Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]([O:18][C:19]([CH2:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].O>CN(C)C=O>[CH2:6]([O:25][C:23]([C@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:20])=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: CCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydrogencarbonate (305 mg) and benzyl bromide (1.0 ml) were added Successively to a solution of 2-(R)-(tert-butoxycarbonylmethyl)heptanoic acid (440 mg), prepared in Referential Example 5, in 18 ml of dimethylformamide (DMF), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was successively washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After the solvent had been distilled off under reduced pressure, the residue was purified by column chromatography through silica gel, using a 20:1 mixture of hexane and ethyl acetate as an eluent, to give 476 mg of the desired compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:16]([OH:18])=O)[CH2:10][CH2:11][S:12][CH2:13][CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1CC(=O)NC1=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CCSCCN)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CC(O)C(=O)N1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCSCCNC1=O
Reaction time: 96 h
Yield: 21.4 %

Procedure:
N-t-Butoxycarbonyl-S-(2-aminoethyl)-D,L-homocysteine (0.1 g) and hydroxysuccinimide (0.044 g) are dissolved in 4 ml of DMF. Dicyclohexylcarbodiimide (0.086 g) in 1 ml of DMF is added dropwise. After 4 days at room temperature, the reaction mixture is filtered, and then lyophilized. The residue is taken up in methylene chloride. Again insoluble white solid is removed by filtration. The crude product is chromatographed on silica gel (20:1 chloroform-methanol) to afford the product as a white solid (0.02 g). The NMR spectrum (in MeOH-d4) shows a multiplet between 4.4 and 4.8, a multiplet between 3.2 and 3.4, complex absorptions between 2.2 and 2.7, and between 1.5 and 1.9, and a singlet at 1.2.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH2:8]1[C:13]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:27][CH2:28][C:29]#[CH:30]>C(#N)C>[CH2:30]([N:11]1[CH2:12][C:13]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[CH2:8][CH2:9][CH2:10]1)[CH2:29][C:28]#[CH:27]
Reactant: C#CCCBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C#CCCN1CCCC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
Cesium carbonate (46.66 g, 143.21 mmol) is added to a suspension of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (16.66 g, 57.28 mmoles) in acetonitrile (167 mL). The mixture is stirred for 10 minutes at ambient temperature then 4-bromobutyne (6.45 mL, 68.74 mmol) is added. The reaction is heated to reflux and stirred for 18 hours. The mixture is cooled and concentrated under reduced pressure. The residue is partitioned between water (200 mL) and ethyl acetate (150 mL). The phases are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with water (200 mL), then brine (150 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (17.2 g, 98% yield). 1H NMR (300.11 MHz, CDCl3): δ 3.43-3.31 (m, 4H), 2.53-2.48 (m, 2H), 2.37-2.29 (m, 4H), 2.20 (s, 2H), 1.94 (t, J=2.6 Hz, 1H), 1.44 (s, 17H).
Reaction SMILES: Br[C:2]1[C:3]([F:15])=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:67]1([CH2:73][SH:74])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:73]([S:74][C:2]1[C:3]([F:15])=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[F:8])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: SCc1ccccc1
Reactant: O=C1CCCN1c1ccc(F)c(Br)c1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN1c1ccc(F)c(SCc2ccccc2)c1F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Intermediate 93 (1 g, 3.62 mmol) in dioxane (30 ml) was stirred under argon. DIPEA (1.26 ml, 7.24 mmol), xantphos (0.126 g, 0.22 mmol) and Pd2(dba)3 (0.099 g, 0.11 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (0.41 ml, 3.44 mmol) was slowly added and the reaction stirred for 3 h. The reaction was quenched by the addition of 150 ml of H2O. After extraction with ethyl acetate (three times), the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the product was purified by silica gel chromatography.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:4]=1)#[N:2].C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N.O1CCOCC1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([NH2:37])=[O:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)C(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC1=C(C(N)=O)C(c2ccc(C#N)cc2S(=O)(=O)C(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h

