Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].[CH2:11](O)[CH2:12][CH2:13][CH2:14][OH:15]>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([O:7][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:6])[CH2:2][CH3:3]
Reactant: OCCCCO
Reactant: CCCC(CCC)C(=O)O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCC(CCC)C(=O)OCCCCO
Yield: 99 %

Procedure:
2-propylpentanoic acid (40.16 g, 278.5 mmol) was mixed with butane-1-4-diol (114.65 g, 1272.2 mmol) and methyl-sulfonic acid (5 drops) in toluene (3500 ml) and the mixture was heated under reflux using a Dean Stark trap for 12 h. After that, toluene was removed under reduced pressure and the crude mixture was dissolved in chloroform (200 ml) and extracted with water (pH 5, 3×200 ml). The combined organic layers were dried over sodium sulfate and the volatiles were removed under reduced pressure giving a clear oil (99%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[N:29][CH:30]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3cncnc3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (223 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light red solid (250 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2=[C:17]3[C:4]=1[CH2:5][CH:6](O)[N:7]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)[C:8]3=[N:9][CH:10]=[N:11]2.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Br:24][C:20]1[CH:19]=[C:18]([N:7]2[CH:6]=[CH:5][C:4]3[C:17]4[C:8]2=[N:9][CH:10]=[N:11][C:12]=4[CH:13]=[C:14]([O:15][CH3:16])[C:3]=3[O:2][CH3:1])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2ncnc3c2c(c1OC)CC(O)N3c1cccc(Br)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc3c2c(c1OC)C=CN3c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7,8-dimethoxy-4-(3-bromo-phenyl)-5,6-dihydro-4H-1,3,4-triaza-phenalen-5-ol (0.17 g, 0.42 mmol) (from Example 22, Step A, supra) and triethylamine (0.35 mL, 2.53 mmol) in dichloromethane (30 mL) at 0° C. was added methanesulfonyl chloride (0.13 mL, 1.68 mmol) (Aldrich). The reaction solution was stirred at room temperature for 2 hours. The solution was then concentrated, the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:1:0.01) as eluent to give the desired 4-(3-bromo-phenyl)-7,8-dimethoxy-4H-1,3,4-triaza-phenalene as an off white solid. (Yield 81 mg, 50%).
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]4[CH3:35])=[C:25]([C:36]([F:39])([F:38])[F:37])[CH:24]=3)[O:20][N:19]=2)[CH:15]=[CH:14][N:13]=1)[CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].Cl>O1CCOCC1>[CH3:1][N:2]([CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]4[CH3:35])=[C:25]([C:36]([F:39])([F:38])[F:37])[CH:24]=3)[O:20][N:19]=2)[CH:15]=[CH:14][N:13]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC1CCCCN1c1ccc(-c2nc(-c3ccnc(CN(C)CC(=O)OC(C)(C)C)c3)no2)cc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccnc(CN(C)CC(=O)O)c3)no2)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To tert-butyl 2-(methyl((4-(5-(4-(2-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)methyl)amino)acetate (0.056 g; 0.10 mmol) was added HCl solution in dioxan (4 M; 3 mL) and the reaction mixture stirred at 70° C. for 4 hours. The solvent was evaporated in vacuo and the residue purified by preparative HPLC, affording the title product as a brown oil. 1H NMR (CDCl3, 400 MHz) δ 8.79 (1 H, d, J=5.1 Hz), 8.49 (1 H, d, J=2.1 Hz), 8.33 (1 H, dd, J=8.4, 2.1 Hz), 8.04-8.00 (2 H, m), 7.55 (1 H, d, J=8.4 Hz), 4.11 (2 H, s), 3.50 (2 H, s), 3.15-3.01 (2 H, m), 2.62 (3 H, s), 2.62-2.54 (1 H, m), 1.90-1.44 (6 H, m), 0.86 (3 H, d, J=6.2 Hz). LC/MS: 490 (M+H)+. HPLC (Method B) Rt 3.46 min (Purity: 98.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:29][CH3:30])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:26](=[O:27])[C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:29][CH3:30])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1

Procedure:
(S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (100 mg, 0.42 mmol), (R)-2-(tert-butoxycarbonylamino)butanoic acid (102 mg, 0.50 mmol), HOBT (68 mg, 0.5 mmol), EDC (155 mg, 1 mmol), DIPEA (129 mg, 1 mmol), and chlororform (2 mL) was stirred overnight at rt. The reaction mixture was then partitioned between methylene chloride and saturated sodium bicarbonate solution, the layers were separated and the organic extracts were dried over magnesium sulfate, filtered, and concentrated to yield the product, which was used in next step without further purification.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:45]>C1COCC1>[Br:45][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=3)[N:11]=2)=[CH:16][CH:17]=1
Reactant: OCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(CBr)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 77.1 %

