Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:19]3[CH2:21][CH2:20]3)[C:10](=[O:18])[N:11]([CH:13]([CH3:17])[C:14](O)=[O:15])[CH:12]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:19]3[CH2:21][CH2:20]3)[C:10](=[O:18])[N:11]([CH:13]([CH3:17])[C:14]([NH:28][CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=3)=[O:15])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CC(C(=O)O)n1cc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C(=O)NCc1cccc(C(F)(F)F)c1)n1cc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.163 mmol) of 2-(4-[4-chlorophenyl]-3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-propionic acid from Example 131A, 31.4 mg (0.179 mmol) of 3-trifluoromethylbenzylamine, 40.6 mg (0.212 mmol) of EDC hydrochloride and 26.4 mg (0.196 mmol) of HOBt are dissolved in 1 ml of dry dimethylformamide and stirred overnight at room temperature. The mixture is partitioned between water and dichloromethane, and the separated organic phase is dried over sodium sulphate and concentrated. The crude product that remains is purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 100:1→50:1). 42 mg (56% of theory) of the target compound are thus obtained.
Reaction SMILES: [OH-].[Li+].C(O)(=O)CS.CN(C=O)C.[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([CH2:31][CH2:32][CH2:33][N:34]([CH2:47][CH2:48][N:49]3[CH:58]=[CH:57][C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:59])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:29]=[CH:30][C:16]1=2)[CH3:14]>O>[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([CH2:31][CH2:32][CH2:33][NH:34][CH2:47][CH2:48][N:49]3[CH:58]=[CH:57][C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:59])[CH:29]=[CH:30][C:16]1=2)[CH3:14]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCN(CCn3ccc4ccccc4c3=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCNCCn3ccc4ccccc4c3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
Lithium hydroxide(3.2 g), and thioglycolic acid(2.4 ml) were added to a DMF solution(27.4 ml) of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propyl]-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide (4.56 g). The mixture was stirred at room temperature for 1 hour. The reaction mixture was condensed under reduced pressure. Water was added to the residue, followed by extraction using dichloromethane. The organic layer was washed with water and saturated saline, dried with magnesium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=10:1). The purified product was condensed under reduced pressure to produce the title compound(2.24 g) as a yellow oil.
Reaction SMILES: [N+]12([S:9]([N-:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:11])=[O:10])CCN(CC1)CC2.N12CCN(CC1)CC2.Cl.[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C@@H:35]([NH:39][C:40]1[N:45]=[CH:44][N:43]=[C:42]([O:46][C@H:47]3[CH2:51][C@H:50]([OH:52])[C@H:49]([CH2:53][OH:54])[CH2:48]3)[CH:41]=1)[C@@H:34]([O:55][CH3:56])[CH2:33]2.O>C(#N)C.CN1CCCC1=O.C(OCC)(=O)C>[Cl:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C@@H:35]([NH:39][C:40]1[N:45]=[CH:44][N:43]=[C:42]([O:46][C@@H:47]3[CH2:48][C@@H:49]([CH2:53][O:54][S:9]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])(=[O:10])=[O:11])[C@@H:50]([OH:52])[CH2:51]3)[CH:41]=1)[C@@H:34]([O:55][CH3:56])[CH2:33]2
Reactant: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO)[C@@H](O)C2)ncn1
Reactant: CC(C)(C)OC(=O)[N-]S(=O)(=O)[N+]12CCN(CC1)CC2
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](COS(=O)(=O)NC(=O)OC(C)(C)C)[C@@H](O)C2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-aza-1-azoniabicyclo[2.2.2]oct-1-ylsulfonyl)(tert-butoxycarbonyl)azanide-1,4-diazabicyclo[2.2.2]octane (1:1) hydrochloride (43.4 g, 98.6 mmol) in acetonitrile (30 mL), in a 500 mL reactor, was added (1S,2S,4R)-4-(6-((1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-ylamino)pyrimidin-4-yloxy)-2-(hydroxymethyl)cyclopentanol (27) (10 g, 24.6 mmol) in N-methylpyrrolidinone (60 mL). The resultant thick slurry was stirred at ambient temperature for 3 hours. Upon reaction completion, water (66.6 mL) was added slowly at ambient temperature. To the resulting mixture, ethyl acetate (66.7 mL) was added. The aqueous layer was extract three times with ethyl acetate (3×66.6 mL). The combined organic layers were washed once with water (66.7 mL) and once with saturated sodium chloride in water (66.7 mL). The combined organic layers were dried over magnesium sulfate (3 g), filtered and concentrated. This product was taken on to the next step without further purification.
Reaction SMILES: [N+:1]1([O-])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:15][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)(=[O:14])[CH3:13]
Reactant: [O-][n+]1cccc2c1CCCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1CCCc2cccnc21
Temperature: 90 °C
Reaction time: 7 h
Yield: 33 %

