Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:32])(=[O:31])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9]C(C)(C)[O:11]2)[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([S:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)[NH2:2]>FC(F)(F)C(O)=O.O>[S:1](=[O:32])(=[O:31])([O:3][CH2:4][C@H:5]1[CH2:6][C@@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([S:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]=3[CH:17]=[CH:16]2)[C@H:8]([OH:9])[C@@H:12]1[OH:11])[NH2:2]
Reactant: CC1(C)O[C@@H]2[C@@H](COS(N)(=O)=O)C[C@@H](n3ccc4c(Sc5ccccc5)ncnc43)[C@@H]2O1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)OC[C@H]1C[C@@H](n2ccc3c(Sc4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Yield: 0.1 %

Procedure:
{(3aR,4R,6R,6aS)-2,2-Dimethyl-6-[4-(phenylsulfanyl)-7H-pyrrolo[2,3-d]-pyrimidin-7-yl]tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methyl sulfamate (14.4 mg, 30.2 mmol) was stirred in 1.00 mL of 90% trifluoroacetic acid in water for 3 h at rt. The solvent was then removed in vacuo and the resulting oil was purified by silica gel chromatography eluting with a gradient of 60 to 100% EtOAc in hexanes to afford the title compound (7.50 mg, 57%). 1H NMR (400 MHz, CD3OD, δ): 8.45 (s, 1H), 7.66-7.36 (m, 2H), 7.51-7.41 (m, 4H), 5.92 (d, J=3.8 Hz, 1H), 5.13-5.06 (m, 1H), 4.58-4.55 (dd, J=3.8, 9.0 Hz, 1H), 4.42-4.37 (dd, J=8.0, 9.8 Hz, 1H), 4.18-4.14 (m, 2H), 2.92-2.82 (m, 1H), 2.24-2.08 (m, 2H) ppm. LC/MS: Rt=1.38 min, ES+ 437 (FA standard).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19]([C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28]5)=[CH:23][CH:22]=4)=[O:20])[CH:14]=3)[C:9]2=[O:38])[CH2:6][CH2:5][C:4](=[O:39])[NH:3]1.Cl>C(Cl)Cl.C(OCC)C>[O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19]([C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][NH:27][CH2:28]5)=[CH:23][CH:22]=4)=[O:20])[CH:14]=3)[C:9]2=[O:38])[CH2:6][CH2:5][C:4](=[O:39])[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=O)NCc3ccc4c(c3)CN(C3CCC(=O)NC3=O)C4=O)cc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc5c(c4)CNCC5)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butyl 7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.53 g, 1.0 mmol) in methylene chloride (100 mL) is treated with HCl (5 mL of a 2N solution in diethyl ether), and stirred at ambient temperature for 48 hours. The mixture is evaporated under vacuum, and triturated in ethyl acetate (10 mL), filtered, and dried under vacuum.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].IC.[O:9]=[C:10]1[CH:24]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[C:23]2[N:22]=[CH:21][N:14]3[CH2:15][C:16](=[O:20])[CH2:17][CH2:18][NH:19][C:12]([C:13]=23)=[CH:11]1>CN(C=O)C>[CH3:1][CH:15]1[N:14]2[CH:21]=[N:22][C:23]3[CH:24]([CH2:25][C:26]([OH:28])=[O:27])[C:10](=[O:9])[CH:11]=[C:12]([C:13]=32)[NH:19][CH2:18][CH2:17][C:16]1=[O:20]
Reactant: CC(C)(C)OC(=O)CC1C(=O)C=C2NCCC(=O)Cn3cnc1c32
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC1C(=O)CCNC2=CC(=O)C(CC(=O)O)c3ncn1c32
Reaction time: 18 h

Procedure:
Cesium carbonate (214 mg, 0.66 mmol) and iodomethane (93 mg, 0.66 mmol) were added to a solution of tert-butyl (2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetate (109 mg, 0.33 mmol, described in Intermediate 13) in DMF (5 mL). After 18 h, the mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=346(M+1).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13].Br[C:15]([CH3:20])([CH3:19])[C:16](Br)=[O:17]>C(Cl)Cl>[CH3:19][CH:15]1[CH2:20][C:10]2[C:11](=[C:6]([CH3:5])[C:7]([CH3:13])=[C:8]([CH3:12])[CH:9]=2)[C:16]1=[O:17]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1cccc(C)c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1C)C(=O)C(C)C2
Reaction time: 2 h

