Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:29])[CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([CH2:21][CH2:20][N:19]([CH3:18])[CH3:29])[CH:23]=1
Reactant: CN(C)CCc1cccc(N)c1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C)CCc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)c1
Yield: 67.7 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (280 mg, 0.91 mmol) was reacted with 3-[2-(dimethylamino)ethyl]aniline (150 mg, 0.91 mmol) to afford the desired product (270 mg, 68%) as a yellow solid: ESI MS m/z 438 [C23H24BrN3O+H]+.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C(#N)C>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 24.8 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (200 mg, 0.613 mmol, Example 11b) in acetonitrile (5 mL) was added potassium carbonate (254 mg, 1.838 mmol) followed by tert-butyl 2-bromoacetate (155 mg, 0.797 mmol). The reaction mixture was stirred at 80° C. for 4 hours. The suspension was filtered and evaporated. The oil was suspended in 2 mL of dioxane and 2 mL of 1 M NaOH. The solution was stirred for 1 hour, then injected on preparatory HPLC (5 to 30% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with NH4OH and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried, filtered and evaporated till dryness. tert-butyl 2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)acetate (55 mg, 0.152 mmol, 24.75% yield) was isolated as colorless oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.20-7.31 (m, 2H), 7.09-7.17 (m, 1H), 6.99-7.09 (m, 2H), 3.12 (s, 2H), 2.91-3.03 (m, 2H), 2.62 (d, J=7.07 Hz, 2H), 2.28-2.36 (m, 1H), 2.11-2.23 (m, 2H), 1.92 (ddd, J=3.28, 5.87, 9.28 Hz, 1H), 1.68-1.83 (m, 2H), 1.52-1.63 (m, 1H), 1.44-1.52 (m, 9H), 1.31 (qd, J=3.92, 12.34 Hz, 2H), 1.08 (dt, J=4.86, 9.47 Hz, 1H), 1.02 (dt, J=5.59, 7.26 Hz, 1H); LC-MS Rt=0.58 min; MS (ESI): 345.3 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:10]=1.[CH3:27][C@H:28]1[CH2:33][O:32][CH2:31][CH2:30][NH:29]1>C(Cl)Cl>[Cl:8][C:9]1[N:10]=[C:11]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:12]=[C:13]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][C@@H:28]2[CH3:27])[N:14]=1
Reactant: C[C@H]1COCCN1
Reactant: O=S(=O)(Cc1cc(Cl)nc(Cl)n1)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(F)cc2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
Triethylamine (1.117 ml, 8.01 mmol) was added to 2,4-dichloro-6-[(4-fluorophenyl)sulfonylmethyl]pyrimidine (2.34 g, 7.29 mmol) in DCM (36.4 mL) at 0° C. followed by (3S)-3-methylmorpholine (0.737 g, 7.29 mmol) in DCM (20 mL) over 15 minutes. The reaction was then stirred at RT for 16 hours. The reaction mixture was washed with water (50 mL), the organic layer dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in DCM, to give the desired material as a beige solid (1.530 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][CH2:13]3)[C:11](=[O:23])[N:10]([CH3:24])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:11](=[O:23])[N:10]([CH3:24])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CN1CN(c2ccc(F)cc2)C2(CCNCC2)C1=O
Yield: 23 %

Procedure:
A mixture of 14.7 parts of ethyl 1-(4-fluorophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4,5]decane-8-carboxylate, 16 parts of sodium hydroxide and 160 parts of 1-butanol is stirred and refluxed for 4 hours. The reaction mixture is evaporated and the residue is taken up in water. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and methanol, yielding 2.7 parts (23%) of 1-(4-fluorophenyl)-3-methyl-1,3,8-triazaspiro[4,5]decan-4-one.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:20]=[O:21])C>C1COCC1>[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:20]=[O:21]
Reactant: Brc1ccncc1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cnccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
A suspension of 4-bromopyridine hydrochloride (5.0 g, 25.7 mmol) in THF (100 mL) was purged with N2 and cooled to −78° C. A solution of lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 27.0 mL, 54.0 mmol) was added over 3 minutes. After 30 minutes, DMF (8.56 mL, 110.6 mmol) was added. The reaction mixture was stirred at −78° C. for 15 minutes before rapidly warming to room temperature in a water bath. The reaction was allowed to stir at ambient temperature for 18 hours. The reaction was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, evaporated, and chromatographed (Analogix 150 g silica gel column eluting with a gradient of 100% heptane 50% EtOAc/heptane over 1 hour) to give 1.50 g (31%) of the title compound as a light yellow solid. MS m/z 186 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:9](=O)[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)(=O)[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C.[OH-].[NH4+]>C(OC(=O)C)(=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[C:29](=[O:31])[O:30][C:9]3=[N:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:4]3[C:1]=2[CH3:2])[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(C)c(-c3cccc(Cl)c3)c(=O)oc2nc1C(=O)OCC
Temperature: 0 °C
Yield: 95.1 %

