Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[S:16][C:17]([Br:20])=[CH:18][CH:19]=1)(=[O:14])[CH3:13].Cl>CCOCC.C1COCC1>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([C:15]1[S:16][C:17]([Br:20])=[CH:18][CH:19]=1)=[O:14]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: CCOC(=O)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)F)c1ccc(Br)s1
Yield: 73.3 %

Procedure:
Ethyl difluoroacetate (2.43 g, 19.6 mmol) was placed in a 100 mL round bottom flask, and dissolved in ether (15 mL). To the stirred solution was added 25 weight % sodium methoxide (4.23 g, 19.5 mmol) followed by 2-acetyl-5-bromothiophene (3.59 g, 17.5 mmol). After two hours a precipitate formed and THF (15 mL) was added to allow stirring to continue. The reaction was stirred at room temperature 6.2 hours, then treated with 3N HCl (20 mL). The organic layer was collected and washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil which was crystallized from methylene chloride/isooctane to give yellow needles (3.63 g, mp 83.5°-85° C., 73% ). 1H NMR (CDCl3) 300 MHz 14.60 (br s, 1H), 7.53 (d, J=4.0 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H), 7.19 (m, 1H), 6.32 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); 19F NMR (CDCl3) 300 MHz: -127.00 (d) ; M+282.
Reaction SMILES: [F:1][CH:2]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([N:5]1[CH2:9][CH2:8][C@H:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=O.CO>C1COCC1>[F:1][CH:2]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:5]1[CH2:9][CH2:8][C@H:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1
Reactant: O=C(C(F)CCc1ccccc1)N1CC[C@H](Sc2ccc(O)cc2)C1
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc(S[C@H]2CCN(CC(F)CCc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
(2RS,3S)-2-Fluoro-1-[3-(4-hydroxy-phenylsulfanyl)-pyrrolidin-1-yl]-4-phenyl-butan-1-one (200 mg, 0.56 mmol) was dissolved in THF (4 ml). Borane-dimethylsulfide complex (170 μl, 1.67 mmol) was added. The mixture was refluxed for 7 hours and then cooled to 0° C. MeOH (0.7 ml) was added dropwise and the solvent was removed in vacuo. The residue was dissolved with THF (3.5 ml) and 5N HCl (1.1 ml) and was stirred at 60° C. for 12 hours. The solvent was removed in vacuo and the residue was taken up in saturated NaHCO3 (3 ml). The aqueous layer was extracted with CH2Cl2 (3 times). The combined organic phases were dried over Na2SO4, filtered and the solvent was evaporated. The residue was chromatographed over silica gel (CH2Cl—MeOH, 99:1) to provide (2RS,3S)-4-[1-(2-fluoro-4-phenyl-butyl)-pyrrolidin-3-ylsulfanyl]-phenol (134 mg, 70%) as colorless oil. MS: m/e 346.3 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.Cl.[NH:27]1[C@H:31]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:30][C@@H:29]2[CH2:42][CH2:43][CH2:44][C@H:28]12>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([N:27]2[C@H:31]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:30][C@@H:29]3[CH2:42][CH2:43][CH2:44][C@H:28]23)=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
4.92 g (30 mmol) of 4-phenylbutyric acid are dissolved together with 8.4 ml of triethylamine in 200 ml of dry tetrahydrofuran. While cooling in ice, 2.9 ml of ethyl chloroformate are added dropwise. After stirring at 0° C. for 1 hour, 7.4 g of benzyl (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride are added, and the mixture is stirred at room temperature for a further 12 hours. Filtration is followed by concentration, and the residue is taken up in 3% NaHCO3 /ethyl acetate. The organic phase is separated off and washed with 10% strength citric acid, 3% strength NaHCO3 solution and saturated brine, once each, dried with MgSO4 and concentrated. Chromatography on silica gel with ethyl acetate/cyclohexane (1:2) as mobile phase results in 9.05 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=O.[P:9]([OH:12])([OH:11])[OH:10].P(Cl)(Cl)Cl>O>[O:6]1[CH2:7][CH2:8][N:3]([CH:1]([P:9]([OH:12])(=[O:10])[OH:11])[P:9]([OH:12])(=[O:11])[OH:10])[CH2:4][CH2:5]1
Reactant: O=CN1CCOCC1
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=P(O)(O)C(N1CCOCC1)P(=O)(O)O
Yield: 35 %

