Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][NH:30][CH:31]3[CH3:34])=[CH:26][CH:25]=2)=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][C:24]([C:19]5[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=5)=[CH:25][CH:26]=4)[CH:31]3[CH3:34])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ncc(-c2ccc3c(c2)C(C)NCC3)c(OC)n1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1ncc(-c2ccc3c(c2)C(C)N(C(=O)c2cc4ncc(Cl)cn4n2)CC3)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:25]([NH2:28])[CH:26]=[CH2:27].O>C(OCC)(=O)C>[CH2:25]([NH:28]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1)[CH:26]=[CH2:27]
Reactant: C=CCN
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 43 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-benzo[b]thiophen-3-ol, phosphorus(V) chloride and a solution of one part by volume of allylamine in 2 parts by volume of water with a yield of 43% of theory. M.p. 104°-106° C. (ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:49])[CH2:9][CH2:10][N:11]([CH3:48])[C@@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33](O)=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:17]2[C:16]2[CH:36]=[CH:37][C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)=[CH:39][C:15]=2[O:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:50][O:51][CH:52]([O:60][CH3:61])[CH2:53][N:54]([CH3:59])[S:55]([NH2:58])(=[O:57])=[O:56].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:27]1([C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:33]([NH:58][S:55]([N:54]([CH2:53][CH:52]([O:51][CH3:50])[O:60][CH3:61])[CH3:59])(=[O:57])=[O:56])=[O:34])=[CH:21][C:20]=3[N:18]3[C:17]=2[C:16]2[CH:36]=[CH:37][C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)=[CH:39][C:15]=2[O:14][CH2:13][C@H:12]([N:11]([CH3:48])[CH2:10][CH2:9][N:8]([CH3:49])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:19]3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(CN(C)S(N)(=O)=O)OC
Reactant: CN(CCN(C)[C@H]1COc2cc(OCc3ccccn3)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN(C)C(=O)OC(C)(C)C)COc1cc(OCc2ccccn2)ccc1-3)OC
Temperature: 40 °C

Procedure:
(7R)-7-[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-3-(pyridin-2-ylmethoxy)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid, N-(2,2-dimethoxyethyl)-N-methylsulfamide (2 eq, see Example 1, Step 1) and DMAP (5 eq) were dissolved in DCM (24 mM) and EDC (3 eq) was added. The mixture was warmed to 40° C. After 2 h the mixture was diluted with DCM and extracted twice with H2O, sat. aq. NH4Cl and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The product was obtained as a yellowish sticky solid and used without further purification (91%). (ES+) m/z 849 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(F)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)(F)F)c(F)c1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (0.17 g, white solid) from 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.15 g, 0.65 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:33]1C=CC(C(C2(C)CCNCC2)=O)=CC=1.C(OC(=O)N[C@H]1CC[C@H](CC=O)CC1)(C)(C)C>>[C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][C:19]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)([CH3:33])[CH2:18][CH2:17]2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C(=O)c2ccc(F)cc2)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1
Agent: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C)(C(=O)c3ccc(F)cc3)CC2)CC1

Procedure:
According to the procedure described for the synthesis of Trans-(4-{2-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester (intermediate E, example 1), the title compound was synthesized from (4-Fluoro-phenyl)-(4-methyl-piperidin-4-yl)-methanone and Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester. MS (m/e): 447.4 (M+H+).
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:34])[C:19]2[CH:24]=[C:23]([CH2:25][NH:26][C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[CH:22]=[CH:21][C:20]=2[Cl:33])=[CH:13][C:12]=1[C:35]([OH:37])=O.[NH2:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=1>C1COCC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:34])[C:19]2[CH:24]=[C:23]([CH2:25][NH:26][C:27]([C:29]([CH3:31])([CH3:32])[CH3:30])=[O:28])[CH:22]=[CH:21][C:20]=2[Cl:33])=[CH:13][C:12]=1[C:35]([NH:38][C:39]1[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:42]=[CH:41][N:40]=1)=[O:37]
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: COc1ccc(NC(=O)c2cc(CNC(=O)C(C)(C)C)ccc2Cl)cc1C(=O)O
Agent: CC(C)=C(Cl)N(C)C
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2cc(CNC(=O)C(C)(C)C)ccc2Cl)cc1C(=O)Nc1cc(C(F)(F)F)ccn1
Reaction time: 2 h

