Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:19][C:20]1[CH:21]=[C:22]([CH2:27][CH2:28][NH2:29])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:29][CH2:28][CH2:27][C:22]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCC#Cc1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-dec-1-ynylbenzaldehyde and 2-(3,4-dichlorophenyl)ethylamine gave the title compound as an oil. M+(LC/MS(ESI)): 416.3. HPLC (Condition A), Rt: 4.91 min (HPLC purity: 72.4%).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[OH:11][NH:12][CH:13]([C:30]#[CH:31])[CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C1COCC1>[OH:11][N:12]([CH:13]([CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1)(=[O:16])=[O:17])[C:30]#[CH:31])[CH:5]=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: C#CC(CS(=O)(=O)N1CCN(c2ccccn2)CC1)NO
Solvent: O=CO
Solvent: C1CCOC1
Product: C#CC(CS(=O)(=O)N1CCN(c2ccccn2)CC1)N(O)C=O
Reaction time: 1 h
Yield: 13.6 %

Procedure:
Acetic anhydride (25 mg; 0.24 mmol; 5.0 eq.) was added to cold (0° C.) formic acid (111 mg; 2.42 mmol; 50.0 eq.). The mixture was stirred 1 h, then a 1 M solution of 1-{[2-(hydroxyamino)-3-butynyl]sulfonyl}-4-(2-pyridinyl)piperazine (15 mg; 0.05 mmol; 1.0 eq.) in THF was added. After 4 h, the solvents were evaporated and the crude product was purified on silicagel (80/20 EtOAc/c-Hex) to give the title compound (12) as a colorless oil (2.3 mg, 14% yield). LC/MS, M+(ESI): 339.2, M−(ESI): 337.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[N:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:15])[N:6]=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc2cc(Br)ccc2n1
Product: Clc1ncc2cc(Br)ccc2n1

Procedure:
A solution of 6-bromoquinazolin-2-ol (31) (6.0 g, 26.7 mmol) in POCl3 (80 mL) was refluxed at 110° C. for 5 hours. An aliquot of the reaction mixture was analyzed by LCMS and indicated that the reaction had proceeded to completion. Most of POCl3 was removed under reduced pressure, and the residue was added dropwise to ice water (500 mL). The resulting precipitate was collected via filtration as a yellow solid (3.5 g, 54%). MS (ES+) C8H4BrClN2 requires: 242. Found: 243, 245 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=[C:19]2[O:18][C:17]2[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:16]3=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C.C(O)C>[F:29][C:28]1[C:16]2[C:15]3([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=[C:19]3[O:18][C:17]=2[CH:25]=[CH:26][CH:27]=1
Reactant: Fc1cccc2c1C1(c3ccc(OCc4ccccc4)cc3)CCCCC=C1O2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1ccc(C23CCCCC=C2Oc2cccc(F)c23)cc1
Yield: 69.6 %

Procedure:
10% Palladium on activated carbon (few mg) was added to a solution of 22 (15 mg) in ethyl acetate (2 mL) and ethanol (2 mL). A balloon filled with H2 was fitted and H2 was bubbled through the solution for 15 s. The mixture was filtered after 15 min, TLC indicated 50% conversion of 22. Work-up by flash chromatography (eluent: dichloromethane −>5% ethyl acetate in dichloromethane) afforded 8 mg of the title product. Starting material (5 mg) was recovered. LC-MS confirmed m/z=295 (M−1). 1H-NMR (400 MHz, CDCl3): δ ppm 7.49-7.46 (m, 2H), 7.05-7.00 (m, 1H), 6.81-6.79 (m, 2H), 6.61-6.59 (m, 1H), 6.53-6.48 (m, 1H), 5.73 (dd, J=4.8, 9.2 Hz, 1H), 3.07-3.02 (m, 1H), 2.00-1.20 (m, 8H).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]>>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[C:23]4[S:19][C:20](=[O:25])[NH:21][C:22]4=[O:24])[CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2ncnc(-c3ccccc3)c2c1
Product: O=C1NC(=O)C(=Cc2ccc3ncnc(-c4ccccc4)c3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from 4-Phenyl-quinazoline-6-carbaldehyde (intermediate 13) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=1)=[O:33]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(Cl)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was dissolved in chloroform (5 ml), and p-fluorophenyl isocyanate (21 μl) was then added to the solution. The mixture was stirred at 60° C. for one hr. The precipitated crystal was collected by filtration and was washed to give 57 mg (yield 81%) of the title compound.
Reaction SMILES: [SH:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:3]=1.Cl[CH2:15][C:16]1[CH:35]=[CH:34][C:19]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:27][C:26]1[O:25][C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:23][C:22]=1[CH2:21][O:20][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][S:1][C:2]2[NH:6][N:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:3]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)CCc1n[nH]c(S)n1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1n[nH]c(SCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 3-(5-mercapto-1H-1,2,4-triazol-3-yl)propionate (450 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (700 mg), potassium carbonate (370 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]-1H-1,2,4-triazol-3-yl]propionate was obtained as crystals (600 mg, yield 56%) from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 114–115° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH2:13]([OH:16])[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C2OCCO2)cc1
Yield: 99.2 %