Procedure:
115 parts of N-formylmorpholine and 82 parts of phosphorous acid were mixed and reacted with 137 parts of phosphorus trichloride. The reaction mixture was then treated with about 5000 parts of water, and the solution was filtered and concentrated. The precipitate obtained was isolated and recrystallized from water/acetone. After drying, a yield of 35% of morpholinomethanediphosphonic acid was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:25])[C:13]4[C:17]([CH:18]=3)=[N:16][N:15](C3CCCCO3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([NH:25][C:40]([C:36]4[O:35][CH:39]=[CH:38][CH:37]=4)=[O:41])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (50 mg) in DCM (1 ml) was added DIPEA (131 μl) followed by 2-furancarbonyl chloride (39 mg) (available from ABCR) and the mixture stirred at RT for 1 h, then the solvent was removed. To a mixture of the residue in methanol (2 ml) was added 4M hydrochloric acid in 1,4-dioxane (2 ml) and the mixture stirred at RT for 2 h. Purification of the residue by mass directed preparative HPLC (Method A), followed by freeze drying gave the title compound as an off white solid (13 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32](OC)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([S:36]([C:39]2[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1.O>CCOCC>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([S:36]([C:39]2[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=2)(=[O:38])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1
Reactant: Cn1ccnc1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C)cc1)C2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3nccn3C)C2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
1-Methyl-1H-imidazole (104 mg, 1.267 mmol) in dry ether (5 mL) was added to butyllithium (2.5M in hexanes) (519 μl, 1.298 mmol) in dry ether (2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes. A solution of (R)-methyl 1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (200 mg, 0.415 mmol) in dry ether (5 mL) was added dropwise and the reaction mixture was stirred for 45 minutes at −78° C., then allowed to warm to room temperature over 2 hours. Water (20 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous phase was extracted with ethyl acetate (3×20 mL), the combined organic phases were washed with brine (20 mL), dried (magnesium sulfate), and solvent removed to give a yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-60% ethyl acetate in isohexane) to afford (R)-(1-(4-fluorophenyl)-6-tosyl-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(1-methyl-1H-imidazol-2-yl)methanone (22 mg) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.52 min, m+H=532.0; 1H NMR (400 MHz, CDCl3): δ 7.61-7.58 (2H, m), 7.46-7.40 (2H, m), 7.31 (1H, s), 7.29-7.27 (2H, m), 7.18 (1H, d, J=0.9 Hz), 7.17-7.12 (2H, m), 6.99 (1H, br. s), 6.50 (1H, d, J=2.2 Hz), 5.53 (1H, dd, J=12.2, 2.2 Hz), 4.45 (1H, d, J=16.7 Hz), 3.88-3.84 (4H, m), 2.92-2.78 (2H, m), 2.60 (1H, d, J=12.2 Hz), 2.50-2.37 (5H, m).
Reaction SMILES: [CH3:1][C:2]1[C@H:8]2[C@H:5]([CH2:6][C:7]2=O)[CH2:4][CH:3]=1.[H-].[Na+].COP([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(OC)=O>O1CCCC1>[CH3:1][C:2]1[C@H:8]2[C@H:5]([CH2:6][C:7]2=[CH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:4][CH:3]=1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: CC1=CC[C@H]2CC(=O)[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CC[C@H]2CC(=CC(=O)OC(C)(C)C)[C@@H]12
Reaction time: 2 h

Procedure:
(±)-(1S,5R)-4-methylbicyclo[3.2.0]hept-3-en-6-one (1.10 g, 9.0 mmol) was added to a reaction solution prepared in advance by adding sodium hydride (>65% oil, 342.8 mg, 9.0 mmol) to a tetrahydrofuran solution (10 mL) of tert-butyl dimethoxyphosphorylacetate (2.08 g, 9.3 mmol) under ice cooling, and the mixture was further stirred for 2 hours. The reaction solution was separated into aqueous and organic layers by the addition of a saturated aqueous solution of ammonium chloride and saturated saline. The aqueous layer was subjected to extraction with ethyl acetate. These organic layers were combined, then washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil substance (1.59 g, 80%, E/Z mixture).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[NH:10][NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl:16][C:17]([Cl:21])([Cl:20])[S:18]Cl>O>[C:1]1([N:7]2[C:8](=[O:13])[N:9]([S:18][C:17]([Cl:21])([Cl:20])[Cl:16])[N:10]([S:18][C:17]([Cl:21])([Cl:20])[Cl:16])[C:11]2=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH][nH]c(=O)n1-c1ccccc1
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1n(-c2ccccc2)c(=O)n(SC(Cl)(Cl)Cl)n1SC(Cl)(Cl)Cl