Procedure:
17.3 g (125 mmol) of AlCl3 were added to a solution of 6.01 g (50 mmol) of 1,2,3-trimethylbenzene in 30 ml of analytical grade methylene chloride, while cooling with ice. 11.9 g (52 mmol) of 2-bromoisobutyryl bromide were then added rapidly, and stirring was continued at 0° C. for 1 hour and at room temperature for 2 hours. The mixture was kept at room temperature for a further 15 hours and then worked up analogously to Example A. The crude product was purified by distillation (0.05 mm Hg/96-107° C.). The yield was 8.1 g (86%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](O)=[O:15])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:24]1([CH2:30][CH2:31][O:32][C:33]2[CH:51]=[CH:50][C:36]3[N:37]4[CH:42]=[C:41]([C:43]5[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=5)[N:40]=[C:38]4[S:39][C:35]=3[CH:34]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:14]([NH:47][C:46]2[CH:45]=[CH:44][C:43]([C:41]3[N:40]=[C:38]4[N:37]([CH:42]=3)[C:36]3[CH:50]=[CH:51][C:33]([O:32][CH2:31][CH2:30][N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[CH:34][C:35]=3[S:39]4)=[CH:49][CH:48]=2)=[O:15])=[O:11])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Reactant: Cc1cc(C)cc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)c1
Temperature: 155 °C
Reaction time: 24 h

Procedure:
Working as in the example 4, but using (S)-2-(2-(3,5-dimethylphenyl)acetamido)-3-phenyl-propionic acid and [4-(7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b]benzothiazol-2-yl]aniline and reagents as HATU and DIPHEA in dry DMF. The reaction mixture was stirred at room temperature for 6 h, at 70° C. for 48 h and at 155° C. for 24 h. Then the solvent was removed under reduced pressure and the crude mixture was purified by flash chromatography to give the desired product (S)-2-(3,5-dimethylphenylacetamido)-3-phenyl-N-[4-(7-(2-morpholin-4-yl-ethoxy)-imidazo[2,1-b]benzothiazol-2-yl)phenyl]propanamide
Reaction SMILES: [ClH:1].FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)COCC(C1C=CC=CC=1)[CH2:11][NH2:12].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.Cl.N[C:49]1[CH:82]=[CH:81][C:52]([C:53]([NH:55][CH2:56][CH:57]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[CH2:58][O:59][CH2:60][C:61]2[CH:66]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:64]=[C:63]([C:71]([F:74])([F:73])[F:72])[CH:62]=2)=[O:54])=[CH:51][CH:50]=1.Cl.O1CCOCC1>O1CCOCC1.C(Cl)Cl>[ClH:1].[NH2:12][CH2:11][C:49]1[CH:50]=[CH:51][C:52]([C:53]([NH:55][CH2:56][CH:57]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[CH2:58][O:59][CH2:60][C:61]2[CH:66]=[C:65]([C:67]([F:70])([F:69])[F:68])[CH:64]=[C:63]([C:71]([F:74])([F:72])[F:73])[CH:62]=2)=[O:54])=[CH:81][CH:82]=1
Reactant: NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: Nc1ccc(C(=O)NCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCc1ccc(C(=O)NCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)cc1
Yield: 59 %

Procedure:
Compound 69 (1.05 g, 86%) was produced as an oily product from 4-tert-butoxycarbonylaminomethylbenzoic acid (0.60 g, 2.4 mmol), the compound produced in Example 17 (0.83 g, 2.0 mmol), triethylamine (0.28 mL, 2.0 mmol), WSC.HCl (0.46 g, 2.4 mmol) and CH2Cl2 (10 mL) according to the same manner as in Example 30. In the same manner as in the case of synthesis of Compound 61, Compound 63 (0.55 g, 59%) was produced from Compound 69 (1.04 g, 1.7 mmol), 4 mol/L hydrogen chloride/dioxane (2.6 mL) and dioxane (2.6 mL).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=2)[NH:3]1.[O:14]=[C:15]1[C:20]2=[CH:21][NH:22][C:23]([CH:24]=O)=[C:19]2[CH2:18][CH2:17][NH:16]1.N1CCCCC1>C(O)C>[O:1]=[C:2]1[C:10](=[CH:24][C:23]2[NH:22][CH:21]=[C:20]3[C:19]=2[CH2:18][CH2:17][NH:16][C:15]3=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=2)[NH:3]1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C
Yield: 24.7 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid (44.5 mg, 0.25 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (41 mg, 0.25 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 6 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol. The solid was then dissolved in methanol, the insoluble materials were removed and the filtrate was concentrated to give 20 mg (25%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=2)=[CH:4][C:5]([C@H:10]2[C@H:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:14]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:13]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:12]([CH2:40][O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:11]2)=[C:6]([CH2:8][OH:9])[CH:7]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC.[C:89]([CH2:93]O)([F:92])([F:91])[F:90]>C1(C)C=CC=CC=1>[CH2:33]([O:32][C@H:13]1[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:10]([C:5]2[CH:4]=[C:3]([CH2:49][C:50]3[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=3)[C:2]([Cl:1])=[CH:7][C:6]=2[CH2:8][O:9][CH2:93][C:89]([F:92])([F:91])[F:90])[O:11][C@@H:12]1[CH2:40][O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CO)cc2Cl)cc1
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(COCC(F)(F)F)cc2Cl)cc1
Reaction time: 0.17 h