Procedure:
5,6,7,8-Tetrahydroquinoline N-oxide (1.6 g, 11 mmol) was mixed with acetic anhydride (9.2 ml) and stirred at 90° C. for 7 hours. After removing the solvent by evaporation under a reduced pressure, the residue was neutralized with sodium hydroxide aqueous solution (1 N) and the reaction product was extracted with chloroform. The extract was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 690 mg (3.6 mmol, 33%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25](OCC)=[O:26])[C:5]2[C:6](=O)[CH:7]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:6]3=[N:31][NH:32][C:25](=[O:26])[C:4]([CH:3]=1)=[C:5]23
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccccc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ncnc1C1c2n[nH]c(=O)c3cc(F)cc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 24 %

Procedure:
To a solution of ethyl 7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (186 mg, 0.47 mmol) in methanol (1 mL) was added hydrazine monohydrate (0.5 mL), and the mixture was stirred at 25° C. for 15 hr. Then the mixture was filtered to obtain a white solid (40 mg, yield 24%). LC-MS (ESI) m/z: 363 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.63 (s, 3H), 4.94-5.03 (m, 2H), 6.91-6.94 (dd, J1=11.6 Hz, J2=2.4 Hz, 1H), 7.05-7.08 (dd, J1=9.6 Hz, J2=2.4 Hz, 1H), 7.29-7.35 (m, 3H), 7.42-7.48 (m, 2H), 7.74 (s, 1H), 7.79 (s, 1H), 12.34 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][C:11](O)([C:14]#[N:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)(Cl)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>N1C=CC=CC=1>[F:1][C:2]1[C:3]([N:8]2[CH2:9][CH:10]=[C:11]([C:14]#[N:15])[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(O)CCN(c2ncccc2F)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#CC1=CCN(c2ncccc2F)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
3′-Fluoro-4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonitrile 19 (100 g, 450.2 mMol) was dissolved in dry pyridine (1,000 mL) and cooled to 0° C. under nitrogen. Phosphorus oxychloride (85 mL, 940 mMol) was added dropwise ensuring the temperature did not rise above 10° C. during the addition, and the resulting mixture stirred at 0° C. overnight using a lagged cooling bath. The mixture was cautiously poured into ice-water (3,000 mL) with stirring, and the pH adjusted to 6.0 using potassium phosphate buffer. The mixture was extracted with ethyl acetate (3×2,000 mL), dried (MgSO4) and the solvent evaporated to dryness in vacuo to leave orange oil. Flash chromatography of the residue eluting with hexanes:ethyl acetate (10:1) gave the title compound 20 (65 g, 72%) as a white solid m.p.=76-77° C. δH {400 MHz, CDCl3} 8.01 (1H, d, J=5 Hz), 7.27 (1H, dd, J=20, 8 Hz), 6.79 (1H, m), 6.71 (1H, m), 4.16 (2H, dd, J=12, 3 Hz), 3.65 (2H, t, J=6 Hz), 2.50 (2H, m).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:35][CH:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CN1CCC(N)CC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NC3CCN(C)CC3)sc2Br)s1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 74 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (200 mg; 0.48 mmol; 1 eq), is dissolved in anhydrous DCM (10 ml). The reaction mixture is cooled down to 0° C. and put under nitrogen. Triethylamine (0.27 ml; 1.92 mmol; 4 eq) and 1-methyl-piperidin-4-ylamine (0.11 ml; 0.96 mmol; 2 eq) are added successively and the reaction mixture is stirred at 0° C. for 40 minutes. It is then washed with water, NaHCO3 and dried over MgSO4, affording the title compound (185 mg; 74%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[OH:13].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[O:13][CH2:15][CH:16]1[CH2:18][CH2:17]1
Reactant: BrCC1CC1
Reactant: COCOc1cc(O)c(Br)cc1F
Product: COCOc1cc(OCC2CC2)c(Br)cc1F

