Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>>[CH:30]1([S:33]([N:3]2[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[O:11])[CH2:4]2)(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCN(S(=O)(=O)C4CC4)C3)cnc21

Procedure:
1-(1-Cyclopropylsulfonyl-piperidin-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and cyclopropylsulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[CH:23]=[CH:22][N:21]=3)[CH2:16][N:15]2[C:32](=[O:49])[CH:33]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:34][CH2:35][CH2:36][O:37][CH2:38]C=C)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]>C1C=CC=CC=1.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:38][O:37][CH2:36][CH2:35][CH2:34][CH:33]([NH:41][C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[C:32](=[O:49])[N:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[CH:23]=[CH:22][N:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCOCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc2nccc3cc(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: c1ccccc1
Product: CCOC(=O)C12CC1C=CCOCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc3nccc4cc(OC)ccc34)CC1C(=O)N2
Temperature: 50 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A solution of 1-{[1-(5-Allyloxy-2-tert-butoxycarbonylamino-pentanoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester (the product of step 26F, 2.0 g, 2.94 mmol) in 800 ml of benzene was treated with Grubb's second generation catalyst (375 mg, 0.44 mmol). The reaction mixture was heated to 50° C., stirred under N2 for 2 h, and then concentrated in vacuo. Flash chromatography (silica gel, 25–100% ethyl acetate/hexane) and treatment with activated carbon gave 677.6 mg (˜35%) of 14-tert-butoxycarbonylamino-18-(6-methoxy-isoquinolin-1-yloxy)-2,15-dioxo-10-oxa-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid ethyl ester as a brown collapsed foam: 1H NMR (500 MHz, METHANOL-D4) δ 1.06–1.30 (m, 12H), 1.51–2.03 (m, 6H), 2.41–2.70 (m, 3H), 3.39–3.50 (m, 1H), 3.51–3.61 (m, 1H), 3.77–3.87 (m, 1H), 3.92 (s, 3H), 4.02–4.18 (m, 3H), 4.24 (d, J=6.41 Hz, 1H), 4.36–4.48 (m, 1H), 4.55 (d, J=11.29 Hz, 1H), 4.65 (t, J=8.39 Hz, 1H), 5.55–5.72 (m, 2H), 5.85 (s, 1H), 7.08 (d, J=8.85 Hz, 1H), 7.17 (s, 1H), 7.24 (d, J=5.80 Hz, 1H), 7.89 (d, J=5.80 Hz, 1H), 8.16 (d, J=9.16 Hz, 1H). LC-MS (Method B, retention time: 1.58 min), MS m/z 653 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].Cl[CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[N:12]([CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:11]=[CH:10]2)=[O:4]
Reactant: CCC(CC)CCl
Reactant: COC(=O)c1cc(Br)cc2cn[nH]c12
Product: CCC(CC)Cn1ncc2cc(Br)cc(C(=O)OC)c21
Yield: 22 %

