Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]#[CH:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]#[C:33][C:2]2[C:3](=[O:18])[N:4]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[CH:5]=[C:6]([Cl:8])[N:7]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(Cn2cc(Cl)nc(Cl)c2=O)cc1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cc(Cl)nc(C#CC3CCN(C(=O)OC(C)(C)C)CC3)c2=O)cc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3,5-dichloro-1-(4-methoxy-benzyl)-1H-pyrazin-2-one (285 mg; for preparation see Tetrahedron Letters 2010, 51, 1739) and 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (272 mg), triethylamine (2 mL) and N,N-dimethylformamide (2 mL) in a microwave oven suited vessel charged with a stir bar is sparged with argon for 10 min. Copper (I) iodide (8 mg) and Pd(PPh3)2Cl2 (10 mg) are added and the vessel is capped. The resulting mixture is stirred under microwave irradiation at 80° C. for 15 min. After cooling the mixture to room temperature, ethyl acetate is added. The organic phase is washed with 2 N aqueous citric acid, water, and brine, dried (MgSO4) and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 40:60) to give the title compound. Yield: 440 mg (96% of theory); LC (method 2): tR=1.47 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>>[C:12]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)(=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)Cl
Reactant: CNc1ccc([N+](=O)[O-])cc1
Product: C=CC(=O)N(C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-methylamino-nitrobenzene and acrylic acid chloride
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:22]#[N:23])([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:24])=O.[Cl-].[Na+].O.CS(C)=O>>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([C:9]2([C:22]#[N:23])[CH2:8][CH2:7][C:6](=[O:24])[CH2:5][CH2:10]2)[CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: COC(=O)C1CC(C#N)(c2ccc([N+](=O)[O-])c(OC)c2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(C2(C#N)CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 165 °C

Procedure:
Into a 8-dram vial, 5-Cyano-5-(3-methoxy-4-nitro-phenyl)-2-oxo-cyclohexanecarboxylic acid methyl ester (2.00 g, 6.02 mmol), Sodium chloride (1.00 g, 17.1 mmol), Water (1.00 mL, 55.5 mmol) and Dimethyl sulfoxide (5.00 g, 64.0 mmol) were added. The reaction mixture was heated at 165° C. for 6 hours. HPLC suggested no SM. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded 1-(3-Methoxy-4-nitro-phenyl)-4-oxo-cyclohexanecarbonitrile a white solid (0.80 g, 48%).
Reaction SMILES: [F:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[N:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:6][CH:7]=[C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)[N:9]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1nc(Cn2ncc(N)n2)co1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3coc(C(C)(F)F)n3)n2)c1

Procedure:
Following general procedure A, starting from 2-((2-(1,1-difluoroethyl)oxazol-4-yl)methyl)-2H-1,2,3-triazol-4-amine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[BrH:25]>C(Cl)(Cl)Cl>[Br:25][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: Br
Solvent: ClC(Cl)Cl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2α, 3α-Epoxy-5α-pregnane-11,20-dione (502 mg) was dissolved in chloroform (30 ml.) and the solution was treated with hydrobromic acid (48 %, 10 ml.). The mixture was stirred vigorously at room temperature for 30 minutes, and then poured into chloroform. The organic solution was washed with dilute sodium bicarbonate solution, then with water, and was then dried over sodium sulphate and evaporated to give a crystalline residue which was recrystallised from acetone-ether to give 2β-bromo-3α-hydroxy-5α-pregnane-11,20-dione (483 mg.) as colourless crystals, m.p. 206°-210° [α]D + 106°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:15][C@H:14]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]2[F:21])[CH:5]=[N:4][C:3]=1[C:22]([OH:24])=O.F[C@@H]1[C@H](O)[C@@H](CO)OC1O.[Cl-].[N+:36](=[CH2:38])=[N-:37]>O1CCCC1.C(OCC)C>[C:11]([O:10][C@@H:9]1[C@@H:14]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[O:15][C@@H:7]([N:6]2[C:2]([N:1]=[CH:5][N:6]([CH3:7])[CH3:2])=[C:3]([C:22](=[O:24])[CH:38]=[N+:36]=[N-:37])[N:4]=[CH:5]2)[C@H:8]1[F:21])(=[O:13])[CH3:12]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N)[C@@H](F)[C@@H]1OC(C)=O
Reactant: C=[N+]=[N-]
Agent: OC[C@H]1OC(O)[C@H](F)[C@@H]1O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)C=[N+]=[N-])c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 75 %

