Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]([C:9]1[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:19])[C:12]([OH:20])=[CH:11][CH:10]=1)=[O:8])[CH2:2]2.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>>[F:26][C:25]([F:28])([F:27])[S:22]([O:20][C:12]1[C:13]2[C:18](=[C:17]([CH3:19])[CH:16]=[CH:15][CH:14]=2)[C:9]([C:7]([N:3]2[CH2:2][CH:1]3[CH:5]([CH2:6]3)[CH2:4]2)=[O:8])=[CH:10][CH:11]=1)(=[O:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc2c(O)ccc(C(=O)N3CC4CC4C3)c12
Product: Cc1cccc2c(OS(=O)(=O)C(F)(F)F)ccc(C(=O)N3CC4CC4C3)c12

Procedure:
The desired intermediate was prepared by treating 3-azabicyclo[3.1.0]hexan-3-yl(4-hydroxy-8-methylnaphthalen-1-yl)methanone (above step-2 intermediate) with Tf2O using the similar procedure as described in Step-8 of Intermediate-22.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)=[O:51]>CN(C=O)C.O>[CH:10]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([N:67]2[CH2:66][CH2:65][N:64]([C:47](=[O:46])[CH2:48][NH:49][C:50]([C:52]3[CH:57]=[CH:56][C:55]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:54][CH:53]=3)=[O:51])[CH2:69][CH2:68]2)=[O:19])[CH2:11][CH2:12]1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1OCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2OCC2CC2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
DIPEA (149.8 mg, 1.16 mmol) was added to the stirred solution of 2-Cyclopropylmethoxy-benzoic acid (59.4 mg, 0.31 mmol) in DMF (3 mL), HOBt (45.9 mg, 0.34 mmol) and EDCI.HCl (148.1 mg, 0.77 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 40 mg (26.0% yield) of biphenyl-4-carboxylic acid {2-[4-(2-cyclopropylmethoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 92.64%. 1H NMR: (DMSO) δ 8.64 (t, 1H), 7.96 (d, 2H), 7.8-7.7 (q, 3H), 7.54-7.46 (t, 2H), 7.44-7.32 (m, 2H), 7.2 (d, 1H), 7.1-6.94 (m, 2H), 4.2 (d, 2H), 3.9 (d, 1H), 3.7-3.4 (m, 6H), 3.25-3.0 (m, 2H), 1.2 (s, 2H), 0.6 (d, 2H), 0.3 (s, 2H).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH:13]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:7][O:8][CH:13]([C:12]2[CH:11]=[C:10]([F:9])[CH:17]=[C:16]([F:18])[CH:15]=2)[O:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: CCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1COC(c2cc(F)cc(F)c2)OC1
Yield: 48 %

Procedure:
2-Propyl-1,3-propanediol (83.2 g; 704 mmol) and 3,5-difluorobenzaldehyde (100 g; 704 mmol) were dissolved in toluene (1 liter), and p-toluenesulfonic acid (hereinafter referred to as PTS; 5 g) was added. The mixture was refluxed for 3 hours while being dehydrated with a Dean-Stark's device. The resultant reaction mixture was washed sequentially with saturated sodium bicarbonate solution and saturated brine and dried over magnesium sulfate. Subsequently, the solvent was evaporated. The residue was recrystallized twice from heptane, to thereby obtain 82.0 g (338 mmol) of 5-propyl-2-(3,5-difluorophenyl)-1,3-dioxane. The yield of the compound from 3,5-difluorobenzaldehyde was 48.0%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH3:22][Sn](C)(C)C>CN(C=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:22])[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2c(c1O)c1ccccc1n2C
Temperature: 120 °C