Procedure:
Diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (12.0 g, 0.043 mol), 3-chlorophenyl acetic acid (7.33 g, 0.043 mol) and triethylamine (6.52 g) are refluxed in 120 mL of acetic anhydride for three hours. The reaction mixture is cooled, poured into 120 mL of ice-cold water and made alkaline to pH 8 with an ammonium hydroxide solution. The crystalline solid is filtered and washed with water to give (17.0 g, 95%) of the product after drying. Recrystallization from ethyl acetate affords the pure product (13.29, 74% yield), melting point 170°-172° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([C:20](=O)[CH3:21])[CH:10]=[CH:11][C:12]=2[O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1.CO.C([BH3-])#[N:26].[Na+].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH:20]([NH2:26])[CH3:21])[CH:10]=[CH:11][C:12]=2[O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccc(OC2CCOCC2)c(-c2ccc(Cl)s2)c1
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1ccc(OC2CCOCC2)c(-c2ccc(Cl)s2)c1

Procedure:
To a solution of the compound yielded from step 2 (1.20 g, 3.56 mmol) in MeOH (20 mL) ammonium acetate (2.75 g, 35.63 mmol) and sodium cyanoborohydride (224 mg, 3.56 mmol) were added. The reaction mixture was refluxed for 6 h. Then the cooled mixture was adjusted with trifluoroacetic acid to pH=2 and evaporated to dryness. Purification of the crude product by prep-HPLC and lyophilization of the relevant fractions lead to the desired product (420 mg, 26%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[N:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1cccnn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2cccnn2)nc(N2CCOCC2)n1
Reaction time: 0.25 h
Yield: 18.2 %

Procedure:
To a solution of 0.159 g (1.67 mmol) of 3-aminopyridazine in THF (3 mL) at 0° C. was added 0.93 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 15 min. A solution of 0.317 g (0.84 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried and concentrated. Chromatography on alumina, eluting first with hexane-EtOAc (8:2) then with CH2Cl2/EtOAc (2:1) to CH2Cl2/EtOAc (1:1) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.065 g (18% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridazinyl)-1,3,5-triazin-2-amine: mp 271-273° C.; 1H NMR (DMSO-d6) δ 11.16 (br s, 1H), 8.98 (dd, J=4.7, 1.4 Hz, 1H), 8.67 (d, J=8.0 Hz, 1H), 8.61 (d, JHF=8.4 Hz, 1H), 8.08 (t, JHF=52.8 Hz, 1H), 7.86 (dd, J=7.7, 0.7 Hz, 1H), 7.73 (dd, J=9.1, 4.7 Hz, 1H), 7.53-7.43 (m, 2H), 3.86 (s, 4H), 3.75 (s, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.1; N, 29.6. Found: C, 53.7; H, 4.2; N, 29.5%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]([OH:18])=O)[CH:7]=1)=[O:5])[CH3:2].[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30](=[O:42])[C@@H:31]([NH2:41])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26][CH2:25]1)=[O:23])[CH3:20].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16](=[O:18])[NH:41][C@H:31]([C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH2:25][CH2:26]2)=[O:42])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)O)nc2ccccc12
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2 g of Quinoline-2,4-dicarboxylic acid 4-ethyl ester and 2.8 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 21 ml of DMF, 1.3 g of HOBT and 1.6 g of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.1 g.
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=1)=[CH:13][C:12]([O:18]C)=[CH:11][CH:10]=4.Cl>>[CH:20]1[C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=[C:3]([OH:2])[CH:21]=1)=[CH:13][C:12]([OH:18])=[CH:11][CH:10]=4
Reactant: COc1ccc2c(c1)SCc1c-2[nH]c2ccc(OC)cc12
Agent: Cl
Product: Oc1ccc2c(c1)SCc1c-2[nH]c2ccc(O)cc12

