Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[C:34]([NH:35]C(=O)OCC3C=CC=CC=3)=[CH:33][C:32]3[C:27](=[CH:28][C:29]([C:46]4[CH2:47][CH2:48][O:49][CH2:50][CH:51]=4)=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:35][C:34]1[C:25]([C:23]([NH:22][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[N:11]2[CH2:12][C@H:13]([CH3:15])[CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]2)=[O:24])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)[CH:28]=2
Reactant: [H][H]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(C4=CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(C4CCOCC4)ccc3cc2N)C1
Yield: 89.2 %

Procedure:
A mixture of benzyl [2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(3,6-dihydro-2H-pyran-4-yl)quinolin-3-yl]carbamate (0.017 g, 0.024 mmol) in 1.5 mL of MeOH was hydrogenated in the presence of 10% Pd on carbon (10 mg) under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl {(3S,5R)-1-[3-({[3-amino-7-(tetrahydro-2H-pyran-4-yl)quinolin-2-yl]carbonyl}amino)pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate (0.012 g, 87%). LCMS calc. for C31H41N6O4 [M+H]+: m/z=561.3. found: 561.4. To the intermediate made above was added 1 mL of 4 M HCl in dioxane and 1 mL of MeOH. The mixture was stirred at room temperature for 1 h, then evaporated under vacuum. The residue was dissolved in 4.5 mL of MeOH and treated with 0.3 mL of NH4OH solution. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C26H33N6O2 [M+H]+: m/z=461.3. found: 461.3.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH3:11]>S(Cl)(Cl)=O.O1CCOCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:11])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: NC(=O)c1cccc(Br)n1
Temperature: 70 °C
Yield: 45 %

Procedure:
6-Bromopicolinic acid (1000 mg, 4.95 mmol) was suspended in thionyl chloride (15 mL) and heated at 70° C. for 5 h. The reaction was cooled to room temperature and the volatiles were condensed under reduced pressure. A solution of ammonia (2M in dioxane (15 mL) was added to the residue and then the solvents were removed under reduced pressure. The crude residue was purified by MPLC with a gradient of 0 to 20% MeOH/dichloromethane to give 6-Bromo-pyridine-2-carboxylic acid amide as a white powder (555 mg, 45%). MS ES (MH+=201.0/203.0).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][C:8]([CH3:15])([CH2:13][CH3:14])[C:9](=[O:12])[CH2:10][Cl:11].CCCCCC.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Cl:33])[C:31]=1[CH3:32])[C:26](Cl)=[O:27]>O.O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Cl:33])[C:31]=1[CH3:32])[C:26]([NH:7][C:8]([CH2:13][CH3:14])([CH3:15])[C:9](=[O:12])[CH2:10][Cl:11])=[O:27]
Reactant: Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Reactant: CCC(C)(N)C(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(NC(=O)c1cc(Cl)c(C)c(Cl)c1)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a well-stirred solution of 1.1 g (13.1 mmol) sodium bicarbonate in 15 mL water was added solid 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride (1 g, 5.4 mmoles) portionwise. To the resulting solution was added 15 mL of hexane followed by dropwise addition of a solution of 3,5-dichloro-4-methylbenzoyl chloride (1.2 g, 5.4 mmol) in 1 mL of tetrahydrofuran. Another 15 mL of hexane was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the resulting white solid was dried in a vacuum oven yielding 1.1 g of 3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide as a white solid (mp 159°-161° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccnc(Cl)c1
Product: O=C(Cl)c1ccnc(Cl)c1

Procedure:
2-Chloroisonicotinic acid (707 mg, 4.49 mmol) was suspended in thionyl chloride (10 mL), followed by stirring under heating and reflux for 7 hours. The reaction mixture was concentrated under reduced pressure to afford 2-chloroisonicotinoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]([CH3:13])[C:3]=1[C:4]([OH:6])=[O:5].CCN=C=N[CH2:19][CH2:20][CH2:21]N(C)C.C1C=CC2N([OH:34])N=NC=2C=1.CCN(C(C)C)C(C)C.C(N)(C)C>Cl.CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([C:11](=[O:34])[NH:12][CH:20]([CH3:21])[CH3:19])[CH:8]=[C:7]([CH3:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C#N)nc(Cl)c1C(=O)O
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(C)C)nc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.2 %

