Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:15]#[N:16])[C:7](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:8]#[N:9])[CH3:2]>C(OCC)(=O)C.C(O)C.CO.[Pt]=O>[CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]2[C:7](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH2:8][N:9]=[C:15]2[NH2:16])[CH3:2]
Reactant: CCOc1cc(C#N)c(C#N)c(F)c1OCC
Agent: O=[Pt]
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc2c(c(F)c1OCC)C(N)=NC2
Temperature: 25 °C
Reaction time: 96 h
Yield: 20 %

Procedure:
After dissolving 4,5-diethoxy-3-fluorophthalonitrile (103 g) in ethyl acetate-ethanol-methanol (600 ml-600 ml-300 ml), platinum oxide (8 g) was added and the mixture was stirred at room temperature for 4 days under a hydrogen stream. The reaction mixture was filtered through celite, the organic layer was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (21 g) as yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[O:16])[C@H:4]([C@H:12]([CH2:14][CH3:15])[CH3:13])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:18][C:19]([F:40])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:40][C:19]([F:18])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26](/[CH:29]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:17])=[O:16])[C@H:12]([CH2:14][CH3:15])[CH3:13])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:25][CH2:24]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CC[C@H](C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC[C@H](C)[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-isoleucinamide (772 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1221 mg) in 2-propanol (10 mL) was added piperidinium acetate (523 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (770 mg).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][O:29][CH:30]([O:37][CH3:38])[CH2:31][CH2:32][C:33](OC)=[O:34]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH2:31][CH:30]([O:37][CH3:38])[O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: COC(=O)CCC(OC)OC
Agent: Cl
Product: COC(CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)OC

Procedure:
The title compound, white solid (114 mg, 99%), MS (ISP) m/z=461.5 [(M+H)+], mp 205.5° C., was prepared in accordance with the general method of example 2 from trans-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl 4,4-dimethoxy-butanoate.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:45].[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59](C(F)(F)F)[CH:58]=2)[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[Cl:45][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[O:56][CH:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[N:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:51][CH2:52]1
Reactant: Cl
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cn(-c2ccccc2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cn(-c2ccccc2)nn1
Reaction time: 0.03 h
Yield: 50 %

Procedure:
DIPEA (137 mg, 11.0 mmol) was added to stirred solution of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid (50 mg, 0.26 mmol) in DMF (3 mL) followed by HOBT (39 mg, 0.29 mmol) and EDCI (100 mg, 0.53 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (90 mg, 0.26 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer collected was dried over sodium sulfate and concentrated under reduced pressure afforded residue. The residue was purified by column chromatography (using 60-120 silica gel and 50% EtOAc in hexane as eluent) afforded 63 mg (50% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 474.14, 94.1%. 1H NMR (300 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.5 (t, 1H), 8.0 (d, 2H), 7.7-7.6 (t, 2H), 7.6-7.5 (t, 2H), 7.36-7.24 (t, 3H), 4.8 (q, 1H), 4.25 (d, 2H), 4.0-3.8 (m, 1H), 3.8-3.7 (m, 1H), 3.5 (m, 2H), 2.0 (m, 2H), 1.8-1.5 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.[F-].[Cs+]>COCCOC.CO.O.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>[Cl:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][CH2:7][CH2:6][C:5]3[CH:34]=[CH:35][C:2]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[Cl:36])=[CH:3][CH:4]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Br)cc4)cc3)c(Cl)cc21
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(-c5ccccc5Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a stirred suspension of ethyl 7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (0.56 g, 1.0 mmol) and 2-chlorophenylboronic acid (0.17 g, 1.1 mmol) in a mixture of 1,2-dimethoxyethane (4 mL) and methanol (2 mL) was added cesium fluoride (0.30 g, 2.0 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.03 mmol). The resulting mixture was stirred in an oil bath set to 80° C. for 1 hour. The mixture was cooled to ambient temperature and diluted with water (20 mL) and extracted with dichloromethane (2×20 mL). The organic layers were combined and dried over sodium sulfate, then concentrated. The residue was purified by chromatography on silica gel, eluting with 80/20 hexanes/ethyl acetate, to afford ethyl 6-chloro-7-(4-(2-(2′-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate as a light brown oil (0.35 g, 59% yield).
Reaction SMILES: Br[C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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:14]1([CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1sc2ccccc2c1Br
Reactant: Cc1ccccc1B(O)O
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1-c1c(C=O)sc2ccccc12
Temperature: 130 °C