Procedure:
Compound (35) (93 mg) obtained in item (3) above was dissolved in tetrahydrofuran (4.5 ml), to which was then added N,N-dimethylchloroforminium chloride (135 mg) under ice-cooling. The resulting mixture was allowed to undergo the reaction for 30 minutes. The reaction solution containing compound (36) thus produced was then added to a 0.2M diazomethane solution (30 ml) in diethylether and the reaction was maintained at room temperature for 1 hour. The reaction solution so obtained was filtered and the filtrate was concentrated to give the titled compound (37) (83 mg) as a syrup. Yield: 75%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:35][O:36][C:37](Cl)=[O:38].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH3:35][O:36][C:37]([N:25]1[CH2:26][CH2:27][CH:22]([C:7]2[C:8]3[S:12][C:11]([NH:13][C:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[O:15])=[N:10][C:9]=3[C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[CH2:23][CH2:24]1)=[O:38]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C2CCNCC2)c2sc(NC(=O)N3CCOCC3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(c2ccc(OC)c3nc(NC(=O)N4CCOCC4)sc23)CC1
Reaction time: 1 h
Yield: 71 %

Procedure:
To a suspension of 0.05 g (0.12 mMol) morpholine-4-carboxylic acid (4-methoxy-7-piperidin-4-yl-benzothiazol-2-yl)-amide hydrochloride (1:1) in 3 ml THF were added 0.019 ml triethyl amine. At 0° C. 0.011 ml (0.13 mMol) chloro formic acid methyl ester was added dropwise and stirred for 1 h. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 10 ml water were added. This was extracted three times with 15 ml ethyl acetate, the combined organic phase were dried over sodium sulfate and evaporated to dryness in vacuo. One obtained 0.037 g (70%) 4-{4-methoxy-2-[(morpholine-4-carbonyl)-amino]-benzothiazol-7-yl}-piperidine-1-carboxylic acid methyl ester as a white solid. F.p.: 179-185° C.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.Cl[S:16]([OH:19])(=[O:18])=[O:17]>>[C:1]1([S:16]([OH:19])(=[O:18])=[O:17])[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: O=S(=O)(O)c1cccc2ncc3ccccc3c12
Temperature: 10 °C
Yield: 49.7 %