Procedure:
A mixture of 1-bromo-4-hydroxy-9-methyl-9H-beta-carboline-3-carboxylic acid ethyl ester (197 mg), tetramethyl tin (0.094 mL), and Pd(PPh3)2Cl2 (20 mg) in DMF (2 mL) was heated at 120° C. for 45 min. The reaction was then partitioned between EtOAc and water, the organic phase was subsequently washed with sat. NaCl solution, dried over anhydrous sodium sulfate and then filtered, concentrated; the residue was purified with column to give the title compound (118 mg). ESI MS (m/z): 285 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28](O)=[O:29])[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10].N[N:33]1[CH:37]=[N:36][CH:35]=[N:34]1.[N:38]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([NH:38][C:35]3[NH:36][CH:37]=[N:33][N:34]=3)=[O:29])[CH2:25][N:26]=1)=[CH:18]2)(=[O:10])=[O:11]
Reactant: Nn1cncn1
Reactant: On1nnc2ccccc21
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)Nc4nnc[nH]4)S3)[nH]c12
Temperature: 25 °C
Yield: 68.8 %

Procedure:
To a mixture of (2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (150 mg), 2-amino-1,2,4-triazole (36 mg), 1H-1,2,3-benzotriazol-1-ol (67 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0-95:5), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (118 mg, yield 69%) as colorless prism crystals. MS: 526 (MH+). melting point 208-209° C.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([C:13]([OH:15])=O)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C@@H:28]([NH2:37])[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C(Cl)CCl>CN(C=O)C.CCN(C(C)C)C(C)C>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C@@H:28]([NH:37][C:13]([C:9]2[CH:10]=[C:11]([OH:12])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:15])[CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CC(=O)OC(C)(C)C)CC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6.6 g 1-phenyl-3-carboxy-5-pyrazolone and 10.6 g 4-((S)-2-Amino-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester in 30 ml DMF 4.9 g HOBT, 10.6 ml DIPEA and 6.2 g EDC were added and the reaction mixture was stirred for 16 h at RT. Then the reaction mixture was evaporated, diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1>N1C=CC=CC=1>[OH:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:16][CH2:17]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: c1ccncc1
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid (235 mg) in pyridine (1.5 mL) was added trans-4-aminocyclohexanol (292 mg), and the mixture was stirred for 3 hours at 80° C. After evaporation of the solvent, the residue was dissolved in water and neutralized with 1N-hydrochloric acid (1.9 mL). The resulting precipitates were collected by filtration and washed successively with water and methanol to give 2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzoic acid (279 mg) as a solid substance.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])(=[O:4])[CH3:3].[N:12]([O-])=O.[Na+]>O>[ClH:1].[N:7]1[C:6]2[C:5](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]([OH:4])=[CH:3][N:12]=1
Reactant: O=N[O-]
Reactant: CC(=O)c1ccccc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1cnnc2ccccc12
Temperature: 65 °C
Yield: 77 %

Procedure:
560 ml of concentrated hydrochloric acid are introduced into a reactor. 111.6 g of 2-acetylaniline are added at ambient temperature. 62.8 g of sodium nitrite, in solution in 170 ml of water, are added to this orange-colored solution at −5° C. over 1 hour. The temperature is kept below 0° C. throughout the introduction. The reaction medium is heated at 65° C. for 3 hours. The mixture is subsequently cooled over 20 minutes and the product is then filtered off and washed with ether. The compound is dried over P2O5 at 45° C. overnight. 118.6 grams (77%) of the expected product are obtained.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[CH2:36]1[CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][N:40]2[CH2:39][CH2:38][N:37]1[C:46]1[CH:55]=[CH:54][C:49]([C:50](OC)=[O:51])=[CH:48][CH:47]=1>C1COCC1>[CH2:36]1[CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][N:40]2[CH2:39][CH2:38][N:37]1[C:46]1[CH:55]=[CH:54][C:49]([C:50]([NH:11][C:12]2[NH:16][N:15]=[C:14]([CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=3)[CH:13]=2)=[O:51])=[CH:48][CH:47]=1
Reactant: COC(=O)c1ccc(N2CCN3CCCCC3C2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN5CCCCC5C4)cc3)[nH]n2)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 9.3 %