Procedure:
To a solution of {4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenyl}-methanol (P-6; 5.033 g, 15.01 mmol) in THF (100 mL) was added triphenylphosphine (6.009 g, 22.91 mmol). Carbon tetrabromide (7.704 g, 23.23 mmol) dissolved in THF (20 mL) was then added dropwise at room temperature. The mixture was allowed to stir at room temperature for 23 h. It was then filtered through Celite, and the solvent was evaporated at room temperature under vacuum. The crude material was purified by silica gel chromatography, eluting with 50% EtOAc/hexane going to 70% EtOAc/hexane and then 100% EtOAc in a two-step gradient. The title product (4.61 g, 77%) was isolated as a beige solid: mp 124-126° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.25-8.13 (m, 2H), 7.89-7.72 (m, 2H), 7.60-7.47 (m, 2H), 7.47-7.34 (m, 2H), 4.57 (s, 2H); ESIMS m/z 400 (M+2H), 399 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[O:51][CH3:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[O:51][CH3:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: COc1ccccc1CCl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COc1ccccc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(chloromethyl)-2-methoxybenzene and isolated as light-yellow gum (5.7 mg, 34%). MS(m/e): 403.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:13]N1C(=O)CCC1=O>>[NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Reactant: O=C1CCC(=O)N1Cl
Product: COC(=O)c1ccc(Cl)c(N)c1Cl

Procedure:
This material was prepared by chlorination of methyl 3-amino-4-chlorobenzoate with N-chlorosuccinimide. The product was isolated as a solid, mp 50°-52° C. The product was characterized by IR and 1H NMR spectroscopy and combustion analysis.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:30])C.[OH-].[Na+].Cl>C(O)C>[Cl:30][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:31])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccc(Cl)cc3)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(Sc2cc(O)cc(C#Cc3ccc(Cl)cc3)c2)cc1Cl
Reaction time: 1 h

Procedure:
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (50 mg; 0.11 mmol) was dissolved in ethanol (6 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep. HPLC (method B). Yield: 36 mg. HPLC-MS: m/z: 445.1 (M+); Rt: 2.44 min.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C.[ClH:22]>>[ClH:22].[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][CH:12]1[N:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(C2CCc3ccccc3C2)CC1
Agent: Cl
Product: O=C(O)C1CCN(C2CCc3ccccc3C2)CC1
Reaction time: 8 h

Procedure:
Ethyl-1-(tetralin-2-yl)piperdine-4-carboxylate (7.1 g, 0.025 mol) was treated with 6N HCl (80 ml) at room temperature. After stirring overnight, the suspension was filtered off and the solid dried in vacuo to yield 1-(tetralin-2-yl)piperdine-4-carboxylic acid hydrochloride salt.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5](Cl)[N:4]=1.[CH2:13]([OH:16])[CH2:14][CH3:15]>>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([O:16][CH2:13][CH2:14][CH3:15])[N:4]=1
Reactant: CCCO
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [Na]
Product: CCCOc1nc(N)nc2nc[nH]c12
Temperature: 85 °C

Procedure:
Sodium (0.68 g, 29.5 mmol Aldrich lot #9621CL) was added in portions to anhydrous propanol (25 mL). Upon complete dissolution 2-amino-6-chloropurine (1 g, 5.9 mmol, Sigma lot #69F4064) was added and the reaction heated in an 85° C. oil bath under a nitrogen atmosphere for 20 hours. The solution was cooled and neutralized with Dowex 50W×12 (H+ form) (BioRad, 140-270 mesh), an acidic ion exchange resin. The resin was filtered, the filtrate collected and adsorbed onto silica gel column and eluted with CHCl3 /MeOH (9:1, v/v). Combination and evaporation of appropriate fractions gave 0.89 g of slightly impure material. Adsorption of this material onto silica gel followed by elution with EtOAc/MeOH (10:1, v/v) gave, after evaporation of combined product fractions, 0.76 g, (3.9 mmol; 67%). mp=198°-200° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([C:19]#[N:20])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1>CO.N>[NH2:20][CH2:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH:17]=[CH:18][C:9]([NH:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[N:10]2
Reactant: Cc1ccc(CNc2ccc3c(C#N)cccc3n2)o1
Agent: N
Solvent: CO
Product: Cc1ccc(CNc2ccc3c(CN)cccc3n2)o1
Yield: 97.5 %