Procedure:
1-Chloro-N,N,2-trimethylpropenylamine (23 was added to a mixture of N-[4-methoxy-3-hydroxycarbonyl-phenyl]-2-chloro-5-(tert-butylcarbonylamino)methyl-benzamide (60.0 mg, 0.143 mmol, prepared from ethyl 5-amino-2-methoxy benzoate in analogy to step 5c and 5d) in 2.0 mL THF and it was stirred for 2 h. additional 80 μL of 1-chloro-N,N,2-trimethylpropenylamine were added and it was stirred for another 2 h. Then TEA (0.100 mL) and 2-amino-4-trifluormethyl-pyridine (23.2 mg, 0.143 mmol) were added and it was stirred overnight. The reaction mixture was concentrated and purified via prep. HPLC (method A) to furnish the title compound.
Reaction SMILES: [CH:1]1([CH:6]([CH3:12])[CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][Li].O>C(OCC)C>[CH:1]1([CH:6]([CH3:12])[CH2:7][CH2:8][C:9](=[O:11])[CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [Li]C
Reactant: CC(CCC(=O)O)C1CCCC1
Solvent: O
Solvent: CCOCC
Product: CC(=O)CCC(C)C1CCCC1
Temperature: 5 °C
Reaction time: 3.5 h
Yield: 53.5 %

Procedure:
4-Cyclopentylpentanoic acid (3.4 g; 20 mmol; prepared in example 6) in diethyl ether (90 ml) was added at 0° C. to 1.6 M diethyl ether solution of methyllithium (25 ml; 40 mmol), and diluted with the same solvent (75 ml). After 3.5 hours stirring at 5° C., water (100 ml) was added, and the separated organic layer was washed with brine (3×400 ml), dried (MgSO4), concentrated in vacuo, and bulb-to-bulb distilled (125° C./0.2 torr) to give 1.8 g (53.5% yield) of 5-cyclopentylhexan-2-one.
Reaction SMILES: [F:1][C:2]([C:5]1[S:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[C:6]=1[CH2:18][OH:19])([F:4])[CH3:3].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>ClCCl>[CH3:20][S:21]([O:19][CH2:18][C:6]1[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[N:8][S:9][C:5]=1[C:2]([F:4])([F:1])[CH3:3])(=[O:23])=[O:22]
Reactant: CCc1ccc(-c2nsc(C(C)(F)F)c2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(-c2nsc(C(C)(F)F)c2COS(C)(=O)=O)cc1
Temperature: 28 °C
Reaction time: 0.5 h

Procedure:
Into a 25-mL round-bottom flask, was placed [5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazol-4-yl]methanol (32 mg, 0.11 mmol, 1.00 equiv), dichloromethane (2 mL), MsCl (0.0258 g), triethylamine (34.2 mg, 0.34 mmol, 2.99 equiv). The resulting solution was stirred for 0.5 h at 28° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water, the organic phase was collected. The aqueous phase was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.061 g (crude) of [5-(1,1-difluoroethyl)-3-(4-ethylphenyl)-1,2-thiazol-4-yl]methyl methanesulfonate as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C15H17F2NO3S2, 362.4 (M+H). found 362.4.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:22])[CH2:4][NH:5][C@@H:6]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@H:6]([N:5]2[CH2:4][CH:3]([OH:22])[CH2:2]2)[C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[CH:16][CH:17]=1
Reactant: N#Cc1cccc([C@@H](NCC(O)CCl)c2ccc(Cl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1cccc([C@H](c2ccc(Cl)cc2)N2CC(O)C2)c1

Procedure:
A solution of 8.0 g (24.0 mmole) of 3-[(S)-[(3-chloro-2-hydroxypropyl)amino](4-chlorophenyl)methyl]benzonitrile and 11.7 g (36 mmole) of Cs2CO3 in 50 mL of dry CH3CN was divided between two 80 mL microwave tubes. The tubes were irradiated in a microwave oven (with coolin) at 160° C. for 8 h. The samples were filtered and the solids were washed with 20 mL of CH3CN and then 20 mL of CH2Cl2. The combined filtrates were concentrated and the residue was portioned between 300 mL ethyl acetate and 100 mL water. The layers were separated and the aqueous layer was washed with 100 mL ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 10-20% ethyl acetate in CH2Cl2 to afford the title compound as a clear oil; 1H-NMR (CDCl3) δ 1.6 (s, 2H, br), 5.24 (s, 1H), 7.24-7.78 (m, 8H), 2.89 (m, 2H), 3.54 (m, 2H), 4.39 (s, 1H), 4.52 (m, 1H), 7.2-7.8 (m, 8H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:54]=[CH:53][C:22]([O:23][CH2:24][C@@H:25]([OH:52])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:51]=[CH:50][C:33]([NH:34][C:35]3[C:40]([NH:41][C:42](=[O:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:52][C@H:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:54][CH:53]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:51]=[CH:50][C:33]([NH:34][C:35]2[C:40]([NH:41][C:42](=[O:49])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(Nc3ncccc3NC(=O)c3ccccc3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O)cc2)cc1)c1ccccc1
Yield: 89.7 %