Procedure:
A mixture of 3-bromobenzo[b]thiophene-2-carbaldehyde (500 mg, 2.07 mmol), 2-methylphenylboronic acid (394 mg, 2.90 mmol), Pd(PPh3)4 (243 mg, 0.21 mmol), Cs2CO3 (2.02 g, 6.21 mmol) in dioxane (12 mL) and water (4 mL) was degassed with a stream of nitrogen then heated at 130° C. in a sealed tube using microwave irradiation for 45 min. The reaction mixture was extracted with EtOAc, and the organic fraction washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-70% DCM in cyclohexane) affording the title compound (quantitative yield). LCMS (Method C): RT 4.16 min
Reaction SMILES: [ClH:1].N[NH:3][C:4]([NH:6][NH2:7])=[NH:5].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[Na+:15].C(#[N:18])C>CC(C)=O>[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[NH2:18][N+:6]([NH2:7])=[C:4]([NH2:5])[NH2:3].[Cl-:1].[Na+:15]
Reactant: CC#N
Reactant: N=C(NN)NN
Reactant: Cl
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(N)=[N+](N)N
Product: [Cl-]

Procedure:
Diaminoguanidinium trifluoroacetate is synthesized by reacting diaminoguanidine hydrochloride and sodium trifluoroacetate in acetone or acetonitrile. Sodium chloride is produced as a byproduct of the reaction and is removed, producing the diaminoguanidinium trifluoroacetate.
Reaction SMILES: C([O:4][C@H:5]([C@H:8]([C@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])[CH3:11])[CH:6]=[O:7])(=O)C.[O:28]=[CH:29][C@@H:30]([C@H]([C@H]([C@@H](CO)O)O)O)O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>ClC(Cl)C>[C:25]([O:24][C@@H:23]1[O:4][C@H:5]([CH2:6][O:7][C:29](=[O:28])[CH3:30])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The synthesis of compounds 26-31 are depicted in FIGS. 3A and 3B and are set forth in the examples hereinbelow. In this figure, the synthesis of compounds 26, 27, 28, and 36 parallels that of compounds 17, 18, 19, and 20 as set forth above and illustrated in FIG. 2. In this regard, benzyl 4,6-O-benzylidene-2-O-benzoyl-3-O-chloroacetyl-β-D-thiogalactopyranoside (compound 31) has been produced without the necessity of chromatography. D-Galactose pentaacetate 26 is produced by slurring D-galactose and about an equimolar amount (e.g., about 1.1 equivalents) of sodium acetate (NaOAc) in dichloroethane (DCE), heating to reflux and adding at least 5 equivalents of acetic anhydride (AcOAc) dropwise to the refluxing solution (about 80°-85° C.) and then maintaining the reaction system at this temperature for a sufficient period of time (about 16-32 hours) to result in formation of compound 26. This procedure optimizes the yield of β-D-galactose pentaacetate 26 and controls the exotherm of heretofore known procedures.
Reaction SMILES: [N+](C1C=CC([O:8][C:9]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=O)=CC=1)([O-])=O.[CH3:19][NH:20][CH2:21][CH2:22][N:23]([CH2:29][C:30]1[CH:31]=[C:32]([CH:66]=[CH:67][CH:68]=1)[C:33]([NH:35][C:36]1[S:37][C:38]2[CH2:65][CH2:64][CH2:63][CH2:62][C:39]=2[C:40]=1[C:41]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][C:52]2[CH:61]=[CH:60][C:55]([C:56]([O:58][CH3:59])=[O:57])=[CH:54][CH:53]=2)=[CH:46][CH:45]=1)=[O:42])=[O:34])[CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26].C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:19][N:20]([CH2:21][CH2:22][N:23]([CH:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:29][C:30]1[CH:31]=[C:32]([CH:66]=[CH:67][CH:68]=1)[C:33]([NH:35][C:36]1[S:37][C:38]2[CH2:65][CH2:64][CH2:63][CH2:62][C:39]=2[C:40]=1[C:41]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]([C:56]([O:58][CH3:59])=[O:57])=[CH:60][CH:61]=2)=[CH:46][CH:45]=1)=[O:42])=[O:34])[C:9](=[O:8])[O:11][CH2:12][C:13](=[O:14])[O:15][CH3:16]
Reactant: COC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CC)N(CCN(C)C(=O)OCC(=O)OC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
