Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][S:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([O:13]CC)=[O:12].Cl>>[O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][S:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1cnc2sccn2c1=O
Agent: Cl
Product: O=C(O)c1cnc2sccn2c1=O

Procedure:
A mixture of ethyl 5-oxo-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (11.2g., 50mM) and 2N hydrochloric acid (75ml) was heated under reflux for 5 hours. The reaction mixture was cooled and filtered to give the required product in 79.7% weight yield (7.81g). νmax (KBr disc) 1720 (acid C=O)cm-1 ; λmax (NaHCO3 solution) 232nm (εm 2650), 263nm (εm 2030), 328nm (εm 6000) and 339nm (εm 5400); (Found: C, 43,65; H, 2.26; N, 14.16; S, 16.62%. C7H4N2O3S requires C, 43.87; H, 2.06; N, 14.28; S, 16.32%.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]2[N:5]([C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:10][CH:11]=2)[CH:6]=[CH:7][N:8]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(=O)([O-])O.[Na+].[Cl-].[Na+]>ClCCl>[CH3:2][C:3]1[C:4]2[N:5]([C:9]([N:12]3[CH2:17][CH2:16][N:15]([C:25](=[O:27])[CH3:26])[CH2:14][CH2:13]3)=[N:10][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Cc1nccn2c(N3CCNCC3)ncc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ncc3c(C)nccn23)CC1
Yield: 60.2 %

Procedure:
To 8-methyl-3-(piperazin-1-yl)imidazo[1,5-a]pyrazine hydrochloride (0.359 mmol, 91 mg) and triethylamine (1.793 mmol, 0.250 ml) in dichloromethane (5 ml) was added acetic anhydride (0.538 mmol, 0.051 ml). After stirring at room temperature for 20 hours saturated aqueous sodium hydrogencarbonate solution was added and the mixture extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate), and concentrated in vacuo to give 24 mg of crude product. To the aqueous layer solid sodium chloride was added and the mixture extracted three times with dichloromethane/methanol (4/1). The combined organic layers were washed with brine, dried (sodium sulfate), and concentrated in vacuo to give an additional 47 mg of crude product. The combined crude samples were purified using column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) to give 1-(4-(8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)ethanone (56 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:49]1[CH2:50][CH2:51][CH:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:52])[CH2:48]1)(=[O:18])[CH3:16]
Reactant: O=C(CC1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 39 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyrrolidin-3-ylacetamide tris(trifluoroacetate) and acetyl chloride as starting materials in 39% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.40 (m, 2H), 9.07 (s, 1H), 8.32 (m, 2H), 8.21 (s, 1H), 7.67 (m, 1H), 7.30 (m, 1H), 7.07 (m, 1H), 3.50 (m, 4H), 3.17 (m, 1H), 2.99 (m, 4H), 2.08 (m, 2H), 1.91 (s, 3H), 1.60 (m, 2H). LCMS for C25H27ClN7O2 (M+H)+: m/z=492.2.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH2:21]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH:22]1[OH:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:27]3[CH2:28][CH2:29][C:24]4([CH2:21][CH:22]([OH:30])[CH2:23]4)[CH2:25][CH2:26]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: OC1CC2(CCNCC2)C1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CCN2CCC3(CC2)CC(O)C3)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (157 mg, 0.53 mmol) in DCE (10 mL) was added 7-azaspiro[3.5]nonan-2-ol (109 mg, 0.77 mmol) and powdered 4 Å molecular sieves. The reaction mixture was stirred at room temperature for 4 h, sodium triacetoxyborohydride (225 mg, 1.06 mmol) was added and the resulting mixture stirred for a further 16 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM) to give the title compound as a colourless oil (155 mg, 69%). LCMS (Method H): RT=2.41 min, [M+H]+ 421.5
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:31]1[CH:36]=[C:35]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([N:17]5[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:19][CH2:18]5)[CH:14]=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:34]=[N:33][CH:32]=1
Reactant: OB(O)c1cncnc1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cncnc5)cc43)n2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
A mixture of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (427 mg, 1.0 mmol), pyrimidin-5-ylboronic acid (372 mg, 3.0 mmol), PdCl2(dppf) (73 mg, 0.1 mmol), and aq. Solution of NaHCO3 (318 mg, 3.0 mmol) in 1,4-dioxane (5.0 mL) in a sealed tube was purged with nitrogen and stirred at 100° C. for 16 hours. After it was cooled to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether:EtOAc (5:1˜1:1) as eluting solvents to afford tert-butyl 4-(6-(6-(pyrimidin-5-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as yellow solid (350 mg, yield 74%). ESI (MS) m/z=473 [M+H]+
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH2:25])[CH:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:26][C:27]1[C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1.C(N1CCC(OC2C=C(C(F)(F)F)C=C(NC(C3C(F)=NC=CC=3)=O)C=2)CC1)(OC(C)(C)C)=O>>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH:25][C:33]([C:32]3[C:27]([Cl:26])=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:34])[CH:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N)cc(C(F)(F)F)c2)CC1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: CC(C)(C)OC(=O)N1CCC(Oc2cc(NC(=O)c3cccnc3F)cc(C(F)(F)F)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(NC(=O)c3cccnc3Cl)cc(C(F)(F)F)c2)CC1