Procedure:
2-Chloro-6-cyano-4-methyl-nicotinic acid (0.315 g, 1.61 mmol) in concentrated HCl (8 ml) was heated at 100° C. for 45 minutes and then all solvent was removed in vacuo to yield a pale yellow crystalline solid. The crude solid, EDCI (0.339 g, 1.77 mmol) and HOBt (0.239 g, 1.77 mmol) were combined in DMF (8 ml) to give a pale yellow solution. To this solution was added DIPEA (1.85 ml, 10.6 mmol) followed by isopropylamine (137 μL, 1.61 mmol) and the resulting mixture was stirred at 25° C. for 16 hours. The reaction mixture was quenched with water (3 ml) and then dry loaded onto silica gel and purified using column chromatography (MeCN/MeOH/NH4OH, 8:1:1, v/v/v) to give 2-chloro-6-isopropylcarbamoyl-4-methyl-nicotinic acid (0.195 g, 47%).
Reaction SMILES: [C:1]([O:5]C(OC(OC(C)(C)C)=O)=O)(C)(C)C.CN(C1C=CC=CN=1)C.[NH2:25][C@@H:26]([C:29]1[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[C:31]([N+:42]([O-:44])=[O:43])[CH:30]=1)[CH2:27][CH3:28].[Cl:45][C:46]1[CH:47]=[CH:48][C:49]([O:75][CH3:76])=[C:50]([CH:74]=1)[CH2:51][C@H:52]1[CH2:58][N:57]([CH2:59][C:60]2[C:65]([O:66][CH3:67])=[CH:64][C:63]([O:68][CH3:69])=[CH:62][C:61]=2[O:70][CH3:71])[C:56](=[O:72])[CH2:55][NH:54][C:53]1=[O:73].CC(C)([O-])C.[K+]>C(#N)C.O1CCCC1.C(O)(=O)C>[Cl:45][C:46]1[CH:47]=[CH:48][C:49]([O:75][CH3:76])=[C:50]([CH:74]=1)[CH2:51][C@@H:52]1[C:53](=[O:73])[N:54]([C:1]([NH:25][C@@H:26]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])=[C:31]([N+:42]([O-:44])=[O:43])[CH:30]=2)[CH2:27][CH3:28])=[O:5])[CH2:55][C:56](=[O:72])[N:57]([CH2:59][C:60]2[C:61]([O:70][CH3:71])=[CH:62][C:63]([O:68][CH3:69])=[CH:64][C:65]=2[O:66][CH3:67])[CH2:58]1
Reactant: CC[C@@H](N)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: COc1cc(OC)c(CN2C[C@H](Cc3cc(Cl)ccc3OC)C(=O)NCC2=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccn1
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC[C@@H](NC(=O)N1CC(=O)N(Cc2c(OC)cc(OC)cc2OC)C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 805.5 %

Procedure:
To a solution of di-tert-butyldicarbonate (7.1 g) and dimethylaminopyridine (3.8 g) in acetonitrile (8 ml) cooled at −10° C., a solution of tert-butyl 4-((1R)-1-aminopropyl)-2-nitrobenzoate (8.7 g) in an acetonitrile (0.9 ml) was added at −10° C., and the mixture was stirred for 15 minutes. Next, the reaction solution was deaerated at an internal pressure of 60 to 100 mmHg for 1 hour, and then (6S)-6-(5-chloro-2-methoxybenzyl)-1-(2,4,6-trimethoxybenzyl)-1,4-diazepan-2,5-dione (1.3 g) was added. Next 1N solution of potassium tert-butoxide in tetrahydrofuran (0.53 ml) was dropwisely added to the mixture. After the end of the addition, acetic acid (2 ml) was added to the reaction solution, the mixture was concentrated in vacuo. Ethyl acetate was added to the obtained residue, and the mixture was washed with water. Then the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The concentrated residue was purified with silica gel chromatography to obtain the title compound (17.4 g) as an oily substance. The 1H-NMR data matches those of Example 329.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2([C:13]([O:15][CH2:16]C)=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]2[OH:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]2[O:12][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1(Cc2ccc(C)cc2)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1(Cc2ccc(C)cc2)CCCC1OC(=O)c1ccccc1

