Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9]1([P:15](Cl)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.O1CCOCC1.O1CCOCC1>[NH2:2][O:3][P:15](=[O:16])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: NOP(=O)(c1ccccc1)c1ccccc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
Into a 500-mL three neck round-bottom flask, was placed a solution of hydroxylamine hydrochloride (30.0 g, 432 mmol) in H2O/dioxane (90/45 mL). The solution was cooled to 0-5° C., then sodium bicarbonate (36.5 g, 434 mmol) was added portion-wise over 10 min and the mixture was stirred at 0-5° C. for 30 min. A solution of diphenylphosphinoyl chloride (41.0 g, 173 mmol) in dioxane (45 mL) was added drop-wise at 0-5° C. over 30 min, then the resulting mixture was stirred for an additional 2 h at ambient temperature. The resulting solids were collected by filtration and washed with water (200 mL), NaOH (0.25 M, 200 mL) and PE (200 mL). The product was dried to yield the title compound as a white solid (20 g, crude).
Reaction SMILES: Br[CH:2]([CH3:19])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1>C(O)C>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[N:20]=[C:21]3[N:25]([C:2]=2[CH3:19])[CH:24]=[CH:23][S:22]3)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(C(=O)C(C)Br)ccc1-c1ccccn1
Reactant: Nc1nccs1
Solvent: CCO
Product: COc1cc(-c2nc3sccn3c2C)ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-one (153 mg, 0.50 mmol) and 2-aminothiazole (50 mg, 0.50 mmol) in ethanol (1 mL) was heated to reflux for 12 h, then concentrated. The residue was dissolved in ethyl acetate (25 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (2:1 to 1:0) to afford 6-(3-methoxy-4-pyridin-2-ylphenyl)-5-methylimidazo[2,1-b][1,3]thiazole. 1H NMR (CDCl3, 500 MHz) δ 8.73 (m, 1H), 7.94 (d, 1H), 7.88 (d, 1H), 7.73 (dt, 1H), 7.52 (s, 1H), 7.35 (dd, 1H), 7.34 (dd, 1H), 7.22 (m, 1H), 6.86 (dd, 1H), 3.98 (s, 3H), 2.66 (s, 3H) ppm. MS (ESI) 322 (M)+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28](O)=[O:29])=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C[O:33][C:34](=[O:37])[CH2:35][NH2:36].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28](=[O:29])[NH:36][CH2:35][C:34]([OH:33])=[O:37])=[CH:23][C:22]=3[F:31])[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(=O)O)cc3F)CC2)CC1
Reactant: COC(=O)CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(=O)NCC(=O)O)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-1 (32 mg, 0.073 mmol), amino-acetic acid methyl ester (0.11 mmol) and HOBT (15 mg, 0.11 mmol) were combined in DCM (1 mL) and stirred at room temperature for 10 minutes. EDC(19 mg, 0.1 mmol) was added and the mixture was stirred for 18 h. The solution was washed with 2 mL of aqueous NaHCO3, concentrated and taken up with 0.5 mL of dioxane. 0.5 mL of 1N NaOH was added and the mixture was stirred at 60° C. for 1 h. It was then cooled to room temperature, acidified with 0.5 mL of 2N HCl and extracted with ethyl acetate (1.5 mL). The organic layer was concentrated under a stream of nitrogen and purified on preparative HPLC to give 30-1: LC-MS 497.4 (MH).
Reaction SMILES: [CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]([CH2:12][CH2:13]C(F)(F)F)[C:6]([O:18][CH3:19])=[N:5]1)([CH3:3])[CH3:2].BrCC[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]([CH2:12][CH2:13][O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:6]([O:18][CH3:19])=[N:5]1)([CH3:2])[CH3:3]
Reactant: COC1=NC(C(C)C)C(OC)=NC1CCC(F)(F)F
Reactant: FC(F)(F)COCCBr
Product: COC1=NC(C(C)C)C(OC)=NC1CCOCC(F)(F)F
Yield: 65 %

