Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[C:18]([OH:21])(=[S:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([S:20][CH2:3][CH2:2][CH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[O:11][CH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][O:15]2)=[CH:8][CH:9]=1)(=[O:21])[CH3:19]
Reactant: CC(O)=S
Reactant: C=CCc1ccc(C2OCC(C)(C)CO2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)SCCCc1ccc(C2OCC(C)(C)CO2)cc1
Temperature: 90 °C
Yield: 63.8 %

Procedure:
Following a general procedure (Lub et al. (1997) Liebigs Ann. Recueil, 2281-2288), 13 (845 mg, 3.60 mmol) and thioacetic acid (910 μL, 12.7 mmol) were dissolved in toluene (20 mL) and the solution was purged with argon for 15 min. Then AIBN (200 mg) was added and the mixture was heated to 90° C. Over a period of 23 h more AIBN (1.10 g) was added in several portions. Then aq NaHCO3 (10%, 50 mL) was added and the phases were separated. The aqueous phase was washed with ether and the combined organic phases were dried (Na2SO4). Purification by column chromatography (silica, ether/hexanes, 1:4) gave an orange oil, which solidified upon standing at −20° C. and was recrystallized from pentane to give 708 mg (63%) of colorless needles. mp 44° C. IR (neat): {tilde over (v)} 2951, 2850, 1692, 1620, 1518; 1H NMR δ 0.79 (s, 3H), 1.29 (s, 3H), 1.78-1.94 (m, 2H), 2.33 (s, 3H), 2.68 (t, 3J=7.3 Hz, 2H), 2.86 (t, 3J=7.3 Hz, 2H), 3.64 (d, 2J=11.0 Hz, 2H), 3.76 (d, 2J=11.0 Hz, 2H), 5.37 (s, 1H), 7.18, 7.42 (AA′BB′, 2×2H); 13C NMR (APT) δ 21.6 (−), 22.8 (−), 28.1 (+), 29.9 (+), 30.4 (−), 30.8 (+), 34.3 (+), 77.3 (+), 101.4 (−), 126.0 (−), 128.1 (−), 136.1 (+), 141.5 (+), 195.3 (+); GC-MS (EI) obsd 308, 307, 265, 232, 221, 204, 199, 180, 146, 133, 115, 91, 69, 43; Anal. Calcd for C17H24O3S: C, 66.20; H, 7.84; S, 10.40. Found: C, 66.19; H, 7.89; S, 10.54.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:18]([Cl:29])[CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].[CH3:38][NH:39][CH2:40][CH2:41][OH:42].O>CN(C)C=O>[Cl:29][C:18]1[CH:17]=[C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:39]([CH2:40][CH2:41][OH:42])[CH3:38])=[C:6]([O:30][CH3:31])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)[CH:21]=[CH:20][C:19]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCBr)c(OC)cc23)cc1Cl
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCN(C)CCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 106 %

Procedure:
A starting compound (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea, 50 mg), potassium carbonate (138 mg), and 2-(methylamino)ethanol (0.040 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 53 mg (yield 106%) of the title compound.
Reaction SMILES: CS(O[CH2:6][C@H:7]([CH:23]([CH3:25])[CH3:24])[CH2:8][C@H:9]1[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN1CCCN(C)C1=O>[N:26]([CH2:6][C@H:7]([CH:23]([CH3:25])[CH3:24])[CH2:8][C@H:9]1[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N+:27]=[N-:28]
Reactant: CC(C)[C@@H](COS(C)(=O)=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: CC(C)[C@@H](CN=[N+]=[N-])C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The mixture of 3.47 g of tert-butyl 4(S)-(2(S)-methanesulphonyloxymethyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxyiate and 3.57 g of sodium azide in 50 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is stirred at 50° C. over 3 hours. The reaction mixture is cooled, poured onto water and extracted with diethyl ether (3×). The combined organic phases are washed successively with water (2×) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.63 (1:1 EtOAc-heptane); Rt=5.86 (gradient I).
Reaction SMILES: C(O)C.C(O[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)=[O:8])C.CC[O-].[Na+].[CH2:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(=O)N2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C1CCc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Yield: 9.5 %