Procedure:
Compound 15 was prepared following general method 1, using 5-bromo-1H-indazole-7-carboxylic acid methyl ester as a starting material and 3-chloromethyl-pentane as alkylating agent. Yield: 22%.
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]CCCCCCC.[CH3:22]CCCCCCCC=CCCCCCCCC.CC(C(O)=O)(C(O)=O)CCCCCCCC=CCCCCCCCCC>C(O)CO>[CH2:2]([CH:1]1[O:19][CH2:22][CH2:21][O:20]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: CCCCCCCCC=CCCCCCCCC
Agent: CCCCCCCCCC=CCCCCCCCC(C)(C(=O)O)C(=O)O
Solvent: OCCO
Product: CCCCCCCCCCC1OCCO1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of 2-undecen-1-ol and methyl 11-hydroxy-9-undecenoate (0.5 ml, obtained from the cross-metathesis of methyl oleate with butenediol; composition: 8.7% methyl oleate, 13.2% 9-octadecene and 1,18-dimethyl-9-octadecenedicarboxylic acid, 61.2% alcohol cross-metathesis products, 16.9% aldehyde cross-metathesis products) and 4.5 ml of ethylene glycol are combined. Further samples are taken for GC, GC-MS and GPC. By means of a magnetic stirrer, the reaction mixture is stirred at 120° C. for 60 minutes. After 5, 30 and 60 minutes the samples for GC, GC-MS and GPC measurements are taken and the reaction is stopped. Conversion of both alcohol cross-metathesis products after 60 minutes: 90%. Total yield (over two steps) of the 2-decyl-[1,3]dioxolane (protected undecanal): 67%; total yield (over two steps) of the methyl undecanoate-11-[1,3]dioxolane (protected methyl 11-oxoundecanoate): 69%; by-products (oligomers): 5%.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:10]2[CH:11]=[CH:12][CH:13]=C[C:9]=2[N:8]=N1.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[Br:42][C:43]1[C:51]([CH3:52])=[CH:50][C:46]([C:47]([OH:49])=O)=[C:45]([CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH:44]=1.CC1CCCN1>O1CCCC1.O.C(OCC)(=O)C>[Br:42][C:43]1[C:51]([CH3:52])=[CH:50][C:46]([C:47]([N:8]2[CH2:9][CH2:10][CH2:11][CH:12]2[CH3:13])=[O:49])=[C:45]([CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH:44]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOC(=O)Cc1cc(Br)c(C)cc1C(=O)O
Agent: CC1CCCN1
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1cc(Br)c(C)cc1C(=O)N1CCCC1C
Reaction time: 0.17 h

Procedure:
2.2 g (6.85 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 2.41 ml (13.9 mmol) of N,N-diisopropylethylamine and 0.27 g (2.0 mmol) of 1-hydroxy-1H-benzotriazole are added successively to a solution of 1.9 g (6.31 mmol) of 4-bromo-2-ethoxycarbonylmethyl-5-methyl-benzoic acid in 660 ml of tetrahydrofuran/H2O (9:1). After 10 minutes' stirring, 0.59 g (6.94 mmol) of rac-2-methyl-pyrrolidine is added, the mixture is stirred for another 19 hours and then diluted with 200 ml of ethyl acetate. The solution obtained is washed with 14% NaCl solution and extracted 2× with ethyl acetate. The combined organic phases are washed with 14% NaCl solution and dried with Na2SO4. After removal of the solvent, by distillation, and flash chromatography (silica gel; methylene chloride/ethanol=98:2) the desired compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:13])[C:10](Cl)=[S:11])[CH:6]=[CH:7][CH:8]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[OH:24].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:13])[C:10](=[S:11])[O:24][C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: COc1cccc(N(C)C(=S)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COc1cccc(N(C)C(=S)Oc2ccc3ccccc3c2)c1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
2.00 g of N-(3-methoxyphenyl)-N-methylthiocarbamoyl chloride, 1.44 g of β-naphthol and 1.66 g of anhydrous potassium carbonate were added to 50 ml of methyl ethyl ketone and heated to reflux for 15 hours. The reaction mixture was poured into water after it was cooled to room temperature and the products were extracted with benzene. The benzene solution was subsequently washed with water and aqueous saturated sodium chloride solution and then benzene was removed by distillation under reduced pressure after drying over anhydrous Magnesium sulfate. The residue was purified by the column chromatography (eluted with benzene on a silica gel) to give 1.45 g of O-2-naphthyl N-(3-methoxyphenyl)-N-methylthiocarbamate in crystalls (Yield: 45%). A part of the crystals was recrystallized from ethanol. Colorless crystalls having melting point of 93° to 94° C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([O:40][CH3:41])(=[O:39])[CH:37]=[CH2:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH3:41][O:40][C:36](=[O:39])/[CH:37]=[CH:38]/[C:24]1[N:22]2[N:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][C:21]2=[N:26][C:25]=1[CH3:27]
Reactant: C=CC(=O)OC
Reactant: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Temperature: 110 °C
Reaction time: 3 h