Procedure:
Starting from 2-bromo-4-fluoro-5-methoxymethoxy-phenol (example A7) and bromomethyl-cyclopropane the title compound is obtained as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:21][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([C:18](O)=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:22])[NH:4][C:3]1=[O:23].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][N:2]1[C:6]2([CH2:21][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([C:18]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:22])[NH:4][C:3]1=[O:23]
Reactant: CN1C(=O)NC(=O)C12Cc1cc3ccc(C(=O)O)nc3cc1C2
Reactant: Nc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1C(=O)NC(=O)C12Cc1cc3ccc(C(=O)Nc4ccccc4)nc3cc1C2

Procedure:
A mixture of (±)-3′-methyl-2′,5′-dioxo-6,8-dihydrospiro[cyclopenta[g]quinoline-7,4′-imidazolidine]-2-carboxylic acid (14 mg, 0.045 mmol, described in Intermediate 18), aniline (4 mg, 0.045 mmol), EDC (26 mg, 0.136 mmol), HOBT (21 mg, 0.136 mmol), and N,N-diisopropylethylamine (0.039 mL, 0.226 mmol) is stirred in DMF (1 mL) at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and concentrated to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[C:13]([OH:19])(=[O:18])[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>O.N1C=CC=CC=1>[C:15]([C:14]([C:13]([OH:19])=[O:18])=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(-c2cccs2)s1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)C(=Cc1ccc(-c2cccs2)s1)C(=O)O
Yield: 100.4 %

Procedure:
3.9 g of 5-formyl-2,2'-bithiophene, 4.2 g of malonic acid, 10 ml of pyridine and 2.5 ml of piperidine were heated at 60° C. for 2 hours. After cooling, 50 ml of water was added into the mixture and acidified by diluted HCl. The crude product collected was recrystallized from ethanol to give a crystal product (5.65 g). The melting point of the product was 220°-221° C. The yield was 86%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=3)=[N:9]2)=[CH:5][CH:4]=1.[Cl-].[NH4+].C(OCC)C>O1CCOCC1.O.[Zn]>[NH2:27][C:23]1[CH:22]=[C:21]([C:10]2[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:12][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=3)[N:9]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc([N+](=O)[O-])c2)ccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(N)c2)ccn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 93.7 %

Procedure:
300 mg (0.72 mmol) of 4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-N-methylpyridin-2-amine were dissolved in a mixture of 20 ml of dioxane and 4 ml of water and 381 mg (7.2 mmol) of ammonium chloride and 190 mg (2.9 mmol) of metallic zinc were added. The reaction was maintained at 100° C. under stirring for 6 hours. The mixture was then filtered through a celite pad and the solvent removed in vacuo. The residue was partitioned between dichloromethane and water, dried over sodium sulphate and evaporated again, giving, after trituration with diethylether, 260 mg (93%) of the title compound.
Reaction SMILES: [Br:1]Br.[CH:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH:15][CH:16]=[O:17])[CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([Br:1])=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH:15][CH:16]=[O:17])[CH2:6]1)=[O:4]
Reactant: BrBr
Reactant: O=CNC1Cc2ccccc2N(C=O)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=CNC1Cc2cc(Br)ccc2N(C=O)C1
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
Bromine (10.2 g, 0.064 mol) was added to a stirred solution of N-(1-formyl-1,2,3,4-tetrahydro-3-quinolyl)formamide (14.0 g, 0.065 mol) in acetic acid (70 mL) containing anhydrous sodium acetate (10.2 g, 0.12 mol). The solution was stirred for 30 minutes and water (500 mL) was added. The precipitate was filtered off and air dried to give 15.8 g (86%) of N-(1-formyl-6-bromo-1,2,3,4-tetrahydro-3-quinolyl)formamide, mp 174°-178° C. A sample was recrystallized from ethanol for analysis; mp 178°-181° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C:10]#[CH:11])(=O)=O.[CH:19]([NH2:22])([CH3:21])[CH3:20]>>[CH:19]([NH:22][CH2:6][CH2:7][N:8]([CH2:9][C:10]#[CH:11])[C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: C#CCN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reactant: CC(C)N
Product: C#CCN(CCNC(C)C)C(=O)OC(C)(C)C