Procedure:
To 100 ml of ethanol was added 2.0 g of 6-ethoxycarbonyl-3,4-dihydrocarbostyril, 0.5 g of sodium ethylate and 1.6 g of benzylpiperazine, the mixture was reacted in an autoclave under 110 atmospheric pressure at 140°-150° C. for 6 hours. After the reaction was completed, the reaction mixture was cooled and concentrated under a reduced pressure. The residue thus obtained was dissolved in 200 ml of chloroform and the chloroform solution was washed with 1%-potassium carbonate aqueous solution, a diluted hydrochloric acid and water in this order, then dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was treated by means of a silica gel column chromatography (Silica gel: Wako C-200, eluate:chloroform:methanol (volume/volume)=20:1) and the crude crystals were recrystallized from ethanol to obtain 300 mg of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 198°-200° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:31]CCl>CN(C)C=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([Cl:31])=[O:27])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCl
Reactant: O=C(O)/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Temperature: 42 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a suspension of (E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoic acid (9a) (0.30 g, 0.69 mmol) in dichloromethane (7 mL) oxalyl chloride (0.2 mL, 2.4 mmol) and a drop of dimethylformamide were added. The reaction mixture was stirred at ambient temperature for 0.5 hours and at 42° C. for 1 hour. The reaction mixture was evaporated and the residue was dried in vacuum to give (E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10a) (0.31 g) in a form of a crude product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][C@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:41]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:41])=[O:26])=[C:21]([O:28][C@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:39])([F:38])[F:40])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@@H](C)c1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: C[C@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example A5, 368 mg of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{(1S)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate and 41 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[OH:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1.CCN(C(C)C)C(C)C.[I-].C(C[P+](C)(C)C)#N>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:22]2[CH2:23][CH2:24][CH2:25][C@@H:20]([OH:19])[CH2:21]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O[C@@H]1CCCNC1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(CCN2CCC[C@@H](O)C2)CC1

Procedure:
It is prepared analogously to 9 starting from tert-butyl ester 8 (3.52 g, 14.41 mmol), (R)-3-hydroxy-piperidine hydrochloride (2.18 g, 15.85 mmol), DIEA (5.6 ml, 33.14 mmol) and cyanomethyl-trimethyl-phosphonium iodide (4.2 g, 17.29 mmol).
Reaction SMILES: [CH:1]([N:4]([CH:25]([CH3:27])[CH3:26])[CH2:5][CH2:6][C:7]([CH2:16][CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].[OH-:28].[Na+]>S(=O)(=O)(O)O>[CH:22]([N:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][C:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:25]([CH3:27])[CH3:26])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]([NH2:9])=[O:28])([CH3:24])[CH3:23]
Reactant: CC(C)N(CCC(C#N)(CCN(C(C)C)C(C)C)c1ccccc1)C(C)C
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)N(CCC(CCN(C(C)C)C(C)C)(C(N)=O)c1ccccc1)C(C)C
Temperature: 0 °C

Procedure:
2 Parts of α,α-bis[2-(diisopropylamino)ethyl]-α-phenylacetonitrile is dissolved in 20 parts by volume of concentrated sulfuric acid and the resulting solution heated on a steam bath for about 90 minutes. The solution is then cooled to about 0° C. and made alkaline by the addition of dilute sodium hydroxide. The alkaline solution is extracted with ether, the ether extract dried over calcium sulfate and stripped of solvent to afford α,α-bis[2-(diisopropylamino)ethyl]-α-phenylacetamide, melting at about 102°-103° C. after crystallization from hexane. This compound has the following structural formula ##STR13##
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3[N:11]=[C:12](S(C)(=O)=O)[N:13]=[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])[C:9]=3[CH:8]=[CH:7][C:6]2=[O:26])[CH2:3][CH2:2]1.[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30]>>[CH:1]1([CH2:4][N:5]2[C:10]3[N:11]=[C:12]([NH:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30])[N:13]=[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])[C:9]=3[CH:8]=[CH:7][C:6]2=[O:26])[CH2:3][CH2:2]1
Reactant: NC(CO)CO
Reactant: CS(=O)(=O)c1nc(-c2ccccc2F)c2ccc(=O)n(CC3CC3)c2n1
Product: O=c1ccc2c(-c3ccccc3F)nc(NC(CO)CO)nc2n1CC1CC1