Procedure:
The reaction was carried out under argon. (rac)-4-{4-Cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (1000 mg, 1.97 mmol) and HATU (3 eq., 2248 mg, 5.9 mmol) were initially charged in dry DMF (25 ml) at 0° C., and a 0.5 M solution of ammonia in dioxane (3 eq., 11.8 ml, 5.9 mmol) and DIEA (3 eq., 764 mg, 5.9 mmol) were added after brief stirring (20 min). The mixture was stirred at RT for 6 h (HPLC control) and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). The title compound was obtained as a solid (750 mg, 75% of theory).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])[C:12]([CH:25]([CH3:27])[CH3:26])=[C:11]([O:28]CC2C=CC=CC=2)[N:10]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[CH:25]([C:12]1[C:11](=[O:28])[NH:10][C:9](=[O:8])[NH:14][C:13]=1[O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:19]#[N:20])([CH3:27])[CH3:26]
Reactant: [H][H]
Reactant: Cc1cc(C#N)cc(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
3-(2,6-Bis-benzyloxy-5-isopropyl-pyrimidin-4-yloxy)-5-methyl-benzonitrile (372 mg, 65% pure, 0.52 mmol) was dissolved in 20 mL of EtOAc and 5 mL of EtOH. 10% Pd/C (75 mg) was added and a hydrogen balloon was applied. The reaction mixture was stirred at room temperature for 1 hour. The Pd/C was filtered through celite, and the filtrate was concentrated and purified using silica gel (EtOAc/hexane) to give a white solid (100 mg, 29%). LC-MS shows 286.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([CH2:21][CH2:20][C:19](=[O:22])[CH:18]=[CH:17]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH:26](N(C)C)N(C)C)[CH3:25]>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH:26]=[C:20]1[CH2:21][C:14]2([CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:16][CH2:15]2)[CH:17]=[CH:18][C:19]1=[O:22])[CH3:25]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Solvent: Cc1ccccc1
Product: CN(C)C=C1CC2(C=CC1=O)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Yield: 100 %

Procedure:
9-oxo-3-aza-spiro[5.5]undec-7-ene-3-carboxylic acid benzyl ester, Preparation I-IA-2 (15.4 g, 51 mmol) was dissolved in 180 mL toluene and tris(dimethylamino)methane (22.2 g, 27 mmol) was added. The reaction was heated to reflux for 5 hours and then allowed to cool to room temperature overnight. The reaction solution was concentrated in vacuo to provide the title compound (18.0 g, 100%): +APCI MS (M+H) 354.6; 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (s, 1H), 7.28-7.40 (m, 5H), 6.59 (d, J=10.16 Hz, 1H), 8.01 (d, J=9.97 Hz, 1H), 5.13 (s, 2H), 3.52-3.66 (m, 2H), 3.39-3.52 (m, 2H), 3.07 (s, 6H), 2.74 (s, 2H), 1.58-1.73 (m, 2H), 1.41-1.58 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([CH:26]=O)[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1.Cl.[CH3:34][NH:35][CH3:36].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([CH2:26][N:35]([CH3:36])[CH3:34])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C=O)[nH]c2c1=O
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: CN(C)Cc1cc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c(=O)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of Example 278a (0.20 g, 0.44 mmol) and dimethylamine hydrochloride (0.071 g, 0.873 mmol) in methanol (6 mL) was added zinc chloride (0.059 g, 0.436 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for one hour, and then sodium cyanoborohydride (0.055 g, 0.873 mmol) was added and the reaction mixture was stirred at ambient temperature for three days. The resulting solid was filtered and washed with methanol (10 mL), and the eluant was concentrated. The residue was purified by preparative thin layer chromatography (silica gel, dichloromethane/methanol, 15/1) to provide the title compound (75 mg, 34% yield). 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (d, J=2.4 Hz, 1H), 7.94 (dd, J=2.4, 6.4 Hz, 1H), 7.38 (s, 1H), 7.25-7.06 (m, 2H), 7.04-6.98 (m, 2H), 6.31 (s, 1H), 3.71 (s, 3H), 3.67 (s, 2H), 3.19 (s, 3H), 2.28 (s, 6H). MS (ESI+) m/z 488.1 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([CH2:26][O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:12]([C:23]([OH:25])=[O:24])[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:35]([O:42][CH2:43][CH2:44][CH2:45]O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:35]([O:42][CH2:43][CH2:44][CH2:45][O:24][C:23]([C:12]1[CH:13]=[C:14]2[C:22](=[C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:11]=1[CH2:26][O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:18]1[O:19][CH2:20][O:21][C:17]=1[CH:16]=[CH:15]2)=[O:25])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCCCOCc1ccccc1
Reactant: O=C(O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCCCOCc1ccccc1)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.2 %