Procedure:
Hydrogenation of 2-[(5-methyl-furan-2-ylmethyl)-amino]-quinoline-5-carbonitrile (200 mg, 0.76 mmol) dissolved in 7N MeOH—NH3 for 23 h at room temperature yielded after removal of the catalyst by filtration and evaporation a yellow oil which was further purified by column chromatography (dichloromethane/MeOH/NH4OH 15:1:0.1) on silica gel to yield (5-aminomethyl-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine as light yellow oil (198 mg, 98%).
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[C-:11]#[N:12].[Na+]>>[CH:1]([CH:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: [C-]#N
Reactant: C=CC(Cl)c1ccccc1
Agent: [Na+]
Product: C=CC(C#N)c1ccccc1

Procedure:
a procedure according to A. Zerroukhi, A. Ainser, A. Arsac, N. Mignard, and B. Marculescu, Polymer Bulletin, 42, 535, 1999, is used. Initially, vinylbenzyl chloride is reacted with sodium cyanide to give vinylbenzyl cyanide, which is then reacted with ethanolamine to give the vinylbenzyloxazoline.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:6]=[C:5]2[N:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1.[CH2:30]([OH:32])[CH3:31]>>[CH2:30]([O:32][C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:6]=[C:5]2[N:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1)[CH3:31]
Reactant: Clc1nc2c(N3CCSCC3)nc(N3CCNCC3)nc2nc1N1CCSCC1
Reactant: CCO
Product: CCOc1nc2c(N3CCSCC3)nc(N3CCNCC3)nc2nc1N1CCSCC1

Procedure:
This compound was prepared analogous to Example 3 from 6-chloro-2-piperazino-4,7-bis-(thiomorpholino)pteridine and ethanol.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH2:17][F:18].[H-].[Na+].O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[C:9]([O:11][CH2:16][CH2:17][F:18])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(O)cc(C(C)(C)C)c1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(OCCF)cc(C(C)(C)C)c1
Reaction time: 8 h

Procedure:
1-(3-tert-Butyl-5-hydroxyphenyl)ethanone (O3.106; 500 mg) was dissolved in DMF (10 ml), and 1-bromo-2-fluoroethane (195 μl) was added while stirring. Sodium hydride (80 mg) was added at RT. After stirring at RT for 3 h, the mixture was left to stand overnight and then further sodium hydride (20 mg) was added and the mixture was stirred for a further 2 h. Then water was added and the mixture was concentrated to dryness. The residue was taken up in EA and washed three times with water. The EA phase was dried over magnesium sulfate, filtered and concentrated. 600 mg of the title compound were obtained. LC-MS rt: 1.13 min [M+H]+: 239.1 (met. b)
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:16][CH:10]([CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:1]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17](=[O:25])[N:2]=2)[N:8]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)Cc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 69.8 %

Procedure:
Ethyl 3-(6-cyano-2-pyridyl)-2-methylpropionate (0.79 g, 3.6 mmol) and methyl thiosalicylate (1.2 g, 7.3 mmol) were dissolved in toluene (3 ml), and triethylamine (0.76 ml, 5.4 mmol) was added thereto. The reaction mixture was refluxed for 21 hrs and subjected to a silica gel (70 g) column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give the titled compound (0.89 g, 70%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[S:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[N:20]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27]>N1C=CC=CC=1>[N:20]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[S:13][C:12]=1[C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:24]=[C:23]([O:22][CH3:21])[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)c1cc(N)cc(-c2nc3ccncc3s2)c1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NC(=O)c2cc(OC)c(OC)c(OC)c2)cc(-c2nc3ccncc3s2)c1
Temperature: 25 °C
Yield: 35.7 %

Procedure:
Methyl 3-amino-5-(thiazolo[5,4-c]pyridin-2-yl)benzoate (150 mg, 0.526 mmol) was mixed together with 3,4,5-trimethoxybenzoyl chloride (121 mg, 0.526 mmol) in 1 mL of pyridine. The reaction mixture was reacted in a Biotage microwave reactor at 160 degrees for 10 min. It was then cooled to room temperature and concentrated. The resulting residue was purified by chromatography using a 9:1 mixture of CH2Cl2 to MeOH to afford 90 mg of methyl 3-(thiazolo[5,4-c]pyridin-2-yl)-5-(3,4,5-trimethoxybenzamido)benzoate(36% yield) (MS, M++H=480).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][NH:15][C:14]=2[N:13]=1
Reactant: COC(=O)CCCCCCCCc1ccc2cccnc2n1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCCCCCCCc1ccc2c(n1)NCCC2
Reaction time: 20 h

