Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24]Cl)[CH:21]=[C:20]([Cl:26])[CH:19]=1.Cl>CN(C)C=O.C(OCC)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][O:11][CH2:24][C:22]1[CH:23]=[C:18]([Cl:17])[CH:19]=[C:20]([Cl:26])[CH:21]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC(COCc1cc(Cl)cc(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-t-butoxycarbonyl-D-serine (10.0 g, 48.7 mol) in N,N-dimethylformamide (150 mL) at about 0° C. was added sodium hydride (4.0 g, 60% dispersion in mineral oil, 99.84 mmol) portionwise. The mixture was stirred for about 30 minutes, and then a solution of 1,3-dichloro-5-chloromethyl-benzene (9.5 mL, 48.7 mmol) in ethyl ether (40 mL) was added. The reaction was allowed to slowly warm to room temperature overnight. The reaction was then quenched with 1N NaOH, the mixture extracted three times with dichloromethane. The combined organic layers were then washed three times with water, 1N, HCl, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give crude product. The original basic aqueous layer was then acidified to about pH 4 with HCl, and the mixture was extracted three times with dichloromethane. These three organic layers were combined and washed three times each with water and brine then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an additional 620 mg of crude product. Both product fractions were combined and purified by silica gel chromatography using 5% methanol/chloroform as eluent and yielded the title compound of part 1-E (12.39 g, 70%): −APcl MS (M−1)− 363, (M−3)− 361; 1H NMR=400 MHz (CDCl3) δ: 7.13 (arom, s, 3H), 5.42 (NH, d, 1H), 4.50 (CHCO2H, m, 1H), 4.45 (PhCH2O, s, 2H), 3.82 (CH2OBz, d of d, 2H), 1.43 (BOC, s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33]([CH2:35][C:36]#[CH:37])[CH3:34]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:37]#[C:36][CH2:35][N:33]([CH3:34])[CH3:32])[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN(C)C
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CN(C)CC#Cc1cc(CC2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Yield: 70 %

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide (0.070 g), copper iodide (0.013 g), Pd(PPh3)2Cl2 (0.007 g) and N,N-dimethylpropargylamine (0.020 mL) in 7 mL diethylamine is stirred at room temperature for 3 days. The reaction is partitioned between CH2Cl2 and H2O. The aqueous layer is extracted 3×with CH2Cl2. The organics are combined, dried over Na2SO4, filtered and concentrated. The residue is dissolved in CH2Cl2 and adsorbed onto silica. Purification by Biotage Flash 40S (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3% MeOH/CH2Cl2 (1L), 4% MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (1L)) affords the product as a tan residue. Recrystallization with CH2Cl2/hexanes affords the desired product (0.046 g, 70%).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:8]=[CH:9][C:10]([Cl:15])=[C:11]([CH:14]=1)[C:12]#[N:13])[CH2:3][N:4]([CH3:6])[CH3:5].O[C:17]1[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH2:29])=[O:28])[C:19]=2[N:20]=[N:21][N:22]=1>>[Cl:15][C:10]1[CH:9]=[CH:8][C:7]([C@H:2]([NH:1][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH2:29])=[O:28])[C:19]=3[N:20]=[N:21][N:22]=2)[CH2:3][N:4]([CH3:6])[CH3:5])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CN(C)C[C@@H](N)c1ccc(Cl)c(C#N)c1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: CN(C)C[C@@H](Nc1nnnc2c(C(N)=O)cccc12)c1ccc(Cl)c(C#N)c1

Procedure:
Compound 17 was prepared following general synthetic scheme 7 wherein (S)-5-(1-amino-2-(dimethylamino)ethyl)-2-chlorobenzonitrile was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [397 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 8.81 (d, 1H), 8.63 (d, 1H), 8.55 (d, 1H), 8.15 (d, 1H), 8.05-8.01 (m, 2H), 7.88 (dd, 1H), 7.72 (d, 1H), 5.78 (q, 1H), 2.95-2.89 (m, 1H), 2.62-2.58 (m, 1H), 2.24 (s, 6H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C-:18]#[N:19].[Na+].S(=O)(=O)(O)O>O1CCOCC1>[C:18]([CH:12]([OH:13])[C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)#[N:19]
Reactant: O=Cc1cccc(C(=O)c2ccccc2)c1
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CC(O)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 1 h

Procedure:
3-Benzoylbenzaldehyde (1.0 g) in dioxan (5 ml) was treated with water (2.5 ml) and sodium cyanide (0.5 g). The whole was cooled below 15° C. and 40% sulphuric acid (1.4 ml) added dropwise (care being taken to ensure that this temperature was not exceeded). Stirring was continued for 1 hour when water (30 ml) was added and the product extracted with methylene chloride and washed with water, saturated NaCl, dried over Na2SO4 and evaporated.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Reaction time: 2.5 h
Yield: 98.1 %