Procedure:
A mixture of 3,8-dimethoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (805 mg, 2.69 mmol) and Py.HCl (3.11 g, 26.9 mmol, 10 eq.) was heated to 210° C. for 30 minutes. The reaction mixture was then partitioned between EtOAc and saturated NaHCO3 aqueous solution. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a crude material. The crude material was purified by silica gel (EtOAc to CH2Cl2:MeOH 5:1) to yield the title compound as a brown solid.
Reaction SMILES: C([O:3][C:4](=[O:39])[C@@H:5]([O:37][CH3:38])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:29]4[S:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:28]=4[CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>>[CH:27]1[C:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30][C:29]=2[C:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:37][CH3:38])[C:4]([OH:39])=[O:3])=[CH:12][CH:11]=3)=[CH:23][CH:22]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(-c3cccc4c3sc3ccccc34)cc2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3cccc4c3sc3ccccc34)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4-Dibenzothiophen-4-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Step A) by Standard Hydrolysis procedure C (NaOH). MS (ES) for C31H28O5S [M+NH4]+: 530.
Reaction SMILES: [C:1]1([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.CC#N>[NH:14]1[CH2:15][CH2:16][CH2:17][C@@H:12]([O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][N:2]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2nccc3ccccc23)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1COCCO1
Product: c1ccc2c(O[C@@H]3CCCNC3)nccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 53 was treated with 4N HCl in dioxane (40 mL) at RT for 3 h. The mixture was concentrated in vacuo to give a viscous oil which was dissolved in MeCN (200 mL). To the solution was added NaHCO3 powder (2.0 g). The mixture was stirred at RT overnight. The mixture was filtered and the filtrate was concentrated. The residue was subjected to flash column chromatography with 0%-100% EtOAc in DCM and then 0%-9% MeOH in DCM to isolate (R)-1-(piperidin-3-yloxy)isoquinoline (54).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[O:14]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C(O)(=O)C>N1C=CC=CC=1>[C:10]([O:9][C:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[NH:1][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:22][CH:23]=1)=[O:29])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)c1ccsc1N
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccsc1NC(=O)Nc1ccc(Oc2ccccc2)cc1
Reaction time: 48 h

Procedure:
To a solution of t-butyl 2-amino-thiophene-3-carboxylate (0.6 g) in dry pyridine (20 ml) was added 4-phenoxyphenylisocyanate (0.84 g). The mixture was stirred for 48 h, then the dark coloured solution was poured into water (200 ml). The stirred mixture was acidified with acetic acid and a precipitate slowly solidified to give a brown solid. After about 1 hr, the solid was filtered off, dried in vacuo and recrystallised from acetonitrile, giving an off-white solid. MP=203-205° C. Yield=0.6 g (48.8%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:14][C:13]2[C:8](=[N:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].C(O)(=O)C>C(O)C>[CH3:16][O:15][C:10]1[N:9]=[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:14][C:13]2=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2nc(OC)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2[nH]c(C(=O)O)cc2n1
Temperature: 70 °C

Procedure:
To a solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester (Preparation 35, 128 mg, 0.58 mmol) in ethanol (10 mL, absolute) was added aqueous sodium hydroxide (0.35 mL, 2M) and the mixture heated to 70° C. for 3 h then cooled to rt. The solution was adjusted to pH 4 by addition of glacial acetic acid and the solvents removed under reduced pressure. Ethyl acetate (20 mL) was added to the resulting oil and the mixture sonicated until a fine suspension formed. The mother liquor was decanted and the remaining solid was washed with ethyl acetate and dried in vacuo to give the title compound as a pale orange powder. δH (CD3OD): 3.92 (3H, s), 6.63 (1H, d), 6.94 (1H, s), 7.72 (1H, d).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])(O)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(C2=CCNCC2)c1Cl

Procedure:
According to Preparation 4: Tert-butyl-4-(2,3-dichlorophenyl)-4-hydroxypiperidine-1-carboxylate (3.0 g, 8.7 mmol), trifluoroacetic acid (30 ml). Yield: 0.88 g. MS m/z (rel. intensity, 70 eV) 229 (63), 228 (M+, 36), 227 (bp), 163 (53), 82 (85).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:15])=[N:7][NH:8]2)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)cc2[nH]nc(F)c12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a solution of 6-bromo-4-nitro-1H-indazole (5 g) in acetonitrile (50 ml) and acetic acid (10 ml) was added Selectfluor (9.39 g). The resulting mixture was heated to 100° C. and stirred for two days. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM and then filtered off. The sample was absorbed onto silica powder then solid loaded onto the companion where it was purified on a 120 g silica column using a 0-100% ethyl acetate:cyclohexane gradient. The appropriate fractions were combined and concentrated to yield the title compound as an orange solid, 2 g.
Reaction SMILES: [C:1]([C:5]1C=C(O)C(=C[CH:11]=1)O)(C)(C)[CH3:2].[S:13]1([CH2:19][CH:18]=[CH:17][CH2:16]1)(=[O:15])=[O:14]>>[S:13]1([CH2:19][CH:18]=[CH:17][CH2:16]1)(=[O:15])=[O:14].[CH2:2]=[CH:1][CH:5]=[CH2:11]
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Agent: O=S1(=O)CC=CC1
Product: C=CC=C