Procedure:
Compound 5 (54.8 mg, 0.12 mmol) in CH2Cl2 (2 mL) at 0° C. was added dropwise to a stirred solution of 3-benzyloxy-1-propanol (16.6 mg, 0.1 mmol), 1,3-dicyclohexylcarbodiimide (31 mg, 0.15 mmol) and 4-dimethylaminopyridine (14.6 mg, 0.12 mmol) in dry CH2Cl2 (1 mL). The mixture was stirred for 4 h at room temperature and concentrated in vacuo. The residue was chromatographed over silica gel using CH2Cl2/MeOH (50:1, v/v) to give 6 (61.2 mg, 84%) as a yellow liquid. 1H NMR (CDCl3) δ 8.16 (s, 1H, H4), 7.47 (d, 1H, H5, J=8.7 Hz), 7.20-7.45 (m, 11H, H6+2×OCH2Ph), 6.82 (d, 1H, H5′, J=7.8 Hz), 6.76 (d, 1H, H2′, J=1.5 Hz), 6.70 (dd, 1H, H6′, J=1.5, 7.8 Hz), 6.06 (AB, 2H, 3′,4′-OCH2O—, Δδ=9.9 Hz, J=1.5 Hz), 5.84 (AB, 2H, 7,8-OCH2O—, Δδ=4.5 Hz, J=1.5 Hz), 4.65 (s, 2H, OCH2Ph), 4.53 (s, 2H, OCH2Ph), 4.42 (t, 2H, 3-COOCH2(CH2)2OBn, J=6.3 Hz), 4.35 (s, 2H, 2-CH2OBn), 3.62 (t, 2H, 3-COO(CH2)2CH2OBn, J=6.3 Hz), 2.06 (quintet, 2H, 3-COOCH2CH2CH2OBn, J=6.3 Hz); MS (EI) m/z 604 [M]+.
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:22]([C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][N:25]2C(OC(C)(C)C)=O)=[O:23])[CH3:20])=[CH:15][CH:14]=1)=[O:12]>>[NH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[C:22]([NH:21][C@H:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:18][CH:17]=1)[CH3:20])=[O:23]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Yield: 95 %

Procedure:
The title compound (D12) (286 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (R)-tert-butyl 2-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate (D5) (405 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH2:17])=[O:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:14]([C:12]([NH:11][CH3:10])=[O:13])[CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CNC(=O)c1cc(N)ccc1OC
Reactant: Fc1cnc(Cl)nc1Cl
Product: CNC(=O)c1cc(Nc2nc(Cl)ncc2F)ccc1OC

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-methylaminocarbonyl-4-methoxyaniline were reacted to produce 2-chloro-5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-4-pyrimidineamine R940305. 1H NMR (DMSO-d6): δ 9.91 (1H, s), 8.31 (1H, d, J=3.6 Hz), 8.11 (1H, d, J=2.7 Hz), 7.78 (1H, dd, J=9 Hz, J=2.7 Hz), 7.59 (1H, m), 6.87 (1H, d, J=9 Hz), 3.90 (3H, s), 2.96 (3H, d, J=4.5 Hz); purity 93%.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])=[CH:27][CH:26]=2)[CH2:6]1)(=O)C.[OH-].[Na+].Cl>O1CCCC1CO>[SH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:34])=[CH:27][CH:26]=2)[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](COc2ccc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: O=C(NCc1ccc(OC[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
To a solution of (2S,4S)-4-acetylthio-N-(p-nitrobenzyloxycarbonyl)-2-[4-[N-(p-nitrobenzyloxycarbonyl)aminomethyl]phenoxymethyl]-pyrrolidine (786 mg, 1.23 mmol) in tetrahydrofuranmethanol (1:1, 20 ml), 1N aqueous sodium hydroxide (1.48 ml, 1.48 mmol) was added in a nitrogen stream under cooling with ice. The reaction solution was stirred at 2 hours, and 1N hydrochloric acid (1.6 ml, 1.6 mmol) was added thereto. The resulting mixed solution was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo to obtain a crude product of (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[4-[N-(p-nitrobenzyloxycarbonyl)aminomethyl]phenoxymethyl]-pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11])=[C:4]([N+:21]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:21][C:4]1[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11]
Reactant: CCCNC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: CCCNC(=O)c1cccc(Oc2ccc(Cl)cc2N)c1
Yield: 77 %