Procedure:
5.24 grams of 2-p-methylbenzyl-2-ethoxycarbonyl-cyclopentanol obtained in Example 18 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 2.44 ml of pyridine was slowly added, then 3.55 ml of benzoyl chloride was dropwise added. Upon the completion of the addition, the reaction was continued under reflux condition for 12 hours. Then the procedure as described in Example 23 was followed, to give 7.41 g of yellow liquid. MS: m/e 367(M++1), 366(M+), 293(M+—CO2CH2CH3), 261(M+—C6H5CO2), 216, 198, 170, 155, 105, 91, 77.
Reaction SMILES: [CH3:1][C:2](=[CH2:13])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([OH:12])=[O:11])=[O:4].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[S:21])[OH:20].C(Cl)Cl.O>C(O)C>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]([S:21][CH2:13][CH:2]([CH3:1])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([OH:12])=[O:11])=[O:4])=[O:20]
Reactant: OC(=S)c1ccco1
Reactant: C=C(C)C(=O)N1CCC[C@H]1C(=O)O
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(CSC(=O)c1ccco1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.4 g (2S)-1-(2- methyl-2-propenoyl)-2-pyrrolidine carboxylic acid are dissolved in 16.5 ml ethanol and 10 g furan-2-thiocarboxylic acid are added dropwise over 15 minutes. The reaction mixture is stirred overnight at room temperature, and methylene chloride and water (9:1) are then added. The so obtained organic phase is decanted and extracted with 0.5 N NaOH. The combined aqueous phases are adjusted to pH 4 and then twice extracted with 0.5 l CH2Cl2. The combined organic phases are dried over MgSO4, filtered and the solvent is evaporated. The residue is dissolved in CH2Cl2 /ether (1:4) and 6 ml tert-butylamine dissolved in ether are added; the tert-butyl ammonium salt of the title compound precipitates (M.P. 132°-140°) ([α]D20 =-67.3°; c=2.2 in H2O).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.Cl.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:24]#[N:25].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.CC#N>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1)[C:24]#[N:25]
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: COc1cc(C#N)ccc1N1CCNCC1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#N)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCCN32)CC1
Temperature: 100 °C
Yield: 44.9 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (150 mg, 0.643 mmol), 3-methoxy-4-(piperazin-1-yl)benzonitrile hydrochloride (163 mg, 0.643 mmol), (cyanomethyl)trimethylphosphonium iodide (250 mg, 1.029 mmol) and N,N-diisopropylethylamine (562 μl, 3.22 mmol) were suspended in Propiononitrile (Volume: 1931 μl) and heated in a closed vial at 100° C. for 2 h. The reaction mixture became a dark brown solution. It was diluted with MeCN (4 mL) and concentrated in vacuo to about 3 mL. The resulting precipitate was filtered, recrystallized from MeCN (5 mL) and dried in vacuum to afford (S)-3-methoxy-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile (125 mg, 0.289 mmol, 44.9% yield) as an off-white solid. 1H NMR (DMSO-d6) δ 10.48 (s, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.30-7.36 (m, 2H), 6.93-6.98 (m, 2H), 4.50 (d, J=12.9 Hz, 1H), 3.79-3.87 (m, 4H), 3.34-3.40 (m, 2H), 3.07 (br. s., 4H), 2.60 (td, J=12.7, 2.7 Hz, 1H), 2.47 (br. s., 4H), 2.02 (br. s., 1H), 1.85 (d, J=12.1 Hz, 1H), 1.64 (d, J=12.4 Hz, 1H), 1.32-1.57 (m, 3H); [M+H] calc'd for C24H28N6O2, 433; found, 433.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]([CH3:22])([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].BrC1C(NCCNC(=O)OC(C)(C)C)=NC(Cl)=NC=1>>[Br:1][C:2]1[C:3]([NH:10][C:11]([CH3:22])([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)(C)OC(=O)NCCNc1nc(Cl)ncc1Br
Product: CC(C)(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br