A mixture of 100 mg of methyl {[(4-nitrophenoxy)carbonyl]oxy}acetate and 5.0 mL of THF was added to a mixture of 180 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 0.15 mL of N-ethyl-N-isopropylpropan-2-amine, and 5.0 mL of THF under ice cooling, followed by stirring for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, followed by extraction with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane:chloroform=4:6), thereby obtaining 204 mg of methyl 4-{2-[4-({[2-({3-[7-methyl-3,6-dioxo-10-(pentan-3-yl)-2,5-dioxa-7,10-diazaundecan-11-yl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate.
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:3]1[C:2]([F:1])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2cc(F)c(=O)[nH]c2c1
Product: COc1ccc2cc(F)c(Cl)nc2c1
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A mixture of 3-fluoro-7-methoxyquinolin-2(1H)-one (1.40 g, 7.25 mmol) and POCl3 (13.3 ml, 145 mmol) was stirred at 110 C (bath) for 1 hour. The POCl3 was removed under reduced pressure. Ethyl acetate (30 mL) and saturated sodium bicarbonate (30 mL) were added and stirred for 10 minutes. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (10:1 hexane/ethyl acetate) to give 2-chloro-3-fluoro-7-methoxyquinoline (0.55 g, 2.60 mmol, 36% yield) as white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][N:8]2[CH2:17][CH2:18][CH2:19][C:7]=12)=[O:5])C.[OH-].[Na+].C(#N)C.Cl>CO>[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][N:8]2[CH2:17][CH2:18][CH2:19][C:7]=12)([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2ccccc2)nn2c1CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: O=C(O)c1c(-c2ccccc2)nn2c1CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 3-ethoxycarbonyl-2-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (2.1 g, 8.2 mmol) in MeOH (20 mL) add a solution of NaOH (15%, 40 mL) followed by acetonitrile (5 mL) and stirr at 50° C. for 3 hours. Cool the mixture to room temperature and add HCl (10%) until a pH of 3 is reached. Extract the mixture with EtOAc (3×100 mL) and wash with saturated aqueous sodium chloride (100 mL), dry (MgSO4), and concentrate in vacuo to give a yellow solid, 1.82 g, 97% yield, MS(ES+): m/z=229.1 (M+H)+
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:19].[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.O1CCCC1>[Br:19][C:11]1[NH:10][C:9]2[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[S:14][C:8]=2[C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Br
Reactant: COC(=O)c1cc2[nH]cc(C3CCCCC3)c2s1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Yield: 73 %

Procedure:
To a solution of methyl 6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate obtained in Step 7 in chloroform (90 ml) and tetrahydrofuran (90 ml) was added pyridinium hydrobromide perbromide (21.7 g, 68 mmol) under ice-cooling. The mixture was stirred under ice-cooling for 2 hr and concentrated under reduced pressure at room temperature. Ethyl acetate (300 ml) was added to the residue, and the mixture was washed successively with 1M aqueous sodium hydrogen sulfite solution (100 ml×3), water (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml×2) and saturated brine (100 ml), and dried over magnesium sulfate. The mixture was filtered and concentrated under reduced pressure, and the obtained solid was washed with a mixed solvent (100 ml) of n-hexane:ethyl acetate (25:1). The solid was collected by filtration, and dried under reduced pressure to give methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (17 g, yield 73%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8]Cl)(=O)C.[OH:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(=O)OCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCCCCO)cc1
Temperature: 90 °C
Reaction time: 11 h