Procedure:
To a solution of (5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)methanol (0.783 g, 1 mmol) (V-1) in toluene (2 mL) was added ADDP (2 mmol) at room temperature. The mixture was stirred for 10 min and then Bu3P (2 mmol) was added. After stirring for 1 h, CF3CH2OH (1.0 g, 10 mmol) was added. The mixture was stirred overnight. After removal of volatiles under reduced pressure, the residue was purified by preparative LC-MS to obtain (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-5-(4-ethylbenzyl)-2-((2,2,2-trifluoroethoxy)methyl)phenyl)tetrahydro-2H-pyran (intermediate V-2).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[C:5]([CH3:12])[C:4]=1[CH3:13].[CH3:14][O:15][CH:16](Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[C:4]([CH3:13])=[C:5]([CH3:12])[C:6]([O:10][CH3:11])=[C:7]([CH3:9])[C:8]=1[CH:3]=[O:2]
Reactant: COc1cc(C)c(OC)c(C)c1C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(C=O)c1C

Procedure:
1,4-Dimethoxy-2,3,5-trimethylbenzene, 9.00 g (50 mmole), was dissolved in CH2C12(60 ml) and stirred with ice-cooling. After addition of 14.4 g (50×2.5 mmole) of dichloromethyl methyl ether, 13.8 ml (50×2.5 mmole) of titanium tetrachloride dissolved in CH2Cl2 (30 ml) was added dropwise over 15 minutes. After stirring for further 15 minutes with ice-cooling, the ice bath was removed and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into crashed ice (about 200 g) and stirred vigorously for 30 minutes. The CH2Cl2 layer was washed with water (3 times), and dried (MgSO4), from which CH2Cl2 was evaporated off. The residue was recrystallized from isopropyl ether/hexane (1:1), to give 6.18 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde. The mother liquor was concentrated, and the residue was purified with silica gel (60 g) column chromatography (eluted with isopropyl ether), to give 3.70 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:3]=1[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([C:19](OCC)=[O:20])=[CH:7][N:6]=1.FC1C=CC(OC)=CC=1C(C1C2C(=CC(OC)=C(OC)C=2)C(C(O)=O)=CN=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:3]=1[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH2:19][OH:20])=[CH:7][N:6]=1
Reactant: CCOC(=O)c1cnc(Cc2cc(OC)ccc2F)c2cc(OC)c(OC)cc12
Agent: COc1ccc(F)c(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(F)c(Cc2ncc(CO)c3cc(OC)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
The 1-(2-fluoro-5-methoxybenzyl)-4-ethoxycarbonyl-6,7-dimethoxyisoquinoline (4.0 g, 10 mmol, intermediate for 1-(2-Fluoro-5-methoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (Example 26) was dissolved in 60 ml of THF. At 0° C., lithium aluminum hydride (371 mg, 1.0 eq) was added and the mixture was stirred at room temperature overnight. TLC showed complete disappearance of the starting material. The mixture was evaporated to remove solvents and the residue was extracted with methylene chloride and saturated ammonium chloride solution. The organic layer was washed with water and brine. After the evaporation of solvents a solid was obtained. The solid was washed with dry ether and hexane to give 1-(2-fluoro-5-methoxybenzyl)-4-hydroxymethyl-6,7-dimethoxyisoquinoline (3.12 g, 87%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.Br.NC(N)=[S:15]>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][SH:15])=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: OCCCc1ccc(I)cc1
Agent: Br
Solvent: O
Product: SCCCc1ccc(I)cc1
Yield: 66 %