Procedure:
The product of Example 50, and serinol were reacted by the procedure of Example 60 to afford the title compound 8-cyclopropylmethyl-4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 0.40 (m, 4H), 1.25 (m, 1H), 3.89 (m, 4H), 4.13 (m, 3H), 5.75 (m, 1H), 6.30 (d, 1H, J=9.8 Hz), 6.59 (br s, 1H), 7.08-7.48 (m, 5H). LC MS (m/e)=385 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[NH:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9][C:8]([Cl:18])=[CH:7][CH:6]=2.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[Cl:18][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:19])[C:2]([NH:1][C:29]([NH:28][C:22]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=1[F:20])=[O:30])=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Nc1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1F)Nc1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A mixture of 3-amino-6-chloro-4-phenyl-2(1H)-quinolone (160 mg), 2,4-difluorophenylisocyanate (0.09 ml) and anhydrous tetrahydrofuran (2 ml) was allowed to stand overnight at room temperature. The precipitated crystals were collected and recrystallized from dimethylformamide containing water to give colorless needles of N-(6-chloro-1,2-dihydro-2-oxo-4-phenyl-3-quinolyl)-N'-(2,4-difluorophenyl)urea (185 mg, 73.4%). mp 222°-224° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:20][OH:21])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH2:17][O:18][CH3:19].I[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[OH:21][CH2:20][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH2:17][O:18][CH3:19])=[C:2]([O:1][CH2:23][CH2:24][CH3:25])[CH:3]=[N:4][CH:5]=1
Reactant: CCCI
Reactant: COCOc1cc(OC)ccc1-c1c(O)cncc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cncc(CO)c1-c1ccc(OC)cc1OCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-hydroxy-5-hydroxymethyl-4-(2-methoxymethoxy-4-methoxy-phenyl)-pyridine (550 mg, 1.89 mmol), iodopropane (0.210 ml, 2.15 mmol), potassium carbonate (3 g) in dry DMF (70 ml) was stirred overnight at rt. The mixture was dissolved in water and extracted with a 1:1 hexane:t-butyl methyl ether solution (×3) and washed with brine, dried (Na2SO4), and concentrated to afford the title compound as a greenish oil. (527 mg, 84%)
Reaction SMILES: O=S1[O:6][CH:5]([C@@H:7]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]O1.[C:26]([NH:30][C:31]([C@@H:33]1[CH2:42][C@H:41]2[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][NH:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[C:26]([NH:30][C:31]([C@@H:33]1[CH2:42][C@H:41]2[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][N:34]1[CH2:4][C@@H:5]([OH:6])[C@@H:7]([N:15]1[C:16](=[O:25])[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:23]1=[O:24])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C1c2ccccc2C(=O)N1[C@@H](Cc1ccccc1)C1COS(=O)O1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Yield: 65 %

Procedure:
A suspension of 0.35 g of the above 83:17 mixture of the two 1:1 mixtures of the (2R,4S) and (2S,4S) and respectively (2R,4R) and (2S,4R) isomers of 2-[(S)-1-[2-oxo-1,3,2-dioxathiolan-4-yl]-2-phenylethyl]-2,3-dihydro-1H-isoindol-1,3-dione, 0.24 g of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 0.21 g of sodium carbonate in 3.5 ml of isobutyl methyl ketone is heated to reflux for 24 hours, thereafter cooled and filtered. The filtrate is purified on silica gel with hexane/ethyl acetate (4:1). After evaporation and drying there is obtained 0.34 g (65%) of pure N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide, IR (KBr): 3388 m (OH), 1771 m and 1708 s (C=O of imide).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:24])[C:17]([CH:25]=O)=[C:16]1[CH3:27].CN1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:5][NH:6][CH2:25][C:17]1[C:18]2[C:23](=[C:22]([CH3:24])[CH:21]=[CH:20][CH:19]=2)[N:15]([CH3:14])[C:16]=1[CH3:27]
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: Cc1cccc2c(C=O)c(C)n(C)c12
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1c(C)n(C)c2c(C)cccc12
Yield: 71 %

Procedure:
According to the procedure of Preparation 13 (c) except substituting 1,2,7-trimethyl-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (570 mg, 71%) was obtained as an oil which slowly crystallized: MS (ES) m/e 405.4 (2M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH2:7].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12]>O.OC1CC(C)(C)[NH+]([O-])C(C)(C)C1>[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH:7][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: COC(CN)OC
Reactant: C=C(C)C(=O)Cl
Agent: CC1(C)CC(O)CC(C)(C)[NH+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)C(=O)NCC(OC)OC
Temperature: -10 °C
Yield: 82.4 %