Procedure:
4-Chlorobutyl acetate (276.6 g; 1.8 mol) is added to a solution of ethyl 4-hydroxybenzoate (249 g; 1.5 mol), potassium iodide (3 g) and potassium carbonate (248 g; 1.8 mol) in dimethylformamide (2 l), and the mixture is stirred at 90° C. for 11 hours. The reaction mixture is transferred into 5 l of ice water, and the resultant precipitate is filtered off with suction and washed with 4 to 5 l of ice water. The crude product is dissolved in 3 l of ethanol, potassium hydroxide (400 g) is added, and the mixture is refluxed for 3 hours. The reaction mixture is transferred into 6 l of ice water, and acidified by means of concentrated hydrochloric acid, and the precipitate is filtered off, washed with water until neutral and then dried.
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]1=[O:4].[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1.C([O-])(O)=O.[Na+]>CO.O>[Cl:10][C:11]1[N:16]=[C:15]([NH:1][CH:2]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]2=[O:4])[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC1CCCCNC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1NCCCCC1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (±)-α-amino-ε-caprolactam (256 mg, 2.0 mmol), 2,4,5-trichloropyrimidine (366 mg, 2.0 mmol, 1 equiv.) and NaHCO3 (168 mg, 2 mmol, 1 equiv.) in a mixture of MeOH (12 mL) and H2O (6 mL) was stirred at room temperature for 15 h. The resulting precipitate was collected by vacuum filtration and washed with small amounts of MeOH and water, providing the product 3-(2,5-dichloropyrimidin-4-ylamino)azepan-2-one; ESMS m/z 275.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=3[OH:12])=[O:15])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(O)cccc2c1O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(O)cccc2c1O
Temperature: 180 °C
Yield: 49.5 %

Procedure:
A mixture of 2-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature. Diphenyl ether (50 mL) is added and the mixture is heated to 240° C. for 90 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to room temperature and the resulting solid is collected and washed with hexanes. The crude solid is recrystallized from acetone to yield 0.650 g of ethyl 4,8-dihydroxyquinoline-3-carboxylate. A mixture of this ester (0.500 g) and 4-chlorobenzylamine (1.518 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature and diluted with CH2Cl2. The resulting solid is collected and chromatographed on silica, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to afford 0.349 g of the desired product as an off-white solid.
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.[CH3:11][CH:12]([NH:19][NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N.[OH:22]O>CO.C(O)C>[NH2:8][C:7]1[N:19]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:11])[N:20]=[C:4]([CH3:5])[C:6]=1[C:9]([NH2:10])=[O:22]
Reactant: CCOC(C)=C(C#N)C#N
Reactant: OO
Reactant: CCCCCCC(C)NN
Agent: N
Solvent: CO
Solvent: CCO
Product: CCCCCCC(C)n1nc(C)c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 65 h

Procedure:
4.72 g (34.66 mmol) of 2-(1-ethoxy-ethylidene)-malononitrile and 5.00 g (34.66 mmol) of (1-methyl-heptyl)-hydrazine are refluxed for 4 hours in 40 ml of methanol. After the solvent has been removed in vacuo, 8.23 g of a red oil are obtained. This is dissolved in 250 ml of ethanol and, after 300 ml of concentrated NH3 solution (25% strength) and 70 ml of hydrogen peroxide solution (30% strength) have been added, the solution is stirred for 65 hours at room temperature. After the non-aqueous solvents have been removed, the mixture is extracted three times with dichloromethane, and the organic phase is dried over sodium sulphate and evaporated on a rotary evaporator. This gives 7.75 g (87%) of a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:14][CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Reactant: BrCc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Clc1ccc(Nc2nccs2)cc1OCc1nccs1
Yield: 33 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-chloro-5-(thiazol-2-ylamino)phenol (100 mg, 0.44 mmol) and Cs2CO3 (147 mg, 0.44 mmol) in acetone (4.4 mL) was treated with 2-bromomethylthiazole (88 mg, 0.44 mmol) at RT. Reaction control by TLC showed full conversion after 3 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 1/1) in 33% yield (47 mg).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([Cl:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(CC(=O)O)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)Cl)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-methyl-3-phenylbutyric acid (0.508 g, 2.85 mmol) in dichloromethane (10 μL) at −78° C. was treated with oxalyl chloride (3.62 , 28.5 mmol) and 1 drop of dimethylformamide. The reaction mixture was stirred at −78° C. for 10 min, and dry ice/acetone bath was removed to stir at room temperature over night. Solvent was removed under reduced pressure, and dried under high vacuum. The product was used directly for subsequent reaction without analysis.