Procedure:
Add phenanthridine (5 g, 28 mmol) in portions to chlorosulfonic acid (5.6 mL, 84 mmol) cooled to 10° C. over 20 minutes Heat the reaction mixture to reflux for 20 hours. Cool the now black reaction mixture to 0° C. and add cautiously to crushed ice (500 mL). Filter the solid and dry in vacuo to give the sulfonic acid (3.61 g) as an ivory colored solid consisting of a partially resolved 7:3 mixture of regioisomers. Rf=0.35 (major), 0.19 (minor (15:85 methanol:methylene chloride, 0.2% acetic acid buffer).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:25])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:7][CH:6]([CH3:8])[CH2:5][C@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:25])[C:3]([OH:26])=[O:2]
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc3ccccc23)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc3ccccc23)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
A mixture of (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.38 g, 1.08 mmol) in tetrahydrofuran (8.1 mL) and water (2.7 mL) was treated with lithium hydroxide monohydrate (54 mg, 1.3 mmol). The reaction was stirred at 25° C. for 2 h. At this time, the reaction was diluted with water (50 mL), acidified with a 2N aqueous hydrochloric acid solution and then extracted with 10% methanol/dichloromethane (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid (0.37 g, 99%) as a pale yellow solid: HR-ES-MS m/z calculated for C20H21NO4 [M+H]+ 340.1544, observed 340.1545; The material was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.3 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 1.43-1.88 (m, 3H), 4.33 (d, J=18.1 Hz, 1H), 4.42 (d, J=18.1 Hz, 1H), 4.64 (dd, J=11.3, 4.4 Hz, 1H), 4.74 (s, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.54-7.68 (m, 3H), 7.91 (d, J=8.2 Hz, 1H), 7.96-8.09 (m, 2H), 12.89 (br. s., 1H).
Reaction SMILES: CN(C)CCO.[Li]CCCC.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH:19]1[CH2:21][CH2:20]1.[C:22](=[O:24])=[O:23].Cl>CCCCCC.C1(C)C=CC=CC=1.C(OCC)C>[Cl:12][C:13]1[C:14]([CH:19]2[CH2:21][CH2:20]2)=[CH:15][N:16]=[C:17]([C:22]([OH:24])=[O:23])[CH:18]=1
Reactant: Clc1ccncc1C1CC1
Reactant: O=C=O
Agent: CN(C)CCO
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(O)c1cc(Cl)c(C2CC2)cn1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
To a solution of N,N-Dimethylethanolamine (CAN 108-01-0, 1.89 g, 2.13 ml, 21.2 mmol) in dry Hexane (40 ml) under an argon atmosphere at −15° C. was slowly added BuLi 1.6M in Hexane (26.4 ml, 42.3 mmol). The reaction mixture was stirred at −15° C. for 15 minutes, then reaction mixture was cooled down to −78° C. followed by addition of a solution of 4-chloro-3-cyclopropylpyridine (Example 48a, 1.3 g, 8.46 mmol) in dry toluene (9 ml). The resulting reaction mixture was stirred at −78° C. for 1 hour. Addition of carbon dioxide (3.72 g, 84.6 mmol) (pellets from a dry ice dispenser) into the mixture. The reaction mixture was let to warm up to −15° C. and kept at −15° C. for 1 hour. The reaction was quenched by addition of water and stirred at r.t for 15 min. The reaction mixture was diluted with ethyl acetate, poured into a separatory funnel and extracted with 4.0M aqueous solution hydrochloric acid (21.2 ml, 84.6 mmol). The organic phase was collected and the aqueous was back-extracted twice with ethylacetate. All organic phases were combined, dried over sodium sulfate and evaporated down to dryness to give a yellow oil. The former oil was dissolved in diethylether which gave a white suspension. The suspension was kept at 0° C. for few hours. The precipitate was collected by filtration, dried under high vacuum to yield the title compound (886 mg, 53%) as a white solid. MS (ESI, m/z): 196.0 (M−H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH:20]([C:26](=O)[CH2:27][CH3:28])[CH2:21][C:22]([O:24]C)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:27]([CH3:28])=[C:26]2[CH:20]([CH3:19])[CH2:21][C:22]([OH:24])=[O:23])=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: CCC(=O)C(C)CC(=O)OC
Agent: Cl
Product: Cc1c(C(C)CC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the method of Example 2, but using 1-[4-chlorobenzyl]-1-(4-fluorophenyl) hydrazine hydrochloride and methyl 3-methyl-4-oxohexanoate as starting materials, the title compound was prepared.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=O.[CH3:8][C:9]1([CH3:29])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH2:17][CH2:18][N:19]([C:22](OC(C)(C)C)=[O:23])[CH2:20][CH:21]=2)[O:10]1.CCN(CC)CC.C(Cl)(=O)CC>C(Cl)Cl>[CH3:8][C:9]1([CH3:29])[C:13]([CH3:14])([CH3:15])[O:12][B:11]([C:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:23])[CH2:1][CH3:3])[CH2:20][CH:21]=2)[O:10]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
TFA (14.75 g, 9.966 mL, 129.4 mmol) was added to a stirred solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5000 mg, 16.17 mmol) in DCM (40 mL) at 0° C. and the reaction stirred at this temperature for 1.5 hours. The solvent was removed in vacuo and the residue azeotroped with MeCN (×3). The residue was re-dissolved in DCM (50 mL) and cooled to 0° C. Et3N (6.545 g, 9.015 mL, 64.68 mmol) was added followed by a solution of propionyl chloride (1.646 g, 1.546 mL, 17.79 mmol) in DCM (5 mL). The reaction mixture was allowed to warm to ambient temperature over 1 hour. The mixture was diluted with DCM and washed with 1:1 1M HCl/brine (×2), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 120 g column, eluting with 20 to 80% EtOAc/Petroleum Ether) to give the sub-title product as a white solid (3.87 g, 90% Yield). 1H NMR (400.0 MHz, CDCl3) δ 1.15 (t, 3H), 1.27 (s, 12H), 2.20-2.44 (m, 4H), 3.47 (t, 1H), 3.64 (s, 1H), 4.06 (d, 2H) and 6.48 (d, 1H) ppm; MS (ES+) 266.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:10](=[O:29])[N:11]([CH:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)[C:12]3[N:13]([N:18]=[C:19]([CH3:21])[N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:30]1[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=1.O1CCCC1.[BH4-].[Na+]>CO>[OH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([N:11]2[C:10](=[O:29])[C:9]([CH2:8][C:6]3[CH:5]=[CH:4][C:3]([C:30]4[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[C:2]([CH3:1])[CH:7]=3)=[C:14]([CH2:15][CH2:16][CH3:17])[N:13]3[N:18]=[C:19]([CH3:21])[N:20]=[C:12]23)[CH2:23][CH2:24]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n(C2CCC(=O)CC2)c2nc(C)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2′-methyl-4′-{[2-methyl-5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.10 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added sodium borohydride (0.05 g) at 0° C., and the mixture was stirred at room temperature for 30 min. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (1.01 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].O=[CH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:14]([O:15][CH3:16])[C:12]=1[OH:13].OO.Cl>CCO>[OH:13][C:12]1[C:14]([O:15][CH3:16])=[CH:17][CH:18]=[CH:19][C:11]=1[C:10]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1S
Reactant: COc1cccc(C=O)c1O
Agent: Cl
Agent: OO
Solvent: CCO
Product: COc1cccc(-c2nc3ccccc3s2)c1O
Yield: 79 %