Procedure:
200 mg (0.375 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-3, 64.5 mg (0.75 mmol) methyl acrylate, 19.4 mg (0.064 mmol) tri-2-tolylphosphane, 16.8 mg (0.075 mmol) palladium(II) acetate and 0.06 mL (0.427 mmol) triethylamine in 2.6 mL degassed acetonitrile were heated in the microwave at 110° C. for three hours. Due to an incomplete reaction additional 32.2 mg (0.375 mmol) methyl acrylate and 8.5 mg (0.037 mmol) palladium(II) acetate were added, and heating in the microwave was continued for three hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed twice with brine, dried, and the solvent was removed. The crude product (300 mg) was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[S:30][C:29]([NH2:31])=[N:28][N:27]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:31][C:29]2[S:30][C:26]([CH3:25])=[N:27][N:28]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nnc(N)s1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2)cc1=O
Product: Cc1nnc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3)cc2=O)s1
Yield: 31.4 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionic acid (Intermediate 19) and 5-methyl-[1,3,4]thiadiazol-2-ylamine afforded 3-cyclopentyl-N-(5-methyl-[1,3,4]thiadiazol-2-yl)-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionamide as a white solid (60.1 mg, 31.4%); ES+-HRMS m/e calcd for C21H23N5O3S [M+Na+] 448.1414, found 448.1413. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.77 (m, 9H), 1.96 (m, 1H), 2.26 (m, 1H), 2.58 (s, 3H), 5.52 (dd, J=4.2, J=10.6 Hz, 1H), 5.73 (d, J=2.7 Hz, 1H), 7.28 (d, J=7.5 Hz, 2H), 7.35 (t, J=7.5 Hz, 1H), 7.52 (t, J=7.5 Hz, 2H), 8.14 (d, J=2.7 Hz, 1H), 12.82 (s, 1H).
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(CNC(N[C@H](C(=O)NCCCCC)CC1C=CC(OC(C(O)=O)C(O)=O)=CC=1)=O)(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].N[C@H](C(O)=O)CC1C=CC(O)=CC=1.C(OC(C1C=C(C[C@H](NC(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)C(O)=O)C=CC=1OCC(OCC)=O)=O)C.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:11][O:10][C:4]1[CH:3]=[CH:2][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(O)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)N=C=NC(C)C
Agent: CCCCCNC(=O)[C@H](Cc1ccc(OC(C(=O)O)C(=O)O)cc1)NC(=O)NCC(=O)O
Solvent: CN(C)C=O
Product: COc1ccccc1C=O
Reaction time: 16 h

Procedure:
The production of the library required seven steps using solid support. Three steps were carried out in a 96 well format. The AMEBA (acid sensitive methoxy benzaldehyde) linker was prepared by reacting Merrifield resin and 4-hydroxy-2-methoxybenzaldehyde with sodium methoxide (see Scheme 4). The AMEBA resin was then treated with the corresponding amine and NaBH(OAc)3 to give the corresponding reductive amination product. The tyrosine scaffold (5) was then coupled to the various amine resins using DIC and HOBT in DMF. The Fmoc protecting group was then removed with piperidine/DMF (1:1). The resin was then plated in a 96 well Robbins block then coupled to the corresponding sulfonyl chloride with DIEA in CH2Cl2. The diethyl ester was hydrolyzed with excess LiOH in THF: MeOH (1:1) for 16 h at rt to yield the dicarboxylic acid on resin. The use of THF: MeOH (1:1) is believed to be crucial for this hydrolysis. The product was then cleaved from the resin with 20% TFA/CH2Cl2 solution. The resin was cleaved twice to yield the maximum possible product. The second cleavage resulted in approximately 10-20% more product without any change in purity levels.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9](O)=[CH:8][C:7]1=[O:13]>C(N)C1C=CC=CC=1>[CH2:5]([NH:6][C:9]1[CH:10]=[CH:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)[C:7](=[O:13])[CH:8]=1)[C:4]1[CH:14]=[CH:15][CH:16]=[CH:2][CH:3]=1
Reactant: O=c1cc(O)ccn1Cc1cccc(F)c1
Solvent: NCc1ccccc1
Product: O=c1cc(NCc2ccccc2)ccn1Cc1cccc(F)c1