Procedure:
A mixture of 13-3 (8.5 g, 28 mmol), 10% Pd/C (1.7 g), and ethanol (140 mL) was stirred under a hydrogen atmosphere for 20 h. The reaction mixture was then filtered through a celite pad and concentrated to give 13-4 as a pale yellow oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]1([N:25]2[C:29](=[S:30])[N:28]=[N:27][NH:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]([OH:42])[CH2:39][CH2:40]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]([OH:42])[CH2:39][CH2:40][S:30][C:29]1[N:25]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[N:26]=[N:27][N:28]=1
Reactant: S=c1nn[nH]n1-c1cccc2ccccc12
Reactant: OCCC(O)c1ccccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OC(CCSc1nnnn1-c1cccc2ccccc12)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
DIAD (82 μL, 0.42 mmol) was added dropwise to a solution of 1,2-dihydro-1-(1-naphthalenyl)-5H-tetrazole-5-thione (80.0 mg, 0.35 mmol), 1-(2-chlorophenyl)-1,3-propanediol (65.4 mg, 0.35 mmol), and PPh3 (110 mg, 0.42 mmol) in THF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h then was concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2:(CH3)2CO, 95:5) to give the title compound (70 mg, 50% yield) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][NH:13][CH2:12][C@@H:11]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:31]([O:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)=[O:32]>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][N:13]([C:31]([O:33][C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[O:32])[CH2:14]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1cccnc1
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[(3S,4R)-4-({[Tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidin-3-yl]pyridine and N,N-diisopropylethylamine were dissolved in THF, methyl 4-[(chlorocarbonyl)oxy]benzoate (mfd. by Fluka) was added in one portion thereto at room temperature and stirred for 3 hours, and then the reaction solution was concentrated under a reduced pressure. Work-up and purification of the residue was carried out in the standard method to produce 4-(methoxycarbonyl)phenyl (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-pyridin-3-ylpyrrolidine-1-carboxylate.
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][CH:10]2[CH2:15][CH2:14][C:13]([N:22]([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)C=CC=CC=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH:10]([NH:9][C:8]([N:38]2[CH2:39][CH2:40][CH2:41][CH:36]([C:30]3[C:29]4[C:33](=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=4)[NH:32][CH:31]=3)[CH2:37]2)=[O:25])[CH2:15][CH2:14]1
Reactant: Fc1ccc2[nH]cc(C3CCCNC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)N2CCCC(c3c[nH]c4ccc(F)cc34)C2)CC1

Procedure:
The polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (338 mg, 1 mmole) was added to a solution of 5-fluoro-3-piperidine-3-yl-1H-indole (218 mg, 1 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×15 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The polar diastereoisomer of 3-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was purified by column chromatography [silica gel 60 (25 g); methanol (250 ml)]. It was obtained as a colourless solid in a yield of 200 mg (43%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22](Br)[S:21]2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37](=[O:70])[NH:38][C@H:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[C:50]1[NH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58](B3OC(C)(C)C(C)(C)O3)=[CH:57][CH:56]=2)=[CH:53][N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41]>>[CH3:35][O:36][C:37](=[O:70])[NH:38][C@H:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[C:50]1[NH:51][C:52]([C:55]2[CH:56]=[CH:57][C:58]([C:22]3[S:21][C:20]4=[N:19][C:18]([NH:17][C:16]([C@@H:12]5[CH2:13][CH2:14][CH2:15][N:11]5[C:9](=[O:10])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:27])=[CH:25][N:24]4[CH:23]=3)=[CH:59][CH:60]=2)=[CH:53][N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cn4cc(NC(=O)[C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC(C)(C)C)c5ccccc5)nc4s3)cc2)[nH]1)C(C)C
Yield: 10 %

Procedure:
Compound A38 was synthesized from compound 23 (0.091 mmol) and compound 8 (0.137 mmol), following the procedure as described for compound A1 (reaction time=1 hr), as a white lyophilized powder in 10% yield. MS (ESI, EI+) m/z=838.39 (MH+).