Procedure:
To a solution of 35.4g (0.2 mole) 4-phenyl urazole in 200 ml water was added a solution of 16g (0.4 mole) sodium hydroxide in 20 ml water. A mixture of 74.4g (0.4 mole)trichloromethylsulfenyl chloride and 3g of an emulsifier solution (EXEM 25, consisting of a mixture of alkyl benzene sulfonate and ethoxylated vegetable oil) in 50 ml water was added dropwise to the above basic solution while keeping the reaction mixture at 0° C. The reactants were mixed so that the reaction mixture was kept at a pH greater than 7. The precipitate that formed was filtered and the filter cake was washed with water. After drying and recrystallizing from benzene there was obtained 4-phenyl-1,2-bis-(trichloromethylthio)urazole having a melting point of 175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:15]([NH:17][C:18]([NH2:20])=[NH:19])#[N:16].[OH-].[K+].O>COCCO>[NH2:16][C:15]1[N:17]=[C:18]([NH2:20])[N:19]=[C:13]([C:12]2[C:3]([O:2][CH3:1])=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:14]=1
Reactant: COc1cc2ccccc2cc1C#N
Reactant: N#CNC(=N)N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: COc1cc2ccccc2cc1-c1nc(N)nc(N)n1

Procedure:
A mixture of 3.24 grams of 2-methoxy-3-naphthonitrile, 2.23 grams of cyanoguanidine and 0.24 gram of KOH was dissolved in 30 ml of methyl cellosolve with heating and the mixture was heated to reflux for 6.5 hours. After the reaction was completed, the reaction solution was was poured into water, the crystals separated out were taken by filtration, and were recrystallized from ethyl alcohol to give 2,4-diamino-6-(2-methoxy-3-naphthyl)-s-triazine, colourless needles, melting point 243° to 244° C., the yield being 4.12 grams.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:6]=1[C:7]([NH:9][C:10]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:13])=[O:8].[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41](O)=[O:42]>C(Cl)Cl>[CH3:35][O:34][C:32]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:13])=[O:8])=[C:5]([O:4][CH2:3][CH2:2][NH:1][C:41]([C:37]2[S:36][CH:40]=[CH:39][CH:38]=2)=[O:42])[CH:33]=1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCN)cc1
Reactant: O=C(O)c1cccs1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCNC(=O)c2cccs2)cc1
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of 2-[2-(2-aminoethoxy)-4-methoxybenzoylamino]-N-(4-methoxy-phenyl)-4-nitrobenzamide (227 mg, 0.47 mmol), P-EPC resin (2.09 g, 1.78 mmol), and thiophene-2-carboxylic acid (144 mg, 1.12 mmol) in methylene chloride (15 mL) was shaken in a screw top vial overnight. The reaction was filtered and the solids were washed with 10% methanol in chloroform. The filtrate was concentrated to yield the desired product (265 mg, 0.45 mmol, 95%) as a greenish solid.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.C1(P(=[CH:30][C:31]([O:33][CH3:34])=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC1C=CC(C)=CC=1>[O:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:2]1
Reactant: O=C1Cc2ccccc2O1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccc(C)cc1
Product: COC(=O)Cc1coc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 0.4 mol of coumaranone and 0.48 mol of methyl (triphenylphosphoranylidene)acetate in 1 liter of p-xylene is maintained at reflux for 18 h. After cooling to room temperature, the solvent is evaporated off, the residue is taken up in 1 liter of ether, the precipitate is filtered off and washed with ether, the filtrate is concentrated and the expected product is obtained after chromatography on silica (eluent: CH2Cl2).
Reaction SMILES: [CH2:1]([C:3]1[N:7](CC2C=CC3NC4C=CC=CC=4CCC=3C=2)[C:6]2[CH:24]=[C:25](C)[CH:26]=[C:27]([CH3:28])[C:5]=2[N:4]=1)[CH3:2].C(C1[NH:33]C2C(C)=CC(C)=CC=2N=1)C>>[CH2:1]([C:3]1[NH:7][C:6]2=[N:33][C:25]([CH3:24])=[CH:26][C:27]([CH3:28])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)cc2n1Cc1ccc2c(c1)CCc1ccccc1N2
Reactant: CCc1nc2cc(C)cc(C)c2[nH]1
Product: CCc1nc2c(C)cc(C)nc2[nH]1