Procedure:
Heated a reaction mixture of 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (1.005 g, 4.5 mmol) in benzylamine (15 mL) at reflux (1850 C) under nitrogen atmosphere for 24 h. The reaction was monitored by ES-MS (MH+ 309). The solvent was removed by vacuum distillation to give a yellow residue.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]([NH2:13])=[N:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:18]=1.[CH2:19]([C@H:27]1[CH2:32]N[CH2:30][CH2:29][NH:28]1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]([N:13]3[CH2:30][CH2:29][NH:28][C@@H:27]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:32]3)=[N:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)Nc1ccccc1N=C2N
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Temperature: 110 °C
Reaction time: 65 h
Yield: 84.9 %

Procedure:
Combine 3-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (400.0 mg, 1.54 mmol), (S)-2-phenethyl-piperazine (879.1 mg, 4.62 mmol), N,N-diisopropylethylamine (199.0 mg, 1.54 mmol), DMSO (0.7 ml), and toluene (2.8 ml). Stir and heat the mixture at 110° C. After 65 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate. Wash the organic layer with 0.1 N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 518.7 mg (85%) of a tan foam: mp 64°–80°; mass spectrum (ion spray): m/z=397.2 (M+1).
Reaction SMILES: [S:1]([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)([O:4]CCC)(=[O:3])=[O:2]>CN(C)C=O.CC(OC)(C)C>[CH3:12][C:11]1[CH:13]=[CH:14][C:8]([S:1]([OH:4])(=[O:3])=[O:2])=[CH:9][CH:10]=1
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A 72 liter unjacketed reactor was charged with 1.84 kg (10.87 mol) of R(+)-2,6 diamino-4,5,6,7-tetrahydro-benzothiazole (R(+) diamine), followed by 14.7 L of dimethyl formamide (DMF). Under continuous stirring, the mixture was heated to a temperature of between 65° C. and 68° C. A solution of 2926 grams propyl tosylate and 1761 grams diisopropylethyleamine in 3.455 L DMF was added slowly over a period of 2 hours. The reaction was continued at 67° C. for an additional 4 hours, after which the solution was gradually cooled to room temperature (18° C. to 22° C.) and stirred for an additional 15 hours. The solution was diluted with 14.72 L of MTBE over a time period of 30 minutes, and stirred for an additional 1 hour. The precipitated material was collected by filtration and washed with 7.32 L, MTBE, followed by 3 washes of 3.68 L each of ethanol, and a wash with 9.2 L heptane. The washed precipitated cake was dried under high vacuum at 30° C. to 35° C. The final weight of the dried product was 2090 grams, representing a 50% yield.
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]2[C:6](=[O:23])[C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][O:19]C(=O)C)[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC([O-])(C)C.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)(C)C.C1(C)C=CC=CC=1>[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH:29][C:2]1[CH:25]=[CH:24][C:5]2[C:6](=[O:23])[C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC(=O)OCCCOc1ccc2c(c1)C(=O)c1ccc(Cl)cc1CC2
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2ccc(OCCCO)cc21
Yield: 40 %

Procedure:
For the preparation of the compound by method C, 0.65 g (1.8 mmol) of 2-chloro-7-(3-acetoxypropoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one, 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2 mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. Yield: 40%; C24H21F2NO3 (Mr=409.44)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(N(CC)CC)C>ClCCl>[N:13]1([CH2:2][C:3]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])=[O:4])[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: c1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)Cn2cccn2)c1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
To a solution of 3-(2-bromoacetyl)benzonitrile (500 mg, 2.23 mmol) in 5 ml dichloromethane was added pyrazole (304 mg, 4.46 mmol) and triethylamine (0.31 ml, 2.23 mmol). Reaction was stirred at room temperature over night. Reaction was then diluted with 20 ml dichloromethane, washed with 2×25 ml water, 2×25 ml 1N HCl, dried over magnesium sulfate, filtered and concentrated in vacuo. Crude residue was chromatographed on silica gel using 2.5% EtOAc in hexane to give 3-[2-(1H-1-pyrazolyl)acetyl]benzonitrile (330 mg, 70%) as a clear oil after drying. ES-MS (M+H+): 212.05
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH:27]([OH:29])[CH3:28])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:30](I)[CH3:31]>[Ag]=O.C(Cl)(Cl)Cl>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH:27]([O:29][CH2:30][CH3:31])[CH3:28])=[CH:20][CH:21]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCI
Reactant: CCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)O)cc2)nc1
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)OCC)cc2)nc1
Yield: 43 %