Procedure:
To stirred solution of methyl 4-formylbenzoate (5.0 g, 30.46 mmol) in toluene (196 mL) was added ethylene glycol (8.49 mL, 152.3 mmol) and para-toluenesulfonic acid monohydrate (0.58 g, 3.05 mmol). The reaction mixture was heated at reflux under Dean and Stark conditions for 1.5 hours. The solvent was evaporated at reduced pressure and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase was removed and washed with further saturated aqueous sodium hydrogen carbonate, brine and dried (magnesium sulfate). The mixture was filtered and the solvent evaporated at reduced pressure to afford the title compound (6.29 g, 99%).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].IC.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1O)([O-:11])=[O:10]>C(O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[C:13]([O:4][CH3:1])[CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: COc1cc(F)ccc1[N+](=O)[O-]
Yield: 10.1 %

Procedure:
Potassium carbonate(14.5 g, 105.1 mol) and iodomethane(7.1 ml, 114.6 mmol) were added to a solution of 2-nitro-5-fluorophenol(15 g, 95.5 mmol) in ethanol (100 ml), which was then refluxed for 12 hours. The resulting solid was filtered, washed with ethanol, and concentrated. The resulting oily residue was diluted with ethyl acetate and washed with water. The separated organic layer was concentrated and the residual oil was purified by column chromatography(ethylacetate/hexane=1/3) to give 1.65 g of the titled compound. (Yield 9.7%).
Reaction SMILES: [NH:1]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)[C:2]([NH2:4])=[S:3].Br[CH2:17][C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)=O>C1COCC1.C(OCC)C>[CH2:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([NH:1][C:2]2[S:3][CH:17]=[C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[N:4]=2)[CH2:6][CH2:7]1)=[O:12])[CH3:15]
Reactant: CCOC(=O)N1CCC(NC(N)=S)CC1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(Nc2nc(-c3ccc(C(=O)O)cc3)cs2)CC1
Temperature: 25 °C
Yield: 70161.2 %

Procedure:
A solution of ethyl 4-thioureidopiperidine-1-carboxylate (3.8 g, 0.0164 mol.) and 4-(2-bromoacetyl)benzoic acid (4 g, 0.0164 mmol) in THF (100 mL) was heated at 70° C. for 2 hours, cooled to room temperature and then diluted with diethyl ether. A resulting solid was collected by filtration and washed with diethyl ether to provide 4-[2-(1-ethoxycarbonylpiperidin-4-ylamino)thiazol-4-yl]benzoic acid (4.32 g, 70% yield) as an off white solid. HNMR (dmso-d6): 7.93 (4H, m), 7.27 (1H, s), 4.05 (2H, q), 3.82 (3H, m), 3.04 (2H, m), 2.02 (2H, m), 1.41 (2H, m), 1.18 (3H, t). LC/MS: M+1: 376.
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[CH2:15]([N:22]1[CH2:31][CH2:30][CH:29]2[C:24](=[N:25][C:26]([S:33][CH3:34])=[N:27][C:28]2=O)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH2:15]([N:22]1[CH2:31][CH2:30][C:29]2[C:28]([Cl:12])=[N:27][C:26]([S:33][CH3:34])=[N:25][C:24]=2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSC1=NC(=O)C2CCN(Cc3ccccc3)CC2=N1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)c1ccccc1
Product: CSc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
N,N-Dimethylaniline (3.2 g, 26.6 mmol) and phosphorus oxychloride (32.6 g, 213 mmol) were added to the solution of 7-benzyl-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4(4aH)-one (7.6 g, 26.6 mmol) in 1,2-dichloroethane (20 mL, anhydrous) and were stirred in a preheated oil bath at 90° C. for 1 hr. Reaction mixture was poured into ice, neutralized by solid sodium carbonate, extracted by ethyl acetate and dried over sodium sulfate. Solvent was removed in vacuo and light brown oil residue was directly gone to next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48]([OH:50])=O)[CH2:15]2)=[CH:10][CH:9]=1.Cl.[CH3:53][NH:54][O:55][CH3:56]>>[CH3:56][O:55][N:54]([CH3:53])[C:48](=[O:50])[CH2:47][C@H:16]1[CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][O:6][CH2:5][C@@H:4]([CH3:51])[CH2:3][O:2][CH3:1])=[CH:9][CH:10]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:18][N:17]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: CNOC
Agent: Cl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)N(C)OC)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21