Procedure:
This compound was made in 65% yield by the same procedure as 2-Isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoro-propyl)-2,5-dihydro-pyrazine, substituting 1-Iodo-3,3,3-trifluoropropane with 2-(2-Bromoethoxy)-1,1,1-trifluoroethane. 1H-NMR: 400 MHz, (CDCl3) δ: 4.11-4.05 (m, 1H), 3.95 (t, J=3.5 Hz, 1H), 3.86-3.75 (m, 3H), 3.74-3.66 (m, 7H), 2.30-2.18 (m, 2H), 1.92-1.82 (m, 1H), 1.03 (d, J=6.9 Hz, 3H), 0.70 (d, J=6.8 Hz, 3H) ppm.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH3:20])=[O:9].[C:25]1([CH:31]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:1][CH:2]([CH2:3][N:41]1[CH2:42][CH2:43][N:38]([CH:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:39][CH2:40]1)[CH2:4][O:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH3:20])=[O:9]
Reactant: Cn1ccc2c(NC(=O)c3ccccc3OCC3CO3)cccc21
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: Cn1ccc2c(NC(=O)c3ccccc3OCC(O)CN3CCN(C(c4ccccc4)c4ccccc4)CC3)cccc21

Procedure:
Using the procedure of Example 28, of Step C, 4 g of 2-[(2-oxiranyl)methoxy]-N-(1-methyl-1H-indol-4-yl)benzamide of Example 34 and and 6.3 g of diphenylmethylpiperazine were reacted to obtain 5.95 of 2-[2-hydroxy-3-[4-(diphenylmethyl)-1-piperazinyl]propoxy]-N-(1-methyl-1H-indol-4-yl)benzamide and then 4.9 g of its hydrochloride melting at 196° C. after crystallization from ethanol.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[NH2:19][C:20]1[S:21][CH:22]=[N:23][N:24]=1>C(O)C>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[N:19]=[C:20]3[N:24]([CH:2]=2)[N:23]=[CH:22][S:21]3)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Nc1nncs1
Reactant: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Solvent: CCO
Product: COc1cc(-c2cn3ncsc3n2)ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (150 mg, 0.49 mmol) and 2-amino-1,3,4-thiadiazole (49 mg, 0.49 mmol) in ethanol (3 mL) was heated to reflux for 2 h, then concentrated. The residue was dissolved in ethyl acetate (25 mL) and washed with saturated aqueous NaHCO3 (10 mL), brine (10 mL), dried (MgSO4), and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (2:1) to afford 6-(3-methoxy-4-pyridin-2-ylphenyl)imidazo[2,1-b][1,3,4]thiadiazole. 1H NMR (CD3OD, 300 MHz) δ 9.28 (s, 1H), 8.91 (s, 1H), 8.84 (d, 1H), 8.68 (dt, 1H), 8.37 (d, 1H), 8.05 (ddd, 1H), 7.85 (d, 1H), 7.81 (br s, 1H), 7.72 (dd, 1H), 4.09 (s, 3H) ppm. MS (ESI) 309 (M)+.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[O:11]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:6])[N:12]1[C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:15][CH:14]=1
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N2C(=O)c3ccccc3C2=O)nc1
Reaction time: 48 h
Yield: 34 %

Procedure:
Phthalic anhydride (0.81 g, 5.48 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.44 g, 1.37 mmole) and sodium bicarbonate (0.58 g, 6.85 mmole) in THF (70 mL) at RT, and the reaction was heated at reflux under nitrogen. After 48 hr, the reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (ethyl acetate). The title compound (0.21 g, 33%) was obtained as a white solid: MS (ES) m/e 451 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(/C=C/C(=O)O)cc2)c2ccc(O)c(Cl)c2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propenoate (128) (0.26 g, 0.57 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Upon concentration and adding hexanes, the title compound 129 was obtained as light yellow foam (0.24 g, 99%). mp 111-114° C. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 6H), 0.88 (s, 6H), 1.25 (s, 2H), 1.87 (s, 2H), 1.90 (s, 2H), 6.45 (d, J=15.9 Hz, 1H), 6.80-6.95 (m, 2H), 7.06 (s, 1H), 7.16 (d, J=7.7 Hz, 2H), 7.53 (d, J=15.9 Hz, 1H), 7.59 (d, J=7.5 Hz, 2H), 10.08 (s, 1H), 12.33 (s, 1H). LCMS (ESI): m/z 423 (M−H)−. Anal. Calcd for C26H29ClO3: C, 73.48; H, 6.88; Found: C, 73.18; H, 7.06.
Reaction SMILES: [OH:1][C@@H]1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2C[C@H](O)[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC=O)C1.C(C=[P:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(OC)=O>C1C=CC=CC=1>[C:46]1([P:33](=[O:1])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: c1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 64.8 g of (0.149) of 3α,12α-dihydroxy-24-cholanal, diformate and 55 g (10% excess) of carbomethoxymethylene triphenylphosphorane 12 in 250 ml of dry benzene was refluxed for 6 hr. The solvent was then removed under reduced pressure and the residue treated with 400 ml of a 3:1 solution of hexane-ether. The resulting precipitate was filtered to give 39 g of crude triphenylphosphine oxide. The filtrate was concentrated, dissolved in a minimum of benzene and washed through 600 g of silica gel with a 2% ethyl acetate-benzene solution. The solvent was removed and the residue crystallized from hexane to give 49 g of 5-(3α,12α-diformyloxy-5β-pregnane-20-yl)-trans-2-pentenoic acid methyl ester mp 112°-115°.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([I:17])[CH:16]=[C:12]2[C:11](=[O:18])[NH:10][CH2:9]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>C(#N)C.CN(C=O)C>[N:19]([CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([I:17])[CH:16]=[C:12]2[C:11](=[O:18])[NH:10][CH2:9]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCC1CNC(=O)c2cc(I)cn21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: [N-]=[N+]=NCCC1CNC(=O)c2cc(I)cn21
Yield: 76.9 %