Procedure:
[step 1] 2-(2-Ethyl-4,6-dimethylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (422 mg, 75%) was obtained in the same manner as in step 1 of Example 1, using 2-ethyl-4,6-dimethylbenzimidazole (256 mg, 1.47 mmol), obtained in Reference Example 1, instead of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[H-].[Na+].[CH3:14][O:15][C:16](=O)[O:17]C>CO>[O:11]=[C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:10][CH2:9][CH2:8][CH:7]1[C:16]([O:15][CH3:14])=[O:17]
Reactant: O=C1CCCCc2sccc21
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCc2sccc2C1=O

Procedure:
To a solution of 5,6,7,8-tetrahydro-cyclohepta[b]thiophen-4-one (0.84 g, 5 mmol), prepared by the method of M. P. Cagniant (Bull. Soc. Chim. France, 1956, 1152-1163), in dimethylcarbonate (6 mL) was added a 60% dispersion of sodium hydride in oil (0.4 g, 10 mmol) and a few drops of dry methanol. The reaction mixture was heated at reflux for 4 hours, then cooled, quenched with 2 N hydrochloric acid solution, and the desired product was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated and chromatographed on silica gel, eluting with 20% ethyl acetate:hexane to provide the title compound: 1H NMR (300 MHz, DMSO-d6) δ 7.34 (d, J=5.42 Hz, 1H,), 7.28 (d, J=5.42 Hz, 1H), 4.04 (dd, J=10.8, 3.39 Hz, 1H), 3.66 (s, 3H), 3.80 (m, 4H), 3.14 (m, 2H); MS (DCI/NH3) m/z 225 (M+H)+, 242 (M+NH4)+.
Reaction SMILES: [C:1]([C:3](=[CH:9][CH:10]([CH3:12])[CH3:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6])#[N:2].[H][H]>CO>[C:1]([CH:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6])#[N:2]
Reactant: COC(=O)CC(C#N)=CC(C)C
Reactant: [H][H]
Solvent: CO
Product: COC(=O)CC(C#N)CC(C)C