Procedure:
tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate is synthesized by treating 5-Bromo-2,4-dichloropyrimidine with tert-butyl N-(2-amino-2-methyl-propyl)carbamate using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI) (M+H) 379
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:11]=[C:12]([CH:19]3[CH2:21][CH2:20]3)[C:13]=2[O:14][C:15]([F:18])([F:17])[F:16])[C:7](OC)=[O:8])[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=[C:12]([CH:19]3[CH2:21][CH2:20]3)[C:13]=2[O:14][C:15]([F:17])([F:18])[F:16])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(C2CC2)c(OC(F)(F)F)c(C2CC2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OCc1cc(C2CC2)c(OC(F)(F)F)c(C2CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
Methyl 3,5-dicyclopropyl-4-(trifluoromethoxy)benzoate (259 mg, 0.863 mmol) was dissolved in DCM (8.6 mL) and the mixture was cooled to 0° C. DIBAL in toluene (1.73 mL, 1.73 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with the addition of 3N HCl and water. The mixture was stirred vigorously for 30 minutes and extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/hexanes) to yield the title compound as a clear oil (190 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([O:8]CC2C=CC=CC=2)[CH:6]([O:16]CC2C=CC=CC=2)[CH:5]([CH2:24][O:25]CC2C=CC=CC=2)[CH2:4][CH:3]1[OH:33].[CH2:34]([N:36]=[C:37]=S)[CH3:35].CI.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:34]([NH:36][C:37]1[O:33][CH:3]2[CH2:4][CH:5]([CH2:24][OH:25])[CH:6]([OH:16])[CH:7]([OH:8])[CH:2]2[N:1]=1)[CH3:35]
Reactant: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: CCN=C=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCNC1=NC2C(CC(CO)C(O)C2O)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 203.1 %

Procedure:
To a solution of Intermediate B (173 mg, 0.387 mmol) in dry THF (5 mL) was added a solution of ethyl isothiocyanate (42 mg, 0.48 mmol) in dry THF (3 mL). The mixture was stirred at room temperature for 24 h. Solvents were evaporated under reduced pressure. The residue was dissolved in acetone (3 mL). MeI (110 mg, 0.774 mmol) was added. The mixture was stirred at room temperature for 9 h. Satd. aqueous NaHCO3 (2 mL) was added and stirred at room temperature for 10 min. The mixture was further diluted with satd. aqueous NaHCO3 (20 mL), extracted with EtOAc (2×15 mL). The combined extracts were washed with brine and dried over Na2SO4. Solvents were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with 96:3:1 EtOAc-MeOH—NH4OH (28% aqueous) to give the aminooxazoline (181 mg, 94%) as a syrup. 1H NMR (400 MHz, CDCl3) δ 7.36-7.25 (m, 15H), 4.88-4.85 (m, 1H), 4.78 (d, J=11.8 Hz, 1H), 4.76 (d, J=11.8 Hz, 1H), 4.66 (d, J=11.3 Hz, 1H), 4.46 (d, J=11.3 Hz, 1H), 4.45 (s, 2H), 4.07 (dd, J=8.0, 5.1 Hz, 1H), 3.67 (t, J=5.7 Hz, 1H), 3.55-3.51 (m, 2H), 3.46 (dd, J=9.0, 4.2 Hz, 1H), 3.29-3.15 (m, 2H), 2.20 (dt, J=14.9, 3.7 Hz, 1H), 2.07-2.00 (m, 1H), 1.89 (ddd, J=15.2, 11.9, 3.6 Hz, 1H); MS, m/z=500 (M+1).
Reaction SMILES: [N:1]([CH:4]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[NH:6][C:5]1=[O:17])=[N+:2]=[N-:3].CC(C)([O-])C.[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[N:1]([CH:4]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[N:6]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]1=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCCCc2ccccc2NC1=O
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCCCc2ccccc21
Reaction time: 2 h

Procedure:
A solution of 3-azido-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (8.9 g) in dry dimethylformamide (100 ml) is added during 30 minutes to a solution of potassium t-butoxide (4.5 g) in dry dimethylformamide (100 ml) maintained at 0° under an atmosphere of dry nitrogen. The reaction mixture is stirred at 0° for 2 hours, when a solution of ethyl bromoacetate (5.8 g) in dimethylformamide (10 ml) is added during 5 minutes. The reaction mixture is stirred at 0° for 2 hours, then evaporated under reduced pressure. The residue is distributed between ethyl acetate (250 ml) and water (150 ml), and the ethyl acetate solution washed with water (100 ml) and dried over sodium sulfate. The solvent is removed under reduced pressure to give 3-azido-1-ethoxycarbonylmethyl-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12].C(O)(=O)C>CO>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]([S:2][CH3:1])[CH2:10][N+:11]([O-:13])=[O:12])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1OC
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C(C[N+](=O)[O-])SC)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.2 %