Procedure:
62 g of 3-(p-iodophenyl) propanol was combined in solution with 161 g of hydrobromic acid (48%) and 23 g of thiourea in 100 ml of water and the thiol product vacuum distilled at 114°-117° and 0.1 mm Hg. A 66% yield of 3-(p-iodophenyl) propane thiol was confirmed having a refractive index of n25D = 1.6202.
Reaction SMILES: C(OC([NH:8][C:9]1[C:17]2[C:12](=[C:13]([F:33])[C:14]([O:30][CH2:31][CH3:32])=[C:15]([NH:18][C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[O:20])[CH:16]=2)[N:11](C(OC(C)(C)C)=O)[N:10]=1)=O)(C)(C)C.Cl.O1CCOCC1>>[NH2:8][C:9]1[C:17]2[C:12](=[C:13]([F:33])[C:14]([O:30][CH2:31][CH3:32])=[C:15]([NH:18][C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[O:20])[CH:16]=2)[NH:11][N:10]=1
Reactant: CCOc1c(NC(=O)NCc2cccc(F)c2)cc2c(NC(=O)OC(C)(C)C)nn(C(=O)OC(C)(C)C)c2c1F
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1c(NC(=O)NCc2cccc(F)c2)cc2c(N)n[nH]c2c1F
Yield: 3.1 %

Procedure:
4.4 250 mg of tert-butyl 3-tert-butoxycarbonylamino-6-ethoxy-7-fluoro-5-[3-(3-fluorobenzyl)ureido]indazole-1-carboxylate (4.5 mmol) are stirred for 16 hours with 5 ml of HCl/dioxane (4 M). The batch is concentrated and evaporated three times with 20 ml of toluene each time in a rotary evaporator. The residue is purified by column chromatography on silica gel (eluent:ethyl acetate:methanol 9:1). Evaporation of the corresponding fractions gives 50 mg of 1-(3-amino-6-ethoxy-7-fluoro-1H-indazol-5-yl)-3-(3-fluorobenzyl)urea (“A14”) (31%), MS-FAB (M+H+)=362.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:25][C:19]1[CH:18]=[C:17]([C@H:9]2[CH2:8][C@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)[CH:22]=[C:21]([F:23])[C:20]=1[F:24]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(F)c(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3cc(F)c(F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorophenyl)piperidine-1-carboxylate (53.4 mg, 0.15 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 1.18 mL, 6.75 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(3,4,5-trifluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (11 mg, 25%). 1H NMR (600 MHz, dmso) δ 1.72-1.88 (m, 3H), 1.97-2.04 (m, 1H), 2.61-2.69 (m, 1H), 2.76-2.83 (m, 1H), 3.06-3.11 (m, 1H), 3.69-3.75 (m, 1H), 5.98 (s, 1H), 7.28-7.36 (m, 2H). HRMS Calculated for [C14H13F3N2O2+H]+: 299.1007. Found: 299.1031
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH:8]([C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])C(OC(C)(C)C)=O)=[O:7])=[C:4]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6](=[O:7])[CH2:8][C:16]([CH:18]2[CH2:19][CH2:20]2)=[O:17])=[C:4]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)c1ccc(Cl)cc1S(C)(=O)=O)C(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(Cl)ccc1C(=O)CC(=O)C1CC1
Yield: 99.6 %

Procedure:
A mixture of t-butyl 2-(4-chloro-2-methylsulphonylbenzoyl)-3-cyclopropyl-3-oxopropionate (9.5 g) and 4-toluenesulphonic acid (1.5 g) in toluene was stirred and heated at reflux for 3 hours. After cooling, the mixture was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 1-(4-chloro-2-methylsulphonylphenyl)-3-cyclopropylpropan-1,3-dione, (7.1 g) as an orange gum, NMR (CDCl3) δ 0.8-1.2(m, 4H), 1.5-1.9(m, 1H), 3.3(s, 3H), 5.8(s, 1H), 7.3-7.6(m, 2H), 7.9(s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:13][C@@H:11]3[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C@@H:10]3[CH2:15]2)[CH:17]=[N:18][CH:19]=1)=[O:22]
Reactant: COc1ccccc1CN
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: COc1ccccc1CNC(=O)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1