Procedure:
At room temperature, 1.6 g (4 mmol) of the (-)-5-octyloxy-2-{4-(6-hydroxy-1-trans-heptenyl)-phenyl}-pyrimidine obtained in Example 9, 20 ml of ethyl iodide and 2.8 g (12 mmol) of silver oxide were stirred for 60 hours, washed successively with 1 N hydrochloric acid and saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture thus obtained was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.76 g (yield 43%) of (-)-5-octyloxy-2-{4-(6-ethoxy-1-trans-heptenyl)-phenyl}-pyrimidine, [α]D20 =-1.2 (c=0.95, CHCl3).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:46]=[CH:45][C:10]2[C:11]3[S:32][C:31]4[CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=[CH:36][C:30]=4[C:12]=3[CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:17][CH:16]=3)[O:14][C:9]=2[CH:8]=1)(=O)=O.C1(P(CCC)C2C=CC=CC=2)C=CC=CC=1.C(O)=O.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:24]1([CH2:23][CH2:22][O:21][C:18]2[CH:17]=[CH:16][C:15]([CH:13]3[C:12]4[C:30]5[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=5[S:32][C:11]=4[C:10]4[CH:45]=[CH:46][CH:7]=[CH:8][C:9]=4[O:14]3)=[CH:20][CH:19]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=S(=O)(Oc1ccc2c(c1)OC(c1ccc(OCCN3CCCCC3)cc1)c1c-2sc2cc(OS(=O)(=O)C(F)(F)F)ccc12)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCP(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OC(c1ccc(OCCN3CCCCC3)cc1)c1c-2sc2ccccc12
Yield: 57 %

Procedure:
A solution of the product of Example 6 (780 mg, 1.06 mmol), palladium(II) acetate (42 mg, 0.19 mmol), 1,2-bis(diphenylphosphinopropane (149 mg, 0.36 mmol), formic acid (0.6 mL), and triethylamine (3.0 mL) in anhydrous dimethylformamide (40 mL) was stirred at ambient temperature for 4 d. After concentration, the residue was subjected chromatography (silica gel, 1:1 hexane:ethylacetate, 2-10% methanol, 0.1% ammonium hydroxide). Product containing fractions were concentrated, partitioned between methylene chloride (100 mL) and saturated sodium bicarbonate (100 mL), and the aqueous layer extracted with methylene chloride (50 mL). The combined organic extracts were dried (sodium sulfate), concentrated, and the residue purified by chromatography (silica gel, 1:1 hexane:ethylacetate, 2-10% methanol, 0.1% ammonium hydroxide) to give 267 mg (57%) of the title compound as an oil which gave a white, crystalline solid, mp 107° C., upon trituration with ether/hexane: 1H NMR (300 MHz, CDCl3) d 7.86 (d, J=7.4 Hz, 1H), 7.40 (m, 1H), 7.1-7.3 (m, 6H), 6.97 (t, J=7.3 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.66 (s, 1H), 4.07 (t, J=6.1 Hz, 2H), 2.75 (t, J=6.1 Hz, 2H), 2.49 (m, 4H), 1.5-1.7 (m, 4H), 1.4-1.5 (m, 2H); 13C NMR (125 MHz, CDCl3) d 159.1, 151.6, 139.3, 137.1, 133.0, 131.5, 129.8, 129.1, 126.8, 124.6, 124.4, 123.7, 122.6, 121.5, 121.5, 119.3, 116.9, 114.6, 77.6, 65.7, 57.7, 54.9, 25.8, 24.0; MS (FD+) m/e 441 (M+); Anal. calc'd for C28H27NO2 S: C, 76.15; H, 6.17; N, 3.17. Found: C, 75.93; H, 6.44; N, 3.01.