Procedure:
1-Boc-4-{3-[(2-chloro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine was prepared from 1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine and 2-chloropyridine-3-carbonyl chloride by a procedure similar to that described in the preparation of 1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([S:10]([CH2:13][S:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]2)(=[O:16])=[O:15])(=[O:12])=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1(C)C=CC(S([N:35]=[N+:36]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:1]([CH:4]1[CH2:5][CH2:6][CH:7]([S:10]([C:13]([S:14]([CH:17]2[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]2)(=[O:16])=[O:15])=[N+:35]=[N-:36])(=[O:12])=[O:11])[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(S(=O)(=O)CS(=O)(=O)C2CCC(CCC)CC2)CC1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC1CCC(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCC(CCC)CC2)CC1
Yield: 49 %

Procedure:
Synthesis was conducted as in Synthesis Example 8 using 8.0 g (0.020 mol) of the bis(4-n-propylcyclohexyl-sulfonyl)methane prepared above, 6.1 g (0.030 mol) of p-toluenesulfonylazide, 73 g of dichloromethane and 3.1 ml (0.020 mol) of DBU. There was obtained 4.1 g of the desired bis(4-n-propylcyclohexylsulfonyl)diazomethane. The yield was 48%.
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=2[O:40][CH3:41])[N:15]=1.[NH2:42][C:43]1[CH:52]=[CH:51][C:50]([C@H:53]2[CH2:58][CH2:57][C@H:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH2:54]2)=[C:49]2[C:44]=1[C:45](=[O:65])[C:46]([CH3:64])=[CH:47][NH:48]2>>[CH2:32]([O:31][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:42][C:43]3[CH:52]=[CH:51][C:50]([C@H:53]4[CH2:54][CH2:55][C@H:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:57][CH2:58]4)=[C:49]4[C:44]=3[C:45](=[O:65])[C:46]([CH3:64])=[CH:47][NH:48]4)[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)([O:34][CH2:35][CH3:36])=[O:37])[CH3:33]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCOC(=O)[C@H]1CC[C@H](c2ccc(N)c3c(=O)c(C)c[nH]c32)CC1
Agent: CNC(=O)c1cc(F)ccc1N
Product: CCOC(=O)[C@H]1CC[C@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c(=O)c(C)c[nH]c32)CC1

Procedure:
The title compound was prepared according to Compound 102A using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (233.0 mg, 0.44 mmol) and ethyl trans-4-(5-amino-3-methyl-4-oxo-1,4-dihydroquinolin-8-yl)cyclohexanecarboxylate (Compound 304A, 172.0 mg, 0.52 mmol). 1H NMR (400 MHz, MeOD) δ ppm 1.26-1.35 (m, 9 H) 1.69-1.94 (m, 6H) 2.14 (s, 3H) 2.31 (d, J=13.64 Hz, 2H) 2.83 (br. s., 1H) 2.97-3.06 (m, 1H) 3.33 (s, 1H) 3.39 (s, 1H) 3.91 (s, 3H) 4.10 (quin, J=7.26 Hz, 4H) 4.24 (q, J=7.24 Hz, 2H) 6.93 (m, J=6.06 Hz, 1H) 7.11 (t, J=2.02 Hz, 1H) 7.35 (d, J=7.83 Hz, 1H) 7.81 (d, J=7.83 Hz, 1H) 7.87 (s, 1H) 8.31 (s, 1H) 8.49 (br. s., 1H). MS (ES+): m/z: 746.20/747.19 (100/40) [MH+]. HPLC: tR=4.42 min (Micromass ZQ3: polar—5 min).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Br:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:30])=[CH:31][CH:32]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
1-Hydroxybenzotriazole (2.02 g, 14.9 mmol) and 2.86 g (14.9 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to a solution of 2.0 g (9.95 mmol) of 4-bromobenzoic acid in N,N-dimethylformamide (15 ml), and the mixture was stirred at room temperature for 10 min. Thereafter, 1.3 ml (14.9 mmol) of morpholine was added thereto, and the mixture was stirred at room temperature for 18 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate, and was then filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 2.66 g (yield 99%) of the title compound.
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[CH:11]=[CH:10][N:9]=[N:8][C:7]=2[O:6][CH2:5]1>N.CO.[Pd]>[N:8]1[C:7]2[O:6][CH2:5][CH:4]([NH2:3])[C:12]=2[CH:11]=[CH:10][N:9]=1
Reactant: CON=C1COc2nnccc21
Agent: [Pd]
Agent: N
Solvent: CO
Product: NC1COc2nnccc21
Reaction time: 1 h