Procedure:
To a solution of N-Boc-piperidone (3.0 g, 15.1 mmol) in THF (76 mL) was added benzylamine (1.65 mL, 15.1 mmol), acetic acid (0.86 mL, 15.1 mmol) and sodium triacetoxyborohydride (4.8 g, 22.6 mmol). After stirring 2.5 hours the reaction mixture was concentrated under reduced pressure and CH2Cl2 (50 mL) and saturated aqueous NaHCO3 solution (50 mL) was added. The organic phase was separated, and the aqueous was extracted with CH2Cl2 (2×50 mL). The combined organic phases were then dried (MgSO4), filtered, and concentrated under reduced pressure to afford 4-benzylamino-piperidine-1-carboxylic acid tert-butyl ester (4.30 g, 98%).
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][CH:4]=[C:5]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7].Cl[CH2:32][C:33]#[CH:34].CN(C)C=O.[H-].[Na+]>O>[F:1][CH:2]([F:30])[O:3][CH:4]=[C:5]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:34][C:33]#[CH:32])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7]
Reactant: C#CCCl
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1ccc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
239 mg of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (0.572 mmol), 128 mg (1.72 mmol) of 3-chloropropyne, 3 ml of anhydrous N,N-dimethylformamide and 20 mg (0.50 mmol) of 60% sodium hydride were mixed and stirred at room temperature for 4 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 225 mg of 3-difluoromethoxy-N-[2-{3-methoxy-4-(2-propynyloxy)phenyl}ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1268).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=O)[N:5]=[N:4][N:3]=1.[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: CCOC(=O)Cn1nnnc1S
Reactant: CNC
Solvent: CCO
Product: CN(C)C(=O)Cn1nnnc1S
Reaction time: 168 h