Procedure:
According to general procedure D, 1.0 mmol of [(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid are reacted with N,O-dimethylhydroxylamine hydrochloride to afford the title compound which is identified based on its Rf-value.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][C:6](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[CH:5][C:4]([CH3:26])([CH3:25])[S:3]1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)O1>>[CH3:27][C:2]1([CH3:1])[CH2:7][C:6]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)=[CH:5][C:4]([CH3:25])([CH3:26])[S:3]1
Reactant: CC1(C)C=C(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC(C)(C)S1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CC1(C)C=C(c2ccc(N)cc2)CC(C)(C)S1

Procedure:
The title compound was prepared from 1,1,2,2,3,3,4,4,4-nonafluoro-butane-1-sulfonic acid 2,2,6,6-tetramethyl-3,6-dihydro-2H-thiopyran-4-yl ester (as prepared in Example 21, step (a)) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine according to the procedure of Example 15, step (c). Mass spectrum (ESI, m/z): Calcd. for C15H21NS, 248.1 (M+H), found 248.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].[N:35]1(C(OC(C)(C)C)=O)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl.O1CCOCC1.Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@H:28]4[CH2:33][CH2:32][C@@H:31]([N:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn(C4CCC(=O)CC4)c3C)cc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cnn([C@H]4CC[C@@H](N5CCNCC5)CC4)c3C)cc12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanone (12.0 mg, 0.0250 mmol), tert-butyl 1-piperazinecarboxylate (46.47 mg, 0.2495 mmol), sodium triacetoxyborohydride (10.58 mg, 0.04990 mmol) and 1,2-dichloroethane (3 mL, 40 mmol) was heated to 60° C. in a sealed tube for 1 h. The solution was extracted with DCM and sat. NaHCO3, and the organic layer was concentrated in vacuo. The material was dissolved in 1,4-dioxane (35 mL, 450 mmol), 4 M of HCl in 1,4-dioxane (1 mL, 4 mmol) was added, and the solution was allowed to stir at rt for 4 h. The material was concentrated in vacuo, loaded onto silica gel for column chromatography, and eluted with 5-10% (7N NH3 in MeOH)/DCM. The fractions containing the cis product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.59-1.77 (m, 4H), 1.82 (d, J=7.3 Hz, 3H), 2.16-2.36 (m, 8H), 2.57 (br. s., 4H), 2.95 (t, J=4.9 Hz, 4H), 3.66 (br. s., 3H), 4.28-4.38 (m, 1H), 5.12 (q, J=7.1 Hz, 1H), 6.90 (dd, J=9.1, 4.3 Hz, 1H), 7.10 (t, J=8.8 Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.42 (s, 1H), 7.46 (s, 1H), 8.12 (d, J=2.0 Hz, 1H). MS (ES+): m/z=551.27/553.27 (100/50) [MH+]. HPLC: tR=1.15 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-nitro-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (3 g, 9.84 mmol) in CH3OH: DCM (40 mL, v/v=3:1) was added Pd/C (600 mg) and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. TLC showed a complete reaction. The solution was filtered and the resulting filtrate was evaporated to dryness to give the crude product, which used directly in the next step (2.6 g, 96%). 1H NMR (300 MHz, CDCl3): δ 7.89 (d, J=2.4 Hz, 1H), 7.26 (dd, J=8.4, 2.4 Hz, 1H), 6.46 (d, J=8.4 Hz, 1H), 4.36 (bs, 2H), 4.23-4.19 (m, 2H), 2.81-2.73 (m, 2H), 2.58-2.47 (m, 1H), 1.78-1.73 (m, 2H), 1.61-1.51 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=O)[CH3:2].[CH3:8][C:9]([CH:11]=[CH2:12])=[O:10].OS(O)(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([C:3]1([CH2:6][CH3:7])[CH2:4][CH2:8][C:9](=[O:10])[CH:11]=[CH:12]1)[CH3:2]
Reactant: CCC(C=O)CC
Reactant: C=CC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCC1(CC)C=CC(=O)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 104.4 %