Procedure:
To a solution of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (1.35 mmol) in 10 mL 7N NH3 in MeOH was added Pd/C (50 mg) and the reaction mixture was stirred under a H2 atmosphere for 1 h. The mixture was then filtered over Celite, washed with 20 mL MeOH and concentrated in vacuo to give the title compound as dark red oil;
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=O)C1C=CC=CC=1.O[C@H]1[C@@H]2CC(=C)CN2C(=O)C2C=C(I)C=CC=2N1NC(OCC(Cl)(Cl)Cl)=O.C(OC(N1C[C@H](O)C[C@H]1CO[Si](C(C)(C)C)(C)C)=O)C=C>C(OCC)(=O)C.C(O)C.[Pd]>[Si:19]([O:18][CH2:17][C@@H:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][NH:11]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C=C1C[C@H]2[C@H](O)N(NC(=O)OCC(Cl)(Cl)Cl)c3ccc(I)cc3C(=O)N2C1
Agent: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)CN1

Procedure:
A slurry of 10% Pd/C (190 mg) in ethyl acetate (20 mL) was added to a solution of TBDMS ether (43) (1.90 g, 5.19 mmol) in ethanol (100 mL). The reaction mixture was hydrogenated (Parr apparatus) for 16 h. The catalyst was removed by vacuum filtration through Celite and excess solvent was evaporated under reduced pressure to give a yellow oil in quantitative yield (1.20 g, 100%). [α]22.2D=+35.6° (c 0.042,CHCl3). 1H NMR (CDCl3): δ −(0.07-0.08) (m, 6H, H1=, H2=), 0.82 (s, 9H, H3=, H4=, H5=), 1.68-1.73 (m, 2H, H1,), 2.99-3.11 (m, 2H, H11), 3.47-3.50 (m, 3H, H11a, H3), 4.09 (bs, 1H, NH or OH), 4.32 (bs, 1H, NH or OH). 13C NMR (CDCl3): δ −5.4 (C3=, C5=, C6=), 18.1 (C4=), 25.8 (C1=, C2=), 37.4 (C1), 54.6 (C11), 58.1 (C2), 64.6 (C3), 72.2 (C11a). IR (thin film): v=3330 (OH), 2928, 2857, 1557, 1421, 1331 (C—CH3), 1249 (CH3-Si), 1204 (t-Bu), 1191 (t-Bu), 1100 (Si—O), 1073, 993, 713 cm−1. MS (Cl) m/e (relative intensity): 232 (M+., 100), 230 (13), 174 (5), 133 (6), 86 (6).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([O:12][CH3:13])=[CH:7][N:6]=1)=[O:4].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].[I-].[K+].O>CN(C)C=O>[Cl:11][C:10]1[C:5]([C:3](=[O:4])[CH2:2][N:18]2[C:17](=[O:19])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:24])=[N:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cnc(C(=O)CBr)c(Cl)c1
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc(C(=O)CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 16.8 %

Procedure:
To 570 mg of 2-bromo-1-(3-chloro-5-methoxypyridin-2-yl)ethanone in 10 ml of N,N-dimethylformamide, 800 mg of potassium phthalimide and 36 mg of potassium iodide were added, and the mixture was stirred at 80° C. for 5 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 20 ml of water and extracted with ethyl acetate (40 ml×1), the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 0.12 g of the desired product as white crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][C:16]2[C:17](=[O:32])[NH:18][N:19]=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1.N>>[F:9][C:4]1[CH:3]=[C:2]([N:18]2[C:17](=[O:32])[C:16]([O:15][C:14]3[CH:33]=[CH:34][C:11]([F:10])=[CH:12][CH:13]=3)=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=3)[CH:20]=[N:19]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Oc2ccc(F)cc2)cc1
Reactant: Fc1ccc(Br)cc1F
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, substituting 1-bromo-3,4-difluorobenzene in place of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 185 mg, 39%). mp 178-180° C. 1H NMR (300 MHz, CDCl3) δ 3.11 (s, 3H), 6.89-7.04 (m, 4H), 7.45-7.52 (m, 1H), 7.45-7.52 (m, 1H), 7.61 (dt, J=6 Hz, 3 Hz, 1H), 7.82 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.08 (s, 1H). MS (DCI/NH3) m/z 473 (M+H)+, 490 (M+NH4)+. Anal. calc. for C23H15F3N2O4S.0.5H2O: C, 57.38; H, 3.33; N, 5.83. Found: C, 57.17; H, 3.13; N, 5.62.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31].[Na+].[Cl-]>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([N:15]2[CH2:26][CH2:27][CH2:28][C:29]([CH3:34])([CH3:33])[C:30]2=[O:31])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC(C)(CCCBr)C(=O)Cl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)CCCN(C2c3cc4nonc4cc3OC(C)(C)C2O)C1=O
Temperature: 25 °C
Yield: 41 %