Procedure:
HMBT was synthesized according to a previous reported method with minor modifications (Guo et al., Chin. Chem. Lett. 2009, 20, 1408-1410. A solution of 2-aminothiophenol (0.3 mL, 4.2 mmol) and o-vanillin (0.48 g, 3.15 mmol) in EtOH (10 mL), aq H2O2 (30%, 18.9 mmol) and aq HCl (37%, 9.45 mmol) was stirred at room temperature for 90 min. The solution was quenched by 10 mL H2O. The precipitate was filtered, dried under vacuum and recrystallized from EtOH to afford the desired product as a light yellow solid (0.64 g, 79% yield). 1H NMR (CDCl3, 400 MHz), δ (ppm): 12.75 (s, 1H), 8.01 (d, 1H, J=7.6 Hz), 7.91 (d, 1H, J=7.2 Hz), 7.51 (t, 1H, J=6.8 Hz), 7.42 (t, 1H, J=7.2 Hz), 7.33 (dd, 1H, J1=1.2 Hz, J2=8.0 Hz), 6.99 (dd, 1H, J1=1.2 Hz, J2=8.0 Hz), 6.91 (t, 1H, J=8.0 Hz), 3.96 (s, 1H). 13C NMR (CDCl3, 100 MHz), δ 169,74, 151.86, 149.13, 148.29, 136.47, 132.70, 126.80, 125.66, 122.36, 121.59, 120.11, 119.23, 116.86, 114.21, 56.36. ESI-FTMS m/z=258.0587 [M+H]+, calc. 258.0589 for C14H12NO2S.
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+].CN(C=O)C.Br[CH2:30][CH2:31][C:32]1[C:33]([CH3:38])=[N:34][NH:35][C:36]=1[CH3:37]>ClCCl>[CH3:38][C:33]1[C:32]([CH2:31][CH2:30][O:17][C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[S:14][C:13]([CH2:15][CH3:16])=[N:12][C:11]=4[C:2]([NH2:1])=[N:3][C:4]=3[CH:5]=2)=[C:36]([CH3:37])[NH:35][N:34]=1
Reactant: Cc1n[nH]c(C)c1CCBr
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(OCCc4c(C)n[nH]c4C)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
A mixture of 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (245 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 4-(Bromoethyl)-3,5-dimethyl-1H-pyrazole (223 mg, 1.1 mmol) was added in portions over a period of 30 minutes. The reaction mixture was stirred for 20 minutes and then the heat source was removed. The reaction mixture was diluted with water (250 mL), stirred overnight, and then filtered. The isolated solid was rinsed with water and then dried to provide a tan powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-30% CMA in chloroform 700 mL and then with 30% CMA in chloroform over 200 mL. The resulting solid was recrystallized from 50:1 acetonitrile:methanol (40 mL) to provide 205 mg of 7-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethoxy]-2-ethylthiazolo[4,5-c]quinolin-4-amine as an off white solid, mp 195.0-197.0° C. MS (APCI) m/z 368 (M+H)+; Anal. calcd for C19H21N5OS: C, 62.10; H, 5.764; N, 19.06. Found C, 61.95; H, 5.53; N, 19.09.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.C[N:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=C([N+]([O-])=O)C1=O.N>>[CH3:1][CH:2]1[C:3]2[N:10]=[CH:15][C:14]([N+:16]([O-:18])=[O:17])=[CH:13][C:4]=2[CH2:5][CH2:6][CH2:7]1
Reactant: CC1CCCCC1=O
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Product: CC1CCCc2cc([N+](=O)[O-])cnc21
Yield: 74.4 %