Procedure:
The product from Example 33B and 2-methoxybenzylamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 453 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][OH:5].C(O)CCCCCCCCC/C=C\CC.Br[C:33]1[O:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][CH:34]=1.ClC1OC(C(O)=O)=CC=1>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][O:5][C:33]1[O:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][CH:34]=1
Reactant: CC(C)CCCC(C)CCCC(C)CCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: CC/C=C\CCCCCCCCCCO
Agent: O=C(O)c1ccc(Cl)o1
Product: CC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)O)o1

Procedure:
In the procedure of Example 4(A), 3,7,11-trimethyldodecanol was substituted for cis-11-tetradecenol and 5-bromo-2-furoic acid substituted for 5-chloro-2-furoic acid to yield 5-(3,7,11-trimethyldodecyloxy)-2-furancarboxylic acid, M.P. 70°-73° C.
Reaction SMILES: [I-].[CH2:2]([N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:3].CC(C)([O-])C.[K+].[C:35]([O:39][C:40]([NH:42][C@:43]([CH3:55])([CH:53]=O)[CH2:44][O:45][C:46](=[O:52])[CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:41])([CH3:38])([CH3:37])[CH3:36].[Cl-].[NH4+]>O1CCCC1>[C:35]([O:39][C:40]([NH:42][C@:43]([CH3:53])([CH:55]=[CH:9][C:5]1[N:4]([CH2:2][CH3:3])[CH:8]=[CH:7][CH:6]=1)[CH2:44][O:45][C:46](=[O:52])[CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCCCCC(=O)OC[C@@](C)(C=O)NC(=O)OC(C)(C)C
Reactant: CCn1cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCCCCC(=O)OC[C@@](C)(C=Cc1cccn1CC)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
(1-Ethylpyrrol-2-yl)methyltriphenylphosphonium iodide (19.8 g, 39.8 mmol) obtained in Reference example 3 (3a) was suspended in tetrahydrofuran,(100 mL) and a solution of potassium t-butoxide (4.47 g, 39.8 mmol) in tetrahydrofuran (70 mL) was added thereto under ice-cooling with stirring over 30 minutes, followed by further stirring of the mixture under ice-cooling for 1 hour and 30 minutes. Then, a solution of (2S)-2-t-butoxycarbonylamino-1-n-hexanoyloxy-2-methyl-3-propanal (10.0 g, 33.2 mmol) obtained in Reference example 1 (1b) in tetrahydrofuran (50 mL) was added to the mixture over 30 minutes and the mixture was stirred under ice-cooling for 1 hour and 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture to stop the reaction and the temperature of the mixture was returned to room temperature. The mixture was concentrated under reduced pressure and water and ethyl acetate were added thereto to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 4:1) to obtain the title compound (11.7 g, yield: 90%).
Reaction SMILES: [Br:1]Br.C(P(CCCC)CCCC)CCC.[PH:16](=[O:19])([OH:18])[OH:17].[CH2:20]([C:22]([CH2:50][CH3:51])([CH:24](O)[C:25]1[N:29]=[CH:28][N:27]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:26]=1)[CH3:23])[CH3:21].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[PH:16](=[O:17])([OH:19])[OH:18].[CH2:20]([C:22]([CH2:50][CH3:51])([CH:24]([Br:1])[C:25]1[N:29]=[CH:28][N:27]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:26]=1)[CH3:23])[CH3:21]
Reactant: BrBr
Reactant: CCC(C)(CC)C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=[PH](O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.3 %

Procedure:
A solution of bromine (0.53 g) in dichloromethane (1 ml) was added dropwise to a solution of tri-n-butylphosphine (0.68 g) in dichloromethane (12 ml), whilst maintaining the temperature below 0° C. The mixture was stirred for ten minutes at this temperature then treated, dropwise with stirring, with a solution of diethyl 3-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.5 g, prepared as described in Example 24) and triethylamine (0.30 g) in dichloromethane (20 ml), maintaining the temperature below 0° C. It was allowed to warm slowly to room temperature, to stand for two days, then diluted with ethyl acetate, washed with water and brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.27 g, m.p. 108°-110° C.). NMR (CDCl3): δ1.13(6H,dt), 1.6-2.1(2H,m), 2.5-2.6 (2H,m), 4.1(4H,m), 5.15(1H,t), 7.1(6H,m), 7.3(9H,m), 7.9(1H,s). M/S: M+ 567,569.