Procedure:
The product from Example 175a (0.88 g, 2.6 mmol) was reacted with SnCl2 as described in Example 1f to give the title compound (0.61 g, 76%).
Reaction SMILES: FC1C=C(C=CC=1F)[O:5][C:6]1[C:7](=[O:23])[O:8][C:9]([CH3:22])([CH3:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.N1C=CC=CC=1.C(OCC(Cl)=O)(=O)C.C1CCN2C(=NCCC2)CC1>CC#N.CCOC(C)=O.O.[Cl-].[Na+].O.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:21][C:9]1([CH3:22])[O:8][C:7](=[O:23])[C:6]([OH:5])=[C:10]1[C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: CC1(C)OC(=O)C(Oc2ccc(F)c(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Agent: CC(=O)OCC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC(=O)C(O)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a 0° C. solution of the alcohol of Example 1, Step 3 (14.0 g, 57.8 mmol) in CH3CN (180 mL) were added pyridine (10.0 mL) and acetoxyacetyl chloride (12.7 g, 93.0 mmol) after a period of 7 h at r.t., DBU (15.0 mL) was added to the reaction mixture. After a period of 1 h at 80° C., a second portion of DBU (20.0 mL) was added. The reaction mixture was kept at 80° C. for 18 h. The reaction mixture allowed to cool to r.t. The mixture was diluted with EtOAc (500 mL) and H2O (500 mL) and acidified with 6NHCl. After the addition of brine (100 mL), the aqueous phase was extracted 2 times with EtOAc. The organic phase was evaporated to provide a brown residue. To the solid was added a 2:1 mixture of CH2Cl2 -toluene (150 mL). The solid was filtered and washed with CH2Cl2 -toluene to provide 7.0 g of the title compound.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[K+].[C:15]([C@@H:17]1[CH2:23][C@:22]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]([CH2:25][CH:26]=[CH2:27])[C@H:18]1[CH:19]=[CH:20][C:21]2=[O:34])#[N:16]>C1COCC1>[C:15]([C@@H:17]1[CH2:23][C@:22]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]([CH2:25][CH:26]=[CH2:27])[C@H:18]1[CH2:19][CH2:20][C@H:21]2[OH:34])#[N:16]
Reactant: C=CCN1[C@H]2C=CC(=O)[C@]1(c1ccccc1)C[C@H]2C#N
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCN1[C@H]2CC[C@@H](O)[C@]1(c1ccccc1)C[C@H]2C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
A solution of K-Selectride® in THF (1M, 20 ml, 20 mmol) was added dropwise to a stirred solution of (1R*,5S*,6R*)-6-cyano-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]oct-3-en-2-one (Description 23a; 1.6 g, 6 mmol) in THF (20 ml) at −70° C. The reaction mixture was slowly warm up to 0° C. over 90 minutes and carefully quenched with a mixture of 2M NaOH (40 ml) and H2O2 (35%, 10 ml). The mixture was stirred for 15 minutes and extracted into dichloromethane (3×100 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-4%) to give the title compound (1.1 g, 68%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:52][C:53]1[CH:67]=[CH:66][C:56]([CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:55][CH:54]=1>CC#N>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([NH:52][C:53]3[CH:67]=[CH:66][C:56]([CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:64])[CH3:62])=[CH:55][CH:54]=3)=[O:17])=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc2ncc(C(=O)O)n2n1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCNc1ccc2ncc(C(=O)Nc3ccc(CNC(=O)OC(C)(C)C)cc3)n2n1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of 6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxylic acid (150 mg, 0.64 mmol) in CH3CN (1 mL) were added BOP reagent (567 mg, 1.28 mmol), triethyl amine (0.26 mL, 1.92 mmol) and tert-butyl 4-aminobenzylcarbamate (143 mg, 0.64 mmol). The reaction was stirred for overnight. Then the reaction was purified ISCO column chromatography on silica gel (10% MeOH/DCM) to give tert-butyl 4-(6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxamido)benzylcarbamate as white solid (280 mg, 100% yield). 20 mg was further purified by prep HPLC (neutral) to afford tert-butyl 4-(6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxamido)benzylcarbamate (5 mg) as white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.10 (s, 1H), 7.76 (d, J=9.70 Hz, 1H), 7.67 (d, J=8.38 Hz, 2H), 7.32 (d, J=8.38 Hz, 2H), 6.90 (d, J=9.70 Hz, 1H), 4.62 (s, 1H), 4.24 (s, 2H), 3.47 (t, J=7.28 Hz, 2H), 1.79 (t, J=7.39 Hz, 2H), 1.46-1.57 (m, 10H), 1.02 (t, J=7.39 Hz, 3H); LRMS (ESI) m/e 439.9 [(M+H)+, calcd for C23H31N6O3 439.5].
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([C:6]1[C:15]([OH:16])=[CH:14][C:9]2[C:10]([C:12]#[N:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5].[OH:22]O.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([C:6]1[C:15]([OH:16])=[CH:14][C:9]2[C:10]([C:12]([NH2:13])=[O:22])=[CH:11][C:8]=2[CH:7]=1)=[O:5]
Reactant: OO
Reactant: N#CC1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reaction time: 6 h

Procedure:
2 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carbonitrile are dissolved in 50 ml of ethanol, the whole is cooled to 0° and, while stirring at 0°, 10 g of 30% hydrogen peroxide are added dropwise thereto. 1.0 ml of 30% sodium hydroxide solution is then added slowly dropwise thereto and stirring is carried out for 6 hours at room temperature. The whole is neutralised with 6N hydrochloric acid and extracted thoroughly by shaking with 250 ml of dichloromethane. The organic phase is dried over magnesium sulphate and concentrated to dryness by evaporation. After recrystallisation from ether/hexane, 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxamide is obtained having a melting point of 174°-175°.