Procedure:
A solution of 900 mg of 10e in 15 ml of isopropyl amine was stirred for 3 days at RT. The reaction mixture was concentrated. The residue was treated with 10 ml of sat. NaHCO3 and extracted with ethyl acetate. After drying and concentration of the organic material 750 mg of essentially pure 10f was obtained as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][CH3:14].[CH3:15][CH2:16][C:17](=O)[CH2:18][CH3:19]>[Pt].CCOCC.C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>[CH2:13]([C:5]1[CH:6]=[CH:7][C:8]([NH:10][CH:17]([CH2:18][CH3:19])[CH2:16][CH3:15])=[CH:9][C:4]=1[CH2:3][O:2][CH3:1])[CH3:14]
Reactant: CCc1ccc([N+](=O)[O-])cc1COC
Reactant: CCC(=O)CC
Agent: [Pt]
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: CCOCC
Product: CCc1ccc(NC(CC)CC)cc1COC
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A mixture of 10.0g of 2-ethyl-5-nitrobenzyl methyl ether, 10.38g of 3-pentanone, 0.23g of 2-naphthalene sulfonic acid, and 0.60g of 5% platinum on carbon catalyst was shaken under hydrogen for 2 hours at room temperature and for 4 hours at 48° C. to 60° C. The mixture was diluted with 200 ml of ether, filtered and the filtrate shaken with 2.5% aqueous sodium hydroxide, washed with water, filtered through sodium sulfate and stirred over magnesium sulfate. The filtered solution was concentrated under vacuum to yield 10.76 grams of an amber liquid, pure by glc and tlc analyses.
Reaction SMILES: C(OC([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([Br:18])=[CH:13][C:12]=2[CH:11]2[CH2:19][CH2:20][CH2:21][C:10]2([F:22])[C:9]1=[O:23])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O.C(OCC)(=O)C>[Br:18][C:14]1[CH:15]=[CH:16][C:17]2[NH:8][C:9](=[O:23])[C:10]3([F:22])[CH2:21][CH2:20][CH2:19][CH:11]3[C:12]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(F)CCCC2c2cc(Br)ccc21
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Br)cc2C2CCCC12F
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A solution of 1.38 g (3.6 mmol) of 5-tert-butoxycarbonyl-8-bromo-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 7 ml of dichloromethane is mixed with 7 ml of trifluoroacetic acid at room temperature. After 2 hours, the batch is diluted with water and ethyl acetate. The organic phase is separated, washed with water, saturated NaHCO3 and saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography of the residue on silica gel with hexane-ethyl acetate yields 0.74 g of product.
Reaction SMILES: [BH4-].[Na+].[CH:3](=[O:13])[CH2:4][CH2:5]/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH4+].[Cl-]>CO>[CH2:3]([OH:13])[CH2:4][CH2:5]/[CH:6]=[CH:7]/[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC/C=C/CCC=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCCCC/C=C/CCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Sodium borohydride (0.60 g, 3.8 mmol) was added in portions to a stirred solution of trans-dec-4-enal (1.54 g, 10.0 mmol) in methanol (50 mL). The reaction was stirred at room temperature for 30 min followed by the addition of saturated NH4Cl. Methanol was evaporated and water was added to the residue. The mixture was extracted with ether and the combined organic layers were washed with water and dried. Evaporation of the solvent gave trans-dec-4-en-1-ol (1.52 g, 97%) as a pale yellow oil, which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ 5.39 (2H, m), 3.60 (2H, t, J=6.6 Hz), 2.02 (5H, m), 1.56 (2H, m), 1.23 (6H, m), 0.84 (3H, t, J=6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 131.31, 129.44, 62.66, 32.80, 32.70, 31.67, 29.51, 29.18, 22.82, 14.36.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH2:9][O:10][C:11]2[N:16]=[C:15](/[N:17]=[CH:18]/N(C)C)[C:14]([F:22])=[CH:13][N:12]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C([O-])(O)=[O:25].[Na+]>O1CCOCC1>[CH:1]1([C:6]([O:8][CH2:9][O:10][C:11]2[N:16]=[C:15]([NH:17][CH:18]=[O:25])[C:14]([F:22])=[CH:13][N:12]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)/C=N/c1nc(OCOC(=O)C2CCCC2)ncc1F
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=CNc1nc(OCOC(=O)C2CCCC2)ncc1F
Reaction time: 5 h
Yield: 95.4 %