Procedure:
Ethyl 5-mercapto-1H-tetrazol-1-ylacetate (1.5 g) in ethanol (10 ml) and 33% dimethylamine in ethanol (6 ml) were mixed and set aside for seven days. Further 33% dimethylamine in ethanol (6 ml) was added and the solution left for 7 more days then evaporated to dryness in vacuo. The residue was dissolved in water (50 ml), adjusted to pH 1.8, and concentrated to ca 20 ml in vacuo. The solution was cooled in ice and the crystalline product collected, 0.94 g (63.0%), m.p. 204°-205°; ε [(CD3)2CO] 3.02 and 3.28 (6H, 2×s --N(CH3)2), 5.35 (2H,s, --CH2CO--), 7.7 (1H,bs, --SH). Found: C, 32.21; H, 5.01; N, 37.63; S, 16.99. C5H9N5OS requires: C, 32.08; H, 4.85; N, 37.41; S, 17.13%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].F[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=1>C1COCC1>[O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=2)[CH2:2]1
Reactant: O[C@H]1CCOC1
Reactant: Nc1cc(F)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1cc(O[C@H]2CCOC2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(S)-tetrahydrofuran-3-ol (707 mg, 8.03 mmol) was treated with KHMDS (1 M in THF, 5.89 ml, 5.89 mmol) and stirred at room temperature for 5 min. Then, the mixture was added to a solution of 4-fluoropyridin-2-amine (300 mg, 2.68 mmol) in THF (15 ml). The resulting brown solution was stirred for 16 h. KHMDS (1 M in THF, 2.68 ml, 2.68 mmol) was added to the reaction and the reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a pink solid. (UPLC-MS 3) tR 0.30 min; ESI-MS 181.1 [M+H]+.
Reaction SMILES: [SH:1][CH:2]([CH:8]([C:13]([NH:15][CH:16]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[O:29])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][C:4]([O:6]C)=[O:5]>C(O)(C)C>[SH:1][CH:2]([CH:8]([C:13]([NH:15][CH:16]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[O:29])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(S)C(CC(C)C)C(=O)NC1CCCCCCCCCCNC1=O
Solvent: CC(C)O
Product: CC(C)CC(C(=O)NC1CCCCCCCCCCNC1=O)C(S)CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 3-mercapto-6-methyl-4-[(2-oxoazacyclotridec-3 yl)aminocarbonyl]heptanoic acid, methyl ester (E2A) (1.03 g) in isopropanol (15 ml), previously purged with nitrogen, was added a solution of sodium hydroxide (0.29 g) in water (5 ml) and the resulting solution was stirred at room temperature, under nitrogen, for 18 h. The solution was acidified with an excess of ethereal-HCl and then evaporated to dryness in vacuo. The residue was treated with isopropanol and then evaporated to dryness in vacuo.
Reaction SMILES: C1C=C2C=C[C:9](O)=[C:10]([C:11]3[C:20]4[C:15](=CC=CC=4)[CH:14]=[CH:13][C:12]=3[OH:21])[C:4]2=CC=1.[CH2:23]([Al](CC)CC)C>C1(C)C=CC=CC=1>[CH3:23][C@H:14]1[CH2:13][C@@H:12]([OH:21])[C@H:11]([C:10]([CH3:9])=[CH2:4])[CH2:20][CH2:15]1
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reactant: CC[Al](CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
In a 300-ml reaction flask, 2.29 g (8.0 mmol) of (R)-1,1′-bi-2-naphthol was placed and the air in the flask was replaced with nitrogen gas. Then, 116 ml of toluene and 5 ml (5.0 mmol) of a toluene solution of triethylaluminum (1.0 mol/L) were successively added thereto and the mixture was stirred at room temperature for 1 hour, to give a catalyst solution. After the catalyst solution was cooled to a temperature of 0 to 5° C., 38.6 g (250 mmol) of d-citronellal was slowly added dropwise thereto, and the mixture was stirred at a temperature of 0 to 5° C. for 9 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo, and continuously toluene was distilled off at a temperature of 110 to 115° C. at a pressure of 2.93 to 3.33 kPa (22 to 25 mmHg), to give 31.0 g of the objective l-isopulegol at the yield of 80.3%. The GC analysis results show that the purity was 99.0% and that the ratio of l-isopulegol to the other isomers was 98.7:1.3.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17](C)=[CH:18]C=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C([Li])CCC.CC1[O:42]C(C=O)=C(C)N=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[O:42][C:17]([CH3:18])=[N:16][C:15]=3[CH3:21])[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(C)c(C=O)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3oc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a 50 mL flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.5 g, 3.48 mmol, Intermediate 47: step d) was added THF (65 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. which remained homogeneous and then n-butyllithium (2.5 M in hexanes, 1.62 mL, 4.04 mmol) was added drop wise. The color of the solution became a dark opaque reddish-brown color. After 2 minutes, 2,4-dimethyloxazole-5-carbaldehyde (520 mg, 4.16 mmol, in 3 mL THF) was introduced and the color of the mixture went from an opaque dark brown to a light yellow homogeneous color within about 1 minute. After 25 minutes the mixture was quenched with aqueous NH4Cl. The reaction was diluted further with water and extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a light yellowish foam. The crude material was chromatographed on silica gel (10% CH3CN-DCM grading to 30% CH3CN containing 1% MeOH) to provide the title compound as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Reactant: Fc1cccc(CBr)c1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-chloro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (100) and 3-fluorobenzyl bromide according to General Procedure B. Yield 214 mg (42%), MP 204° C.; 1H-NMR (DMSO-d6): δ 3.76 (m, 4H), 3.92 (m, 4H), 5.51 (s, 2H), 7.06 (m, 3H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.33 (m, 1H), 7.50 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (dd, J=1.2, 5.2 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H); EIMS: 508 (M+1). Anal. (C25H19ClFN5O2S) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])[S:5][CH:6]=1.[Br:13]Br.O>C(O)(=O)C>[Br:13][C:6]1[S:5][C:4]([NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[N:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1csc(NC(=O)C2CC2)n1
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(NC(=O)C2CC2)sc1Br
Reaction time: 0.5 h

Procedure:
To N-(4-methylthiazol-2-yl)cyclopropanecarboxamide (10.05 g) in acetic acid (100 ml) under an ice-water bath was added bromine (3.2 ml). After 30 min, water (100 ml) was added. Filtration, washing with water (3×) and drying under vacuum afforded N-(5-bromo-4-methylthiazol-2-yl)cyclopropanecarboxamide as a white solid (12.47 g). H NMR (500 MHz, CDCl3) 2.39 (s, 3 H), 1.64-1.60 (m, 1 H), 1.27-1.24 (m, 2 H), 1.00-0.96 (m, 2 H) ppm; LC/MS: 261 (M+1)/2.91 min.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8]([C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][C:15]([OH:17])=[O:16])=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:7]=[C:2]1[NH:3][C:4](=[O:6])[C:5](=[CH:8][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[O:13][CH2:14][C:15]([OH:17])=[O:16])[S:1]1
Reactant: O=Cc1cccc(OCC(=O)O)c1
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)COc1cccc(C=C2SC(=O)NC2=O)c1
Yield: 55.7 %