Procedure:
A 1M solution of NaHMDS in THF (1.13 ml, 1.05 mmol) was added to a stirred solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and methyl 4-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)benzoate (231 mg, 0.84 mmol) in THF (5 ml) at 0° C. under nitrogen, over 5 minutes. The reaction mixture was stirred for an additional 5 minutes at 0° C., then stirred at 20° C. for 18 h. An additional amount of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (80 mg, 0.23 mmol ) was added with 1M NaHMDS in THF (1.13 ml, 1.13 mmol). The reaction mixture was stirred for an additional 3 h. The reaction mixture was quenched with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3×20 ml). The extracts were washed with saturated brine solution (15 ml), dried (MgSO4) and evaporated to give crude product. The crude product was purified by reverse phase prep. HPLC (basic) using a 38-58% gradient of acetonitrile in water containing 1% 0.880 ammonium hydroxide. The clean fractions were taken and evaporated to afford the title compound as a white solid (32 mg, 9%); 1H NMR (500.13 MHz, DMSO-d6) δ 1.25 (1H, s), 1.62 (2H, t), 1.72 (1H, d), 1.93-1.95 (2H, m), 2.19-2.20 (1H, m), 2.44 (1H, s), 2.81 (3H, q), 2.87 (4H, s), 3.28 (1H, s), 3.69 (1H, s), 3.72 (6H, s), 3.77 (1H, d), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s), 6.96 (2H, d), 7.89 (2H, d), 10.29 (1H, s), 12.07 (1H, s). MS: m/z 490 (MH+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13]CC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O.O1CCOCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-phenoxybenzoate (0.220 g; 0.725 mmol) was added to a mixture of NaOH in water (1.5 mL; 2M) and dioxane (1.5 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated in vacuo and extracted with dichloromethane. The aqueous layer was acidified with a 6N solution of hydrochloric acid in water. The precipitated product was collected by filtration to yield 0.200 g (quantitative) of the title compound as a white solid which was used without further purifications.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[CH:7][CH:8]=1)[NH2:2].[OH-].[K+].[C:17](=S)=[S:18]>C(O)C.O>[CH3:14][N:12]1[CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]3[N:4]([C:17]([SH:18])=[N:2][N:1]=3)[N:5]=2)[CH:10]=[N:11]1
Reactant: Cn1cc(-c2ccc(NN)nn2)cn1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Temperature: 63.5 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a solution of 3-hydrazinyl-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (53 g, 278.6 mmol) in ethanol (550 ml) is added an aqueous solution of KOH (17.2 g, 306.6 mmol) in water (130 mL), followed by CS2 (36 mL, 596.7 mmol). The mixture is stirred at 60-67° C. for 3 h under N2 atmosphere and cooled to RT. Solvents are removed under vacuum and the residue is dissolved in 1N aqueous NaOH (350 mL). The insolubles are filtered off and the filtrate is acidified to pH 2-3 with 1N aqueous HCl. The precipitate is collected, washed with water, and dried under vacuum to provide the title compound (50 g, 77.3%). MS (m/z): 233.0 (M+H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]([NH:22][C@H:23]([C:28](O)=[O:29])[CH2:24][CH2:25][S:26][CH3:27])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[CH2:15]([O:14][C:12]([NH:22][C@@H:23]([CH2:24][CH2:25][S:26][CH3:27])[C:28]([NH:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:29])=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC1CCC2(CC1)OCCO2
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)NC1CCC2(CC1)OCCO2
Reaction time: 8 h
Yield: 64.7 %