Procedure:
Except that 0.166 g (1.0 mmol) of 4-t-butylcatechol was used instead of 0.186 g (1.0 mmol) of ferrocene used in manufacturing of sulfolene, a 3-sulfolene aqueous solution was prepared in the same manner as in Example 1. The amount of 3-sulfolene in the obtained aqueous solution was 87 g (0.75 mol) and the yield from 1,3-butadiene was 75%. An amount of 3.8 g of polymers was found on the filter paper after filtering the 3-sulfolene aqueous solution. Next, the obtained 3-sulfolene aqueous solution was hydrogenated in the same manner as in Example 1. The reaction time was 70 minutes and the reaction was 100% progressed. Table 1 shows the measurements of the amount of generated polymers and the reaction time of hydrogenation.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.O=C1CCC(=O)N1[O:20][C:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:21](=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])(=[O:7])[O:5][CH3:6]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCCCCNC(=O)OC(C)(C)C)OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 105.8 %

Procedure:
A solution of dimethyl methylphosphonate (9.308 g, 75.01 mmol) in THF (30 mL) was cooled to −78 ° C. and treated with n-butyllithium (29.5 mL of 2.5 M). The reaction mixture was stirred at −78 ° C. for 10 min, followed by addition of 6-tert-butoxycarbonylamino-hexanoic acid 2,5-dioxo-pyrrolidin-1-yl ester (24-1) (5.060 g, 15.41 mmol) in THF (30 mL). After 15 min the reaction was quenched with aqueous NH4Cl and allowed to warm to room temperature overnight. The water was extracted three times with ethyl acetate and the combined organics washed with brine and dried (Na2SO4). The solvent was removed in vacuo to afford the title compound 24-2 as a pale yellow oil (5.5 g).
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([C@@H:7]2[O:11][C@H:10]([CH2:12][O:13][P:14]([O:17][P:18]([O:21][CH2:22][C@H:23]3[O:27][C@@H:26]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH2:37])[C:31]=5[N:30]=[CH:29]4)[C@H:25]([O:38][P:39]([OH:42])([OH:41])=[O:40])[C@@H:24]3[OH:43])([OH:20])=[O:19])([OH:16])=[O:15])[C@@H:9]([OH:44])[C@H:8]2[OH:45])[CH:4]=[C:3]([C:46]([NH2:48])=[O:47])[CH:2]=1.C(OP(O)(O)=O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O.[Mg+2].[Cl-].[Cl-]>>[CH:34]1[N:35]=[C:36]([NH2:37])[C:31]2[N:30]=[CH:29][N:28]([C@@H:26]3[O:27][C@H:23]([CH2:22][O:21][P:18]([O:17][P:14]([O:13][CH2:12][C@H:10]4[O:11][C@@H:7]([N:5]5[CH:4]=[C:3]([C:46]([NH2:48])=[O:47])[CH2:2][CH:1]=[CH:6]5)[C@H:8]([OH:45])[C@@H:9]4[OH:44])([OH:16])=[O:15])([OH:20])=[O:19])[C@@H:24]([OH:43])[C@H:25]3[O:38][P:39]([OH:42])([OH:41])=[O:40])[C:32]=2[N:33]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=P(O)(O)OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Cl-]
Agent: [Mg+2]
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Temperature: 37 °C

Procedure:
An NADPH production system was prepared by mixing 42 mg of NADP, 5 ml of 100 mM glucose-6-phosphatase (G6P) and 5 ml of 100 mM MgCl2, and adding 57 μl of G6P dehydrogenase (about 1750 U/5 mg/ml) to the mixture. This was heated at 37° C. for 5 minutes and then ice-cooled until its use.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:11]=[CH2:12])=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH2:13]([O:16][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=1)[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)[CH:14]=[CH2:15]>>[CH2:13]([O:16][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=1)[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=2[CH:11]=[CH2:12])=[CH:23][CH:22]=1)[CH:14]=[CH2:15]
Reactant: C=CCOc1cccc(Oc2ccc(C=O)cc2)c1
Reactant: C=Cc1c(N)cccc1[N+](=O)[O-]
Product: C=CCOc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C=C)cc2)c1

Procedure:
The product from Example 44B and the product from Example 61C were processed as in Example 6A to provide the title compound.