Procedure:
220 g (5.5 mol) of sodium hydroxide are dissolved in 300 g of water and 700 g of ice in a 3-liter reactor having a stirrer and a cooling system. The sodium hydroxide solution is cooled to 10° C. and 526 g (5.0 mol) of aminoacetaldehyde dimethylacetal and 50 mg of 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxide (radical inhibitor) are added. 548.6 g (5.5 mol) of methacrylic acid chloride are slowly added at 10° C. to the solution over a period of 3.5 hours. When the addition is complete, the pH value drops slowly to 7.2 and amine can no longer be detected by GC. The reaction mixture is extracted with 500 ml of petroleum ether, and in order to remove impurities, the aqueous phase is saturated with sodium chloride and extracted three times with 500 ml of tert-butyl methyl ether. The organic phase is dried with magnesium sulfate, filtered and concentrated using a rotary evaporator. The resulting 882.2 g of yellowish oil are slowly stirred into 2000 ml of petroleum ether at -10° C. by means of an Ultraturax. The product crystallises, and is isolated by filtration and dried. 713.8 g of methacrylamidoacetaldehyde dimethylacetal (86% of theory), melting point 30°-32° C., are obtained; the product is 99.7% according to GC.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13]Br)=[O:6])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[SH:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>CC(C)=O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:25]2[CH:26]=[CH:27][C:22]([SH:21])=[CH:23][CH:24]=2)=[CH:24][CH:23]=1)=[O:6])#[N:2]
Reactant: Sc1ccc(S)cc1
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CSc1ccc(Sc2ccc(S)cc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
trans-2-Bromomethyl-cyclohexanecarboxylic acid cyanomethylamide (259 mg) and cesium carbonate (340 mg) were weighed into a 15 mL vial fitted with a stir bar and a vent cap. Acetone (3 mL) and 4-mercaptothiophenol (256 mg) were added. The reaction mixture was stirred at 50° C. overnight and then diluted with hot acetone (7 mL) and filtered through Celite™. The Celite™ was washed with hot acetone (25 mL). The filtrate and wash were combined and the solvent was removed on a rotary evaporator. Chromatography of the crude product on C-18 reverse-phase HPLC provided the title compound as a cream solid. 1H NMR (DMSO-d6): δ=8.65 (1H, t), 7.46 (2H, dd), 7.27 (4H, d), 7.21 (2H, dd), 4.12 (2H, d), 3.50 (1H, br m), 2.98 (1H, d), 2.6 (1H, m), 2.1 (2H, m), 1.7 (4H, m), 1.1 (4H, m).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15]([CH3:18])([CH3:17])[NH:14][C:13](=O)[C:12]=2[CH:20]=1)#[N:7]>CN(C)C=O>[Cl:3][C:13]1[C:12]2[CH:20]=[C:8]([C:6]#[N:7])[CH:9]=[CH:10][C:11]=2[O:16][C:15]([CH3:18])([CH3:17])[N:14]=1
Reactant: CC1(C)NC(=O)c2cc(C#N)ccc2O1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C)N=C(Cl)c2cc(C#N)ccc2O1
Reaction time: 0.17 h

Procedure:
Phosphorous oxychloride (0.5 ml) was added with ice-cooling to dimethylformamide (10 ml) and the mixture was stirred for 10 minutes. To the mixture was added 6-cyano-2,2-dimethyl-3,4-dihydro-2H-1,3-benzoxazin-4-one (1.0 g), and the mixture was stirred with ice-cooling for 1 hour and then at room temperature for 2 hours. The mixture was extracted with addition of ethyl acetate and ice water. The ethyl acetate layer was successively washed with an aqueous sodium bicarbonate solution and saturated saline, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Hexane was added to the residue and 4-chloro-6-cyano-2,2-dimethyl-2H-1,3-benzoxazine (0.41 g, mp. 124°-126° C.) was obtained by crystallization therefrom.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([S:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH:47][C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([S:25][CH:8]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccc(SC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1ccc(SC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a mixture of 4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoic acid (100 mg, 0.5 mmol) in methylene chloride (5 mL) are added triethyl amine (0.09 mL, 0.62 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (86.2 mg, 0.62 mmol) and EDCI (118.7 mg, 0.62 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-(4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoylamino)-propionic acid methyl ester (90 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12]S(C)(=O)=O)=[CH:9][CH2:8][CH:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[O:19])[C:6]1=[O:30].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][N:32]=[N+:33]=[N-:34])=[CH:9][CH2:8][CH:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[O:19])[C:6]1=[O:30]
Reactant: COC(=O)CN1CC(CS(C)(=O)=O)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1CC(CN=[N+]=[N-])=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a solution of {6-[(methane-sulfonyl)methyl]-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 23, (1.62 g, 3.52 mmol) in DMF(10 mL) is added sodium azide at room temperature. The reaction is then heated to 50° C. and stirred 18 hours after which time the solution is diluted with water. The resulting solution is extracted three times with CH2Cl2 (70 mL), the organic layers combined and washed with saturated NaHCO3, saturated NaCl, and dried (Na2SO4). The solvent is removed in vacuo and the resulting residue is purified by HPLC to afford 0.46 g (59% yield) of the desired product. 1H NMR (CDCl3) δ 9.49–9.46 (m, 1H), 9.21–9.19 (d, J=6.9 Hz, 1H), 8.48–8.46 (m, 1H), 7.81–7.74 (m, 2H), 7.69–7.60 (m, 2H), 5.83–5.81 (m, 1H), 5.51–5.43 (m, 1H), 4.76–4.69 d, d, J=17.4, 2.4 Hz, 1H), 4.46–4.40 (d, J=17.4 Hz, 1H), 4.20–4.14 (d, J=17.7 Hz, 1H), 3.84–3.76 (d, J=13.2 Hz, 1H), 3.74–3.70 (m, 3H), 3.68–3.64 (d, J=13.2 Hz, 1H), 3.44–3.39 d, J=17.7 Hz, 1H), 2.99–2.92 (d, d, J=18.3, 3.9 Hz, 1H), 2.50–2.40 (d, d, J=15.6, 14.7 Hz, 1H); MS 409 (M+H)+.