Procedure:
To 289 mg of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole dissolved in 5 mL of ethyl acetate were added 149 mg of triethylamine. The mixture was dropwise added with 308 mg of 5-bromo-2,2-dimethylvaleryl chloride, followed by stirring at the room temperature for one and half hours. The mixture was added with 10 mL of saturated aqueous NaCl solution and twice extracted with ethyl acetate (each 20 mL). After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 33 mL of dimethylformamide and was dropped with 1.24 g of 10% tetramethylammonium hydroxide solution under ice-cooling over 15-minute period. After the mixture was reacted under ice-cooling for one hour, the solvent was distilled off under reduced pressure and added with 10 mL of saturated aqueous NaCl solution and extracted twice with chloroform (each 20 mL). After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography (ethyl acetate:n-hexane=1:1, Rf=0.5) to obtain 174 mg of the intended compound as fine yellow crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35](=[O:38])[NH:36][CH3:37])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:66])(=O)=O)CCCCCCCCCCCCCCC>>[I:66][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][C:35](=[O:38])[NH:36][CH3:37])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC(=O)NC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)OC(=O)NC

Procedure:
3-(3-Chloropropylsulfonylamino)-2-methylcarbamoyloxy-1-octadecylcarbamoyloxypropane IIIc2 is allowed to react and worked up by the same procedure as described in (5). m.p. 97°-99° C. The summary of the experimental condition and the physical data of the prodcut are listed in the Table 8.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C.CN1CCOCC1.[NH2:42][OH:43].Cl.[OH-].[K+]>C1COCC1.CO>[Br:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([S:17]([N:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6](=[O:5])[NH:42][OH:43])(=[O:19])=[O:18])=[CH:21][CH:22]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: O=C(O)CN(CC(=O)NO)S(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
{Carboxymethyl-[4-(4-bromo-phenoxy)-benzenesulphonyl]-amino}-acetic acid (4d) (1.90 g, 4.30 mmol) was dissolved in dry THF (50 mL). ECF (0.35 mL, 3.70 mmol), and NMM (0.40 mL, 3.70 mmol) were added and stirred for 40 min at 0° C. NH2OH×HCl (0.30 g, 4.30 mmol) and KOH (0.24 g, 4.30 mmol) were dissolved in dry MeOH (20 mL) and stirred at 0° C. for 30 min. The solids were filtered off, and the THF solution was added dropwise to the methanol filtrate and stirred for 2 h at 0° C. The reaction mixture was filtered, the solvent evaporated, and the residue dissolved in H2O (20 mL). After adjusting the pH to 1-2, the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4 and evaporated in vacuo to yield the pure product as white crystals. Yield: 1.80 g, 3.90 mmol, 91%. 1H NMR (D2O): δ 7.7 (d, J=8.2 Hz, 2H, ArH), 7.5 (d, J=8.8 Hz, 2H, ArH), 7.0 (d, J=8.8 Hz, 2H, ArH), 4.0 (s, 4H, CH2COOH). ESI-MS calcd for C16H15BrN2O7S 457.98 [M-H]−, obsd 459.27.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][CH:38]=O)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:51]1([O:56][C:57](=[O:64])[C@H:58]([CH2:60][CH:61]([CH3:63])[CH3:62])[NH2:59])[CH2:55][CH2:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][CH2:38][NH:59][C@H:58]([C:57]([O:56][CH:51]3[CH2:52][CH2:53][CH2:54][CH2:55]3)=[O:64])[CH2:60][CH:61]([CH3:62])[CH3:63])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(CC=O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(CCN[C@@H](CC(C)C)C(=O)OC4CCCC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 39.7 %

Procedure:
To a solution of Intermediate F (0.165 g, 0.32 mmol) in dichloroethane (10 mL) was added L-leucine cyclopentyl ester tosylate (0.197 g, 0.52 mmol) and sodium triacetoxyborohydride (0.151 g, 0.71 mmol). The mixture was stirred for 90 minutes, then quenched by addition of saturated ammonium chloride (20 mL). The product was extracted with dichloromethane (3 times 100 mL) and the combined organic extracts were dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, ethyl acetate) to yield the desired product (0.089 g, 53% yield). LC/MS: m/z 701.25 [M+H]+