Procedure:
2-Methylcyclohexanone (170 mg, 1.52 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone (296 mg, 1.49 mmol) in 1M methanolic ammonia (30 mL, 30 mmol) and heated at reflux for 3 h. The solvent was evaporated off and the residue was suspended in CHCl3 and flash chromatographed over silica gel (19 g) eluting with EtOAc/hexane (1:10) to afford a white solid (213 mg, 75% yield): mp 61°-63° C.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:15])=[CH:8][C:7]=1[Cl:25])C.C1COCC1.[OH-].[Na+].Cl>C(O)C>[Cl:25][C:7]1[CH:8]=[C:9]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:15])[C:10]([Cl:12])=[CH:11][C:6]=1[CH2:5][C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2c[nH]c3ccccc23)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1cc(Cl)c(NC(=O)c2c[nH]c3ccccc23)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.3 %

Procedure:
This [2,5-dichloro-4-[(1H-indol-3-ylcarbonyl)amino]phenyl]acetic acid ethyl ester (5.7 g, 14.57 mmol) was added to THF (50 mL) and ethanol (30 mL), and a 0.25N-aqueous solution of sodium hydroxide (120 mL) was added thereto. The mixture was stirred for 15 hours at room temperature, and then for one hour at 60° C. The reaction mixture was left to cool naturally to room temperature, and then 1N—HCl (32 mL) was added thereto while stirring the reaction mixture under ice cooling. Precipitated crystals were collected by filtration under reduced pressure, washed with water, and then dried, to obtain the title compound (4.25 g, 80%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=2[C:11]#[N:12])=[C:4]([N+:21]([O-])=O)[CH:3]=1.[Sn](Cl)[Cl:25]>C(O)C.Cl>[ClH:25].[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=3[C:11]([NH2:12])=[N:21][C:4]=2[CH:3]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: NC1=Nc2cc(F)ccc2Nc2ccc(C(F)(F)F)cc21
Reaction time: 18 h
Yield: 22.1 %

Procedure:
Heat a solution of 2-(4-fluoro-2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (9.995 g, 30.73 mmol) in ethanol (170 ml) to 60° C. Add to a solution of tin (II) chloride (29.1 g, 153.67 mmol) in 5.0 N hydrochloric acid (170 ml) and heat to reflux. After 18 hours, cool the reaction to room temperature and place in a freezer for 24 hours. The product precipitates from the solution and is collected by filtration. Obtained 2.253 g of the title compound (6.79 mmol, 22% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 296(M+1).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[CH2:6]([O:8][C:9](=[O:13])[CH2:10][C:11]#[N:12])[CH3:7].C(N(CC)CC)C>O>[CH2:6]([O:8][C:9](=[O:13])[CH:10]([C:11]#[N:12])[C:4](=[S:5])[NH:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCN=C=S
Reactant: CCOC(=O)CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCNC(=S)C(C#N)C(=O)OCC
Temperature: 50 °C

Procedure:
4.25 ml of ethyl isothiocyanate is added to a mixture that consists of 5 g of cyanoacetic acid ethyl ester and 5 ml of triethylamine at 25° C. Then, it is allowed to stir for 6 more hours at 50° C. Then, the reaction mixture is concentrated by evaporation in a vacuum. The residue is taken up in ethanol and poured into 150 ml of ice-cold IN hydrochloric acid. It is allowed to stir for 3 more hours at 25° C., and then the residue is filtered off. The solid that is obtained is rewashed with water. 7 g of product is obtained.