500 μL, 2.002 mmol) were then added and the mixture was stirred at rt for 1 h. The RM was diluted with EtOAc/NaHCO3. The organic layer was separated and washed with brine (2×) then dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100) and precipitated in Et2O to afford the title compound as a foam (tR 2.87 min (conditions 3), MH+=400.1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([O:8][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCC(Oc2ccccc2[N+](=O)[O-])(c2ccccc2)CC1
Reaction time: 1 h
Yield: 32.8 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (7.65 g, 40 mM) in dry DMSO (100 ml) was treated with sodium hydride (2.0 g of 50% dispersion in oil 42 mM), the mixture stirred for 1 hour and then treated with 2-fluoronitrobenzene (5.65 g, 40 mM). After 24 hours the reaction mixture was poured in to water (500 ml) and extracted with ether (2×500 ml). The organic extract was washed with brine, dried and the solvents removed under reduced pressure. Recrystallisation of the residue from cyclohexane gave the title compound (4.1 g) m.p. 80°-2° C.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1=[O:1])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(Cc2ccccc2)C1=O
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
To a stirring solution of (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (250 mg, 1.10 mmol) in DMF (1 mL) was added a solution of 20 weight % LiHMDS in THF (870 mg, 1.04 mmol) at −70° C. under argon. The reaction mixture was stirred at −70° C. for 10 min followed by the addition of (bromomethyl)benzene (0.137 mL, 1.15 mmol) at the same temperature. Then the reaction was allowed to stir at rt for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-80% EtOAc/Hex to give (S)-tert-butyl 1-benzyl-2-oxoazepan-3-ylcarbamate (300 mg, 0.942 mmol, 86% yield) as a colorless oil. Anal. Calcd. for C18H26N2O3 m/z 318.4. found: 319.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:35]1[S:36][CH:37]=[C:38]([C:40]([O:42][CH3:43])=[O:41])[N:39]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:35]2[S:36][CH:37]=[C:38]([C:40]([O:42][CH3:43])=[O:41])[N:39]=2)[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1csc(Br)n1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1csc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a mixture of 136 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 64 mg of methyl 2-bromo-1,3-thiazole-4-carboxylate, and 38 mg of potassium carbonate was added 1.5 mL of DMSO at room temperature, and the mixed solution was stirred at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate, and the organic layer was then washed with water and saturated brine in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 113 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-1,3-thiazole-4-carboxylate as a colorless foamy substance. ESI+: 586
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6].[Na+].C1(CC([O-])=O)C=CC=CC=1.[C:24]1([NH:30][C:31](=[O:54])[CH:32]([CH:38]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=O)[C:33](=O)[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:24]1([NH:30][C:31]([C:32]2[C:38]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[C:39]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[N:2]([CH2:3][CH2:4][C:5]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[O:6])[C:33]=2[CH:34]([CH3:36])[CH3:35])=[O:54])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: NCCC(=O)N1CCOCC1
Agent: Cl
Agent: O=C([O-])Cc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC(=O)N1CCOCC1
Yield: 78 %

Procedure:
A nitrogen inerted reactor, equipped with a suitable reflux condenser and soxhlet extractor containing freshly activated 3A molecular sieves (4-8 mesh; 36 g), is charged with 3-amino-1-morpholin-4-yl-propan-1-one hydrochloride (170 mmol), phenylacetic acid sodium salt (170 mmol) and 2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid phenylamide (100 mmol). THF (150 mL) is added, and the resulting solution is stirred vigorously as the reaction is heated at reflux temperature for ca. 24 hours, during which time the product begins to precipitate. Aqueous NaHCO3 (100 mL) is added slowly, and the reaction mixture is cooled with continued stirring to ca. 0° C. MtBE (100 mL) is added, and the solids are collected via filtration. The yellow-colored solid is washed with distilled water (15 mL) and MtBE (2×15 mL), collected, and dried under vacuum at ≦50° C. to afford 5-(4-fluorophenyl)-2-isopropyl-1-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide as a white solid (42.1 g). This material is carried on to subsequent steps without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][OH:22].C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][C:9]1[C:10]([CH2:11][NH:19][CH2:20][CH2:21][OH:22])=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(C=O)c(OCc2ccccc2)n1
Reactant: NCCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNCCO)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
To a suspension of 2-(benzyloxy)-4,6-dimethylnicotinaldehyde (Cpd JJ, 6.4 g, 27 mmol) in methanol (100 mL) was added 2-aminoethanol (8.34 mL, 133 mmol). The reaction mixture was stirred at room temperature for 1 hour then cooled to 0° C. Sodium cyanoborohydride (4.9 g, 66 mmol) was added in one portion and the reaction was slowly warmed to room temperature and stirred overnight. The methanol was removed under vacuum then the residue was diluted with water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over magnesium sulfate, concentrated under vacuum and purified by column chromatography (EtOAc) to give 2-(((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)amino)-ethanol (Cpd KK, 4.2 g, 55% yield) as a pale yellow solid.