Procedure:
2-(7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)ethyl methanesulfonate (0.150 g, 0.39 mmol) was reacted with sodium azide (0.076 g, 1.17 mmol) in ACN/DMF (4 ml, 1:1 ratio) for 4 hours at 80° C. under N2. The solvents were removed under vacuum, the residue was partitioned between water and DCM. The organic phase was dried (Na2SO4), filtered and evaporated, yielding the title compound as a white solid (0.097 g, 0.30 mmol, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:15]=1[C:16](Cl)=[O:17]>>[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:15]=1[C:16]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:17]
Reactant: Cc1cccc(C)c1C(=O)Cl
Reactant: CN1CCc2c(N)cccc2C1
Product: Cc1cccc(C)c1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2,6-dimethylbenzoyl chloride according to the procedure of Example 19 to yield 5-(2,6-dimethylbenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 199.5°-201° C. after purification from ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][CH:11]=C)=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[O:23]=[O+][O-].O=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][CH:11]=[O:23])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: C=CCC(C)C(=O)N(CC)c1cn(-c2cccnc2)nc1Cl
Reactant: O=[O+][O-]
Agent: O=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCN(C(=O)C(C)CC=O)c1cn(-c2cccnc2)nc1Cl
Temperature: -78 °C

Procedure:
To N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methylpent-4-enamide (0.450 g, 1.41 mmol) in a flask with a stir bar dissolved in CH2Cl2 (13 mL) and MeOH (1.3 mL) was added Sudan III indicator solution (0.01 M, 0.060 mL). The flask was attached to an ozone generator and a flow of oxygen was initiated, with stirring. The reaction was cooled to −78° C., and the ozone production was bubbled through the solution for approxmately 6 minutes before the pink color was absent and the yellow solution started to turn green/blue. The ozone generation was arrested, and pure oxygen was bubbled through the reaction for approximately 5 minutes as the dark colors faded and the yellow color became prominent. While still at −78° C., triphenylphosphine (0.555 g, 2.12 mmol) was added as a solid, and the cooling bath was removed. A nitrogen gas inlet was attached to the flask, and the reaction was allowed to warm slowly to room temperature. The product was then concentrated and loaded onto CELITE®. Purification by flash column chromatography using 0-40% acetone/hexanes provided the title compound as a clear yellow oil that crystallized upon standing (0.390 g, 73%).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH2:18][OH:19])[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[Cl:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[O:29])[CH2:27]Br)[N:25]=1>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:17][CH2:18][O:19][C:26]([OH:29])([C:24]3[N:25]=[C:21]([Cl:20])[S:22][CH:23]=3)[CH2:27]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C(CBr)c1csc(Cl)n1
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Product: COC(=O)COc1ccc(CC(C)N2CCOC(O)(c3csc(Cl)n3)C2)cc1