Procedure:
A 25 mL vial was charged with (E)-(4-((dimethylamino)methyleneamino)-5-fluoropyrimidin-2-yloxy)methyl cyclopentanecarboxylate (50.0 mg, 0.161 mmol), 1,4-dioxane (4 mL), and 1.0 M aqueous HCl (78 μL, 0.078 mmol) and was agitated on an orbital shaker for 5 h. The reaction was monitored by ultra performance liquid chromatography (UPLC) and determined to be incomplete, therefore an additional portion of 1.0 M aqueous HCl (78 μL, 0.078 mmol) was added. After 1 h, the reaction was quenched by the addition of 1.0 M aqueous NaHCO3 (260 μL, 0.260 mmol) and concentrated under reduced pressure at 45° C. The dried residue was then extracted with EtOAc (5 mL×4), and concentrated to dryness under reduced pressure to obtain (5-fluoro-4-formamidopyrimidin-2-yloxy)methyl cyclopentanecarboxylate (43.5 mg, 95%) as a white solid: mp 76-79° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.38 (bs, 1H), 9.31 (d, J=5.7 Hz, 1H), 8.52 (d, J=2.6 Hz, 1H), 5.97 (s, 2H), 2.71-2.85 (m, 1H), 1.40-1.89 (m, 8H); MS (ESI) m/z 306 (M+Na)+, 282 (M−H)−.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8](OC)=[O:9])(=[O:4])(=[O:3])[NH2:2].[NH2:15][NH2:16]>CO>[NH:15]([C:8]([C:7]1[CH:6]=[C:5]([S:1]([NH2:2])(=[O:4])=[O:3])[CH:14]=[CH:13][CH:12]=1)=[O:9])[NH2:16]
Reactant: COC(=O)c1cccc(S(N)(=O)=O)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1cccc(S(N)(=O)=O)c1
Temperature: 65 °C
Yield: 50.9 %

Procedure:
Methyl 3-sulfamoylbenzoate (110 mg, 0.511 mmol) was added to the hydrazine (32.8 mg, 1.022 mmol) in methanol and refluxed for 8 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography (5% methanol/DCM) to yield the 3-(hydrazinecarbonyl)benzenesulfonamide (57 mg, 0.260 mmol, 50.8% yield) as a white solid. 1H NMR (CD3OD, 400 MHz): δ 8.32 (m, 1H), 8.04 (d, 1H, J=7.6 Hz), 7.97 (d, 1H, J=7.6 Hz), 7.63 (t, 1H, J=8.0 Hz). Mass [M+H]+:216.0
Reaction SMILES: C(OP([CH2:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11])(OCC)=O)C.[H-].[Na+].[Cl-].[NH4+]>C1COCC1>[CH3:10][CH:12]([CH3:17])/[CH:13]=[CH:9]/[C:10]([CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)[CH2:16][CH2:17]1)=[O:11]
Reactant: CCOP(=O)(CC(=O)C1CCN(c2cc(C)ccn2)CC1)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccnc(N2CCC(C(=O)/C=C/C(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 22 %

Procedure:
2-Diethoxyphosphoryl-1-[1-(4-methyl-2-pyridyl)-4-piperidyl]ethanone (product of step B, 350 mg, 1 mmol) was dissolved in anhydrous THF (40 ml) and cooled under argon to 0° C. Sodium hydride (60%, 60 mg, 1.5 mmol) was added and the mixture was stirred at room temperature for 20 minutes. Isobutyryl aldehyde (186 μl, 2 mmol) was added and stirring was continued for 90 minutes. The mixture was poured into saturated ammonium chloride solution (100 ml), the mixture was extracted with DCM, the aqueous layer was extracted again with DCM (2×), and the combined organic phases were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 30 mg of a brown solid (0.11 mmol, 11%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([O:9]C=CC)=[CH:5][CH:4]=1.S(=O)(=O)(O)O>CO>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[CH:7][CH:8]=1
Reactant: CC=COc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: Oc1ccc(C(F)(F)F)cc1
Yield: 69.5 %

Procedure:
A mixture of 60.0 g of propenyl 4-trifluoromethylphenyl ether, 350 ml of methanol and aqueous sulphuric acid (20 ml 98% H2SO4 in 50 ml water) was refluxed for 4 hours. After dilution with 1200 ml water, the product was extracted twice with toluene. Removal of solvent and distillation of the residue gave 33.43 g of 4-trifluoromethylphenol, b.p.: 63°-64° C. at 6 Torr.