Procedure:
To a solution of sodium methanethiolate (0.62 g, 8.8 mmol) in methanol (20 ml), trans-3,4-dimethoxy-β-nitrostyrene (1.42 g, 8 mmol) was added and stirred at room temperature for 5 minutes. Further, acetic acid (0.46 ml) was added and stirred for 5 minutes. After evaporating methanol to a half amount under reduced pressure, water was added and extracted with dichloromethane and the organic layers were combined, washed with water and dried over sodium sulfate. The solvent was distilled out under reduced pressure and the residue was isolated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to yield 2-(3,4-dimethoxyphenyl)-2-(methylthio)nitroethane (1.24 g, 60%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])(=[O:19])=[O:18].C[O:28][C:29](=[O:38])[CH:30](Br)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][CH:30]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:17]([CH3:16])(=[O:18])=[O:19])[CH:6]=[N:5]2)[C:29]([OH:28])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: CS(=O)(=O)c1ccccc1O
Reactant: COC(=O)C(Br)CC1CCCC1
Product: CS(=O)(=O)c1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Yield: 68 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-methanesulfonyl-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2-methanesulfonyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (15 g, 68%) as a white solid; LC-MS: [M+H+]=407; HPLC (0.17% trifluoroacetic acid in acetonitrile/water, 50%-100% acetonitrile, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm), purity 98%. 1H-NMR (300 MHz, DMSO-d6) δ 1.42 (m, 2H), 1.55 (m, 7H), 1.57 (s, 1H), 1.59 (s, 1H), 3.31 (s, 1H), 5.31 (m, 1H), 7.63 (m, 1H), 7.87 (s, 2H), 7.98 (m, 1H), 8.19 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([N:22](/C=C/C)/C=C/C)=[N:20][N:21]=3)[CH:18]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)CO[C:33](=[O:51])[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[NH2:22][C:19]1[N:17]2[CH:18]=[C:13]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH:1][C:33]([NH:34][C:35]4[N:36]([C:44]5[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=5)[N:37]=[C:38]([C:40]([CH3:42])([CH3:41])[CH3:43])[CH:39]=4)=[O:51])[CH2:3][CH2:4]3)[CH:14]=[CH:15][C:16]2=[N:21][N:20]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: C/C=C/N(/C=C/C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N)n4c3)c3ccccc32)cc1
Yield: 39 %

Procedure:
A mixture of Intermediate 101c (1.33 g, 3.54 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (for reference procedure see Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 2.0 g, 4.96 mmol) and DIPEA (1.82, 14.16 mmol) in DMF (20 mL) was stirred at RT for 20 h. The reaction mixture was diluted with MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The product containing fractions were concentrated in vacuo and the resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM, followed by recrystallization from 5% MeOH in DCM (few drops of cyclohexane added to start recrystallization), to give the title compound (760 mg, 39%) as an off white dust. LCMS (Method 5): Rt 3.81 min, m/z 551 [MH+]. 1H NMR (400 MHz, CD3OD): 1.34 (9H, s), 1.86-2.08 (2H, m), 2.09-2.19 (1H, m), 2.22-2.34 (1H, m), 2.42 (3H, s), 4.89-4.96 (1H, m), 5.32 (1H, t, J=4.4 Hz), 6.37 (1H, s), 7.05 (1H, dd, J=10.0, 2.1 Hz), 7.23-7.44 (9H, m), 7.83 (1H, d, J=2.0 Hz).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH:9](O)[C:8]2[CH:12]=[C:13]([S:15]([NH:18]C(C)(C)C)(=[O:17])=[O:16])[S:14][C:7]=2[S:6]1(=[O:24])=[O:23].C1(C)C=CC(S([Cl:34])(=O)=O)=CC=1.[CH2:36]([NH2:38])[CH3:37]>C1COCC1>[ClH:34].[CH2:36]([NH:38][CH:9]1[C:8]2[CH:12]=[C:13]([S:15]([NH2:18])(=[O:16])=[O:17])[S:14][C:7]=2[S:6](=[O:23])(=[O:24])[N:5]([CH2:4][CH2:3][CH2:2][F:1])[CH2:10]1)[CH3:37]
Reactant: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)N(CCCF)CC2O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNC1CN(CCCF)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Product: Cl

Procedure:
A solution of the product from Step A (0.99 g, 2.87 mmol) in THF (6.0 mL) at 0° C. was treated with p-toluenesulfonyl chloride (1.09 g, 5.75 mmol) and subsequently ethylamine (5 mL) in a manner identical to that described in Example 7, Step D to give the desired compound (700 mg, recrystallized from ethyl acetate/methylene chloride): mp 238°-239° C. Analysis. Calculated for C11H19 ClFN3O4S3 : C, 32.38; H, 4.69; N, 10.30. Found: C, 32.52; H, 4.90; N, 10.29.