Procedure:
1,4-Dioxaspiro[4.5]decan-8-amine (5.03 g, 32.0 mmol, 1 eq.), CBZ-L-methionine (10.90, 38.4 mmol, 1.2 eq.), 1-hydroxybenzotriazole hydrate (HOBT) (5.19 g, 38.4 mmol, 1.2 eq.), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide HCl (EDCI) (7.36 g, 38.4 mmol, 1.2 eq.), triethylamine (8.92 mL, 64.0 mmol, 2 eq.) and methylene chloride (150 mL) were stirred at room temperature under nitrogen for 72 hours. Worked up by rinsing 3 times with saturated sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate and stripped to give an amber oil which solidified. The solids were triturated with diethyl ether (100 mL) and stirred overnight. The solids were filtered to give 8-((2S)-2-(benzyloxycarbonylamino)-4-(methylthio)butanamido)-1,4-dioxaspiro[4.5]decane (8.75 g) as a white solid. Yield=64%. Mass Spec (ESI) detects (M+H)+=423.22.
Reaction SMILES: [C:1]1([CH:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:32][N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][CH:36](O)[CH2:37]2>CN(C=O)C>[C:1]1([CH:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:10][CH:36]2[CH2:37][CH:38]3[N:33]([CH3:32])[CH:34]([CH2:40][CH2:39]3)[CH2:35]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(Nc1ccccc1)c1ccccc1
Reactant: CN1C2CCC1CC(O)C2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1C2CCC1CC(OC(=O)C(Nc1ccccc1)c1ccccc1)C2
Temperature: 100 °C
Yield: 7 %

Procedure:
A mixture of 2-phenyl-2-(phenylamino)acetic acid I1 (250 mg, 0.90 mmol), EDC (255 mg, 1.35 mmol), HOBt (245 mg, 1.80 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-ol (380 mg, 2.71 mmol) in dry DMF (10 mL) is heated under microwave irradiation at 100° C. for 1 hour (LC-MS monitoring: complete conversion). The reaction is concentrated under reduced pressure and the residue is portioned between EtOAc and water. The organic phase is dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is purified by preparative HPLC. The collected compound is partitioned between 1N NaHCO3 and DCM, the organic phase is separated dried over Na2SO4, filtered and evaporated under vacuum to give 20.1 mg of the title compound as a colorless oil (7% yield, mixture of diastereoisomers).
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([N:8]2[C:7]3[C:2]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:3][C:4]([C:17]([F:20])([F:19])[F:18])=[CH:5][C:6]=3[N:10]=[CH:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)c1cc(-c2ccccc2)c2c(c1)ncn2-c1ccccc1
Yield: 47.3 %

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (370 mg, 1 mmol), benzeneboronic acid (180 mg, 1.5 mmol), potassium carbonate (700 mg, 5 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) in a mixture of water (5 ml) and dimethoxyethane (10 ml) was stirred at reflux overnight. The cooled mixture was partitioned between water and ethyl acetate. The organic phase was collected, washed with brine, dried and concentrated under reduced pressure. Recrystallisation from methanol afforded the product as an off-white solid (160 mg, 47%), m/z, 339.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]#[CH:26]>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:15]([C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:17][CH2:26][C:25]#[CH:24])=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:16]
Reactant: C#CCBr
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOc1ccc2c(c1)nc(N)c1nc(CC)sc12
Temperature: 65 °C

Procedure:
To a stirred solution (pale orange) of 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (0.24 g, 1.0 mmol) was dissolved in anhydrous DMF (5 mL) was added cesium carbonate (3.0 eq., 1.0 g, 3.0 mmol) and 1.1 eq. of an 80% solution of propargyl bromide in toluene (0.16 g). The mixture was heated to 65° C. and maintained overnight. The reaction was quenched by slowly adding the reaction mixture to 10 volumes of water (50 mL). The resulting solid was collected by vacuum filtration, rinsed with acetonitrile and air dried, to provide 0.22 g of 2-ethyl-7-[(prop-2-ynyl)oxy]thiazolo[4,5-c]quinolin-4-amine as a pale-peach colored crystalline solid. MS (ACPI) m/z=284 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: c1nc[nH]n1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(-n2cncn2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 24 h

Procedure:
4-Fluoro-2-methyl-nitrobenzene (2 g, 0.013 mol), 1,2,4-triazole (0.9 g, 0.013 mol), potassium carbonate (1.78 g, 0.013 mol) were dissolved in DMSO (50 ml) and stirred at 90° C. for 24 h under dry conditions. The yellow suspension was poured into water (150 ml), extracted (EtOAc), dried (Na2SO4) and evaporated under reduced pressure to afford an orange solid which was purified by flash column chromatography on silica eluting with n-pentane/ethyl acetate (50-100%) to afford a white solid (2.83 g 69%).