Procedure:
A mixture of 2-ethylbutyraldehyde (12.3 mL, 100 mmol), methylvinylketone (5.6 mL, 67.3 mmol) and H2SO4 (0.07 mL) is stirred at 40° C. overnight. Another portion of methylvinylketone (5.6 mL, 67.3 mmol) and H2SO4 is added and stirring is continued at 40° C. for 2 d. The yellow solution is diluted with chloroform and the solvent is removed again under reduced pressure. The crude product is purified by vacuum distillation to give 4,4-diethyl-cyclohex-2-enone (10.7 g) as a colourless oil; Bp11 mbar=88° C.; 1H NMR (CDCl3): δ 6.71 (d, J=10.0 Hz, 1H), 5.92 (d, J=10.5 Hz, 1H), 2.42 (t, J=7.0 Hz, 2H), 1.84 (t, J=7.0 Hz, 2H), 1.57-1.40 (m, 4H), 0.87 (t, J=7.6 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.Cl.[NH2:17][C@@H:18]([CH3:22])[C:19]([NH2:21])=[O:20].C(N(CC)CC)C.CO>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:17]([C@@H:18]([CH3:22])[C:19]([NH2:21])=[O:20])[CH:6]=[CH:5]2
Reactant: C[C@H](N)C(N)=O
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 6-chloro-5-nitro-1H-isochromen-1-one (230 mg, 0.00102 mol), (S)-2-aminopropanamide hydrochloride (127 mg, 0.00102 mol), triethylamine (142 μL, 0.00102 mol) and methanol (20 mL, 0.5 mol) was stirred at 60° C. for 3 hours. the solvent was removed under reduced pressure and the residue was purified by flash chromatography to afford the product as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[C:18]([O:22][NH2:23])([CH3:21])([CH3:20])[CH3:19]>CO.N1C=CC=CC=1>[C:18]([O:22][N:23]=[C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][CH:9]=1)[CH3:2])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)ON
Reactant: CC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=NOC(C)(C)C)c1cnc(NC(=O)C(C)(C)C)cn1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of N-(5-acetyl-pyrazin-2-yl)-2,2-dimethyl-propionamide (800.0 mg, 3.62 mmol) in methanol (9 mL) and pyridine (9 mL) was treated with O-(tert-butyl)hydroxylamine hydrochloride (681.1 mg, 5.42 mmol). The resulting reaction mixture was heated under reflux for 30 min. The reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. The resulting residue was diluted with ethyl acetate (50 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/9 ethyl acetate/hexanes) afforded N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-2,2-dimethyl-propionamide (1.04 g, 98%) as a white solid: mp 123–124° C.; EI-HRMS m/e calcd for C15H24N4O2 (M+) 292.1899, found 292.1901.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][NH:12][C:11](=[O:16])[C:10]=3[N:9]=[C:8]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]([F:46])([F:45])[S:32]([NH:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39])(=[O:34])=[O:33]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:17]([C:8]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=3[NH:35][S:32]([C:31]([F:46])([F:30])[F:45])(=[O:34])=[O:33])=[CH:22][CH:21]=2)[C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:16])[C:10]=2[N:9]=1)[CH2:18][CH2:19][CH3:20]
Reactant: O=C(Cl)c1ccccc1NS(=O)(=O)C(F)(F)F
Reactant: CCCCc1nc2c(=O)[nH]ccc2n1Cc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2c(=O)[nH]ccc2n1Cc1ccc(NC(=O)c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
A mixture of 2.96 g of 1-p-aminobenzyl-2-butyl-4,5-dihydro-4-oxo-1H-imidazo[4,5-c]pyridine, 3 ml of triethylamine, 0.5 g of 4-dimethylaminopyridine and 120 ml of CH2Cl2 is cooled to 5° and a solution of 2.88 g of o-trifluoromethanesulphonamidobenzoyl chloride in 20 ml of CH2Cl2 is added dropwise. The mixture is stirred at 20° for a further 16 hours, evaporated and worked up in conventional manner to give 2-butyl-4-oxo-1-[4-(2-trifluoromethanesulphonamidobenzamido)benzyl]-4,5-dihydro-1H-imidazo[4,5-c]pyridine.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[CH:10]2>CN(C=O)C.O>[CH2:1]([S:3][CH2:15][CH2:16][CH2:7][O:6][C:16]1[CH:15]=[C:14]2[C:9]([CH:10]=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:6][CH3:5])[CH3:2]
Reactant: COc1ccc2ncncc2c1
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCCCOc1cc2ncncc2cc1OC
Temperature: 70 °C
Yield: 108.4 %

Procedure:
A mixture of sodium ethanethiolate (120 mg, 1.5 mmol) and 4-(4-chloro-2-fluoroanilino)-73chloropropoxy)6-methoxyquinazoline (227 mg, 0.57 mmol) in DMF (10 ml) was stirred and heated at 70° C. for 3 hours. The reaction mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×75 ml). The extracts were combined, washed with water (×2), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was recrystallised from ethyl acetate/hexane to give 4-chloro-2-fuoroanilino)-7-(3-(ethylthio)propoxy)6-methoxyquinazoline (86 mg, 40%).