Procedure:
Thiazolidine-2,4-dione (3.9 g, 33 mmol), 3-formylphenoxyacetic acid (6.0 g, 33 mmol), anhydrous sodium acetate (13.6 g, 165 mmol) and acetic acid (100 mL) was refluxed for 16 h. After cooling, the mixture was filtered and washed with acetic acid and water. Drying in vacuo afforded 5.13 g (56%) of [3-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]acetic acid as a solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9](=[O:12])[CH:10]=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23]>CO>[CH2:1]([C@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9](=[O:12])[CH2:10][CH2:11][N:22]([CH3:23])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CNC
Solvent: CO
Product: CN(C)CCC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared according to Scheme 1 in an analogous manner as intermediate III with the one additional step; step B involving Michael addition using dimethyl amine (vida infra). Step A: To a solution of N-Boc-phenylalanine-Weinreb amide (10.0 g, 32.4 mmol) in 200 mL THF cooled to −40° C. was added vinyl magnesium bromide (97.0 mL, 97.0 mmol, 1.0 M in THF) dropwise. After stirring at −40 to −20° C. for 5 h. The reaction mixture was poured onto cold 3N HCl (600 mL), extracted with EtOAc (3×200 mL), the organic layers combined and washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford crude tert-butyl (1S)-1-benzyl-2-oxobut-3-enylcarbamate which was used as is in the following Michael addition reaction. Step B: In a flask containing tert-butyl (1S)-1-benzyl-2-oxobut-3-enylcarbamate (0.75 g, 2.72 mmol) in MeOH (10 mL) was added dimethyl amine (2.73 mL, 2.0 M MeOH, 5.45 mmol). The mixture was stirred at rt for 1 h. The mixture was concentrated to dryness to give tert-butyl (1S)-1-benzyl-4-(dimethylamino)-2-oxobutylcarbamate which was used in the next reaction without further purification. Step C: In a 50 mL flask containing ketone (825 mg, 2.57 mmol) from step B in 25 mL of EtOH at room temperature was added NaBH4 (92 mg, 2.57 mmol) in two portions. The mixture was stirred overnight and lmL of H2O added. The reaction was concentrated to dryness and partitioned between EtOAc and H2O. The layers were separated and the aqueous layer extracted once again. The combined organic layers were washed with brine, dried over Na4SO4 and concentrated to dryness to give crude tert-butyl (1S,2RS)-1-benzyl-4-(dimethylamino)-2-hydroxybutylcarbamate. 1H NMR indicated a mixture of alpha and beta diastereomers. The crude material was deprotected in step D below without further purification. Step D: A scintillation vial containing tert-butyl (1S,2RS)-1-benzyl-4-(dimethylamino)-2-hydroxybutylcarbamate (250 mg, 0.78 mmol) in EtOAc was cooled to 0° C. HCl (g) was gently bubbled into the mixture for ca. 1 min. The vial was sealed with a cap and allowed to warm to rt. After 30 min. the mixture was concentrated with N2 and then concentrated further via rotorary evaporation to give an off-white solid intermediate XII, N-(2S,3RS)-2-amino-5-(dimethylamino)-1-phenylpentan-3-ol as hydrochloride salt: (2:1 ratio of diastereomers, major isomer reported) 1H NMR (400 MHz, MeOD) δ 7.28 (m, 5H), 3.91 (dt, J=6.9 Hz, 3.6 Hz, 1H), 3.61 (m, 1H), 3.35 (m, 2H) 3.22 (m, 2H), 2.9-3.0 (overlapping m, 2H), 2.89 (s, 6H); ES MS (M+H)=223.3.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH2:10][NH+:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2].[I-].[OH-:29].[Na+]>O>[CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[C:10](=[O:29])[N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2]
Reactant: CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Reactant: [OH-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCc1c2n(c(=O)c3c(OC)c(OC)ccc13)CCc1cc3c(cc1-2)OCO3
Yield: 12 %

Procedure:
A mixture of 13-ethyl-9,10-dimethoxy-5,6-dihydro[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (1.1 g, 2.2 mmol) and 30% sodium hydroxide in water (150 mL) was refluxed for 56 h. The precipitate formed was collected and treated with hot 3% hydrochloric acid. The precipitate was collected and re-crystallized from ethanol to afford 13-ethyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-8-one (100 mg. 12%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][CH3:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:9][NH:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[C:1]([O:5][C:6]([CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH3:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:9][NH:10][CH3:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNCC(C(=O)OC(C)(C)C)c1ccc([C@H]2CC[C@H](NC)CC2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CNCC(C(=O)OC(C)(C)C)c1ccc([C@H]2CC[C@H](N(C)C(=O)c3ccc(Cl)cc3)CC2)cc1

Procedure:
from trans-4-[4-(1-tert.butoxycarbonyl-methylaminoethyl)-phenyl]-N-methylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 172°-174° C.