Procedure:
from N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2- hydroxy-ethanamine and 2-chloro-4-bromoacetyl-thiazole.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH2:8][CH2:7]1)=[O:5].[N:31]1([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@H:32]1[C:41](O)=[O:42].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>>[CH3:21][N:20]([CH3:22])[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([C:4](=[O:5])[C@H:3]([NH:2][C:41]([C@@H:32]2[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:40][N:31]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:42])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:11][CH2:10]1)=[O:19]
Reactant: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl 3-[N-((1R)-2-{4-[2-(N,N-dimethylcarbamoyl)-phenyl]piperazinyl}-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl](3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate was prepared according to the procedure described in Preparation V by using (2-{4-[(2R)-2-amino-3-(4-chlorophenyl)-propanoyl]-piperazinyl}phenyl)-N,N-dimethylcarboxamide HCl salt (Step 5) (230 mg, 0.50 mmol), Boc-L-Tic-OH (Bachem Company) (150 mg, 0.55 mmol), HOAT (Aldrich) (68 mg, 0. 50 mmol), EDC (Aldrich) (190 mg, 1.00 mmol) and DIEA (Aldrich) (87 μL, 0.50 mmol). The compound was isolated and purified by column chromatography (CH2Cl2: 1.5% 2 M NH3 in MeOH). (255 mg). MS (ESI, pos. ion) m/z: 674 (M+H). Calc'd for C37H44ClN5O5: 674.23.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Br[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1>[Pd]>[CH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[CH:44][C:35]=1[CH2:34][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCCOc3ccccc3)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCCOc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 44 (e), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46 (b)] with (E)-(4-bromo-but-2-enyloxy)-benzene there was obtained tert-butyl (E)-(3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-but-2-enyloxy)-phenyl]-piperidine-1-carboxylate. Subsequent hydrogenation with palladium/charcoal analogously to Example 73 (c) yielded tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-butoxy)-phenyl]-piperidine-1-carboxylate, alkylation of which with 2-bromomethyl-naphthalene analogously to Example 1 (g) gave tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(4-phenoxy-butoxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 582 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](O)=[O:26])[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1.N1C(F)=NC(F)=NC=1[F:39].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([F:39])=[O:26])[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1N(CC(=O)O)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(F)cc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 100 %

Procedure:
In a manner similar to the method described in example 34a, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(hydroxycarbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione g, 0.19 mmol) prepared in example 55d was reacted with cyanuric fluoride (51 mg, 0.38 mmol) (Alfa) and pyridine (45 mg, 0.57 mmol) in dichloromethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (yield: 0.1 g, 100%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:9](=[O:12])[CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.Br[C:22]1[N:23]=[C:24]([NH:35][CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42]OCC2)C(NCC(OCC)=O)=NC=1.Cl>C(O)C>[NH:35]1[C:24]2=[N:23][CH:22]=[C:42]([C:2]3[N:7]=[C:6]4[N:8]([CH2:13][CH2:14][CH:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)[C:9](=[O:12])[CH2:10][NH:11][C:5]4=[N:4][CH:3]=3)[CH:43]=[C:38]2[CH:37]=[CH:36]1
Reactant: CCOC(=O)CNc1ncc(Br)nc1NCCC1CCOCC1
Reactant: O=C1CNc2ncc(Br)nc2N1CCC1CCOCC1
Agent: Cl
Solvent: CCO
Product: O=C1CNc2ncc(-c3cnc4[nH]ccc4c3)nc2N1CCC1CCOCC1
Temperature: 100 °C

Procedure:
7-Bromo-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. Ethyl 2-(5-bromo-3-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)pyrazin-2-ylamino)acetate (0.5 g, 1.291 mmol) and hydrochloric acid (6 M in water, 0.215 mL, 1.291 mmol) were combined in ethanol (2 mL) and the resulting mixture was heated in a Biotage Emrys Optimizer microwave reactor at 100° C. for 2400 s. The reaction mixture was concentrated and purified using silica gel chromatography (33% ethyl acetate in hexanes) to yield the title compound (quantitative yield). MS (ESI) m/z 341.1 [M]+, 343.1 [M+2]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([CH3:11])[CH:3]=1.Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:9]2=[S:10])=[C:4]([CH3:11])[CH:3]=1
Reactant: CCOC(=O)CNC
Reactant: Cc1cc(Cl)ccc1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)ccc1N1C(=O)CN(C)C1=S
Yield: 58.9 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 9.18 g of 4-chloro-2-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the title compound (7.5 g) as an off-white solid, m.p. 113°-115° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.72; H, 4.17; N, 10.88. Mass spectrum (EI, M.+) m/z 254/256.