Procedure:
By following the general procedure of Example 3.1, 200 mg (1.190 mmol) of methyl 3-cyano-5-methyl-hex-3-enoate was dissolved in 3 mL of methanol and reacted with hydrogen gas (60 psi) in the presence of 43 mg (0.06 mmol) of [(R,R)-Et-DuPHOS]Rh(COD)+BF4− to afford 10% conversion to methyl 3-cyano-5-methylhexanoate having 33% e.e. (R).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]([CH2:19]O)[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(C)(=O)=O.[CH2:27]([N:29](CC)CC)C.[C-]#N.[NH4+].[NH4+].[NH4+].[NH4+].[C-]#N.[C-]#N.[C-]#N>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([CH2:19][C:27]#[N:29])[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CO)CCOCc1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CC#N)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3-Benzyloxy-1-hydroxymethyl-propyl)-carbamic acid tert-butyl ester (7.4 g, 25 mmole) was dissolved in 100 ml DCM. Mesyl chloride (4.3 g, 37.5 mmole) and triethylamine (5.0 g, 50 mmole) were added. The reaction was stirred at room temperature for 20 minutes. 100 ml DCM and 100 ml water were added. The organic layer was washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was dissolved in 200 ml toluene. Tetraammonium cyanide (10 g, 37.5 mmole) was added and the reaction was stirred at room temperature overnight. The organic layer was washed with water (2×100 ml), brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by column (EtOAc/hexane from 100/0 to 30/70 in 45 minutes). Yield, 6.4 g, 84%. 1H NMR (CDCl3 400 MHz δ 7.29-7.38 (m, 5H), 5.20 (d, J=5.9 Hz, 1H), 4.50 (m, 2H), 3.91 (m, 1H), 3.54-3.66 (m, 2H), 2.60-2.77 (m, 2H), 1.89-1.99 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][C:28](=[O:31])[N:27]([CH2:32][CH2:33][CH2:34][CH:35]=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][C:28](=[O:31])[N:27]([CH2:32][CH2:33][CH2:34][CH2:35][N:13]([CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)[CH2:14][CH2:15][CH3:16])[CH2:26][CH2:25]1)=[O:23])([CH3:18])([CH3:19])[CH3:20]
Reactant: CCCNC1CCc2ccc(OC)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CCCC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCN(CCCCN1CCN(C(=O)OC(C)(C)C)CCC1=O)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine prepared as described in Example 1 (800 mg, 3.3 mmol, 1 eq) in 1,2-dichlororethane (40 mL) under inert atmosphere was added 5-oxo-4-(4-oxo-butyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.0 g, 3.6 mmol, 1.1 eq.) in a single portion followed by the sodium triacetoxyborohydride (1.7 g, 8.25 mmol, 2.5 eq.). The reaction was stirred at room temperature for 20 hr, concentrated in-vacuo and then partitioned between 10% KOH (50 mL) and ethyl acetate (100 mL). The organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by silica gel chromatography gave 1.1 g of 4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-5 -oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:12]([Cl:11])(=[O:14])=[O:13]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At 5-10° C., to stirred chlorosulfonic acid (200 mL) was added 4-chlorobenzoic acid (78 g, 0.5 mol). The reaction mixture was then brought up to 150˜160° C. for 5 hours. After being cooled down to room temperature, the reaction mixture was slowly poured onto a large amount of ice and extracted with ether. The combined organic extracts were washed with ice water and dried over anhydrous magnesium sulfate. Evaporation of solvents afforded 4-chloro-3-(chlorosulfonyl)benzoic acid as a solid (76 g), which was directly used in the next steps.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([O:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: OCCn1ccnc1
Product: CC(=O)OCCn1ccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
In a nitrogen atmosphere, a mixture of 112 g of 2-(1H-imidazol-1-yl)ethanol, synthesized in Synthesis Example 1, and 122 g of acetic anhydride was stirred at room temperature for 16 hours. The reaction mixture was subjected to conventional aqueous work-up and then purified by vacuum distillation, obtaining 131 g of 2-(1H-imidazol-1-yl)ethyl acetate (boiling point 102° C./27 Pa, yield 85%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](S(C)(=O)=O)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[O:18]1CCOCC1>>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:18])[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: C1COCCO1
Reactant: Cc1nc(C)c(-c2ccnc(S(C)(=O)=O)n2)s1
Product: Cc1nc(C)c(-c2cc[nH]c(=O)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
4-(2,4-dimethyl-thiazol-5-yl)-2-methanesulfonyl-pyrimidine (288 mg, 1.07 mmol) was dissolved in dioxane (13 ml) and then 2N NaOHaq (6 ml, 12 mmol) was added. After stirring at room temperature for 1 hour, the solution was acidified with 37% HClaq. The mixture was evaporated and the residue was purified by flash chromatography with DCM-MeOH (9-1) to give 166 mg of the title compound. (75% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.CCN(C(C)C)C(C)C.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[C:25]([C:9]1[CH:8]=[N:7][N:6]2[CH:27]=[C:3]([NH:2][S:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:46])=[O:45])[C:4]([CH3:28])=[C:5]2[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)#[N:26]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(NS(=O)(=O)c2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12

Procedure:
To 6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (8.2 mg, 0.021 mmol) and DIEA (5.4 mg, 0.042 mmol) in dichloromethane (1.0 ml) was added benzenesulfonyl chloride (3.7 mg, 0.021 mmol) at RT for 2 hrs. The reaction mixture was quenched with pH 7 phosphate buffer (2 ml), dried over Na2SO4, concentrated and purified by silica gel flash chromatography to isolate 377 as a yellow film (3 mg, 29%). [M+H]+=496.1.