Procedure:
N-{2-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-3-pyridinyl}benzamide (0.064 g, 0.087 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.039 g, 0.078 mmol).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]([F:47])([F:46])[C:6]1[CH:7]=[C:8]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[C:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27]([OH:29])=O)[CH2:13][C@H:12]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:10].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O1CCCC1>[F:43][C:42]([F:44])([F:45])[C:40]1[CH:39]=[C:8]([CH:7]=[C:6]([C:5]([F:4])([F:47])[F:46])[CH:41]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[C:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](=[O:29])[N:2]([CH3:3])[CH3:1])[CH2:13][C@H:12]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:10]
Reactant: CNC
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOC[C@H]3C(=O)O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOC[C@H]3C(=O)N(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A tetrahydrofuran solution of dimethylamine (2 M, 0.32 ml) was added to a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-carboxymorpholino)-2-butynyl]piperazine (0.13 g), 1-hydroxybenzotriazole (85 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g) in N,N-dimethylformamide (5 ml), and the whole was stirred at room temperature for 5 hours. After the solvent was removed by evaporation, dichloromethane and sodium hydrogen carbonate solution were added to the residue. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with 3% of methanol in dichloromethane as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-dimethylcarbamoylmorpholino)-2-butynyl]piperazine. It was dissolved in ethyl acetate (10 ml) and the solution was added 4N hydrogen chloride in ethyl acetate (0.26 ml). The mixture was evaporated in vacuo and the residue was triturated with a mixture of ethyl acetate and isopropyl ether to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-dimethylcarbamoylmorpholino)-2-butynyl]piperazine dihydrochloride (0.12 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][C:6](=[O:14])[CH2:5]2>C(O)(=O)C.[Pd]>[NH2:11][C:9]1[CH:10]=[C:2]([F:1])[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:14])[CH2:5]2
Reactant: O=C1Cc2cc(F)cc([N+](=O)[O-])c2N1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cc(F)cc2c1NC(=O)C2
Yield: 96.3 %

Procedure:
5-Fluoro-7-nitro-1,3-dihydro-indol-2-one 20a (4.0 g, 20 mmol) was dissolved in 200 ml of acetic acid under stirring, and added with palladium on activated carbon (1.0 g, 5%) at room temperature. The reaction system was stirred under a hydrogen atmosphere. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered, and concentrated under reduced pressure to obtain the title compound 7-amino-5-fluoro-1,3-dihydro-indol-2-one 20b (3.2 g, yield 97.5%) as a white solid.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:19][CH2:20][S:21][CH3:22])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])(=[O:3])[CH3:2].[OH:23]O>CO>[C:1]([O:4][CH:5]([CH2:19][CH2:20][S:21]([CH3:22])=[O:23])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCNC(=O)C(CCSC)OC(C)=O
Reactant: OO
Solvent: CO
Product: CCCCCCCCCCNC(=O)C(CCS(C)=O)OC(C)=O
Reaction time: 5.5 h
Yield: 101.7 %

Procedure:
To a solution of 1-(decylamino)-4-(methylthio)-1-oxobutan-2-yl acetate (21.1 g, 63.4 mmol) in methanol (110 mL) at 0° C. was added hydrogen peroxide (30%, 19.43 mL, 190 mmol) and the ice bath was removed. The reaction was allowed to stir for 5.5 hr. The reaction was diluted with water (400 mL) and then extracted with EtOAc (200 mL) to give an emulsion which did not separate after 18 hrs. The emulsion was treated with brine (250 mL) and the layers separated. The aqueous layer was extracted with EtOAc (200 mL) and the combined organic layers were washed with 10% sodium bisulfite. The organic layer was dried over magnesium sulfate, filtered and evaporated to give an orange oil (22.4 g, 100%). m/z 348 (MH+).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:17])([CH:14]([F:16])[F:15])[CH2:12][OH:13].[H-].[Na+]>>[F:10][C:11]([F:17])([CH:14]([F:16])[F:15])[CH2:12][O:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)C(F)F
Reactant: N#Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1ccc(OCC(F)(F)C(F)F)cc1

Procedure:
In a first step, p-chlorobenzonitrile is reacted with 2,2,3,3-tetrafluoropropanol in the presence of bases, for example sodium hydride, with exchange of the p-chlorine atom to give 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile. The second step is to reduce the 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile by metal hydrides, for example diisobutylaluminum hydride, 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde being formed. The 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde is reacted stereoselectively with ethyl diethylphosphonoacetate in a third reaction step to give ethyl (E)-4-(2,2,3,3-tetrafluoropropoxy)cinnamate.
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)[C:4]=2[O:3]1.[F:26][C:27]1[CH:28]=[C:29]([NH:33][NH2:34])[CH:30]=[CH:31][CH:32]=1>>[F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:33]([C:29]5[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=5)[N:34]=[CH:20][CH:19]=4)=[N:12]3)[C:4]=2[O:3]1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc3c2OC(F)(F)O3)ccc1=O
Product: O=c1ccn(-c2cccc3c2OC(F)(F)O3)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-15) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=413.2 (M+H)+
Reaction SMILES: [CH3:1]I.[OH:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[S:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=2)[C:6](=[O:21])[CH:5]=1>>[CH3:1][O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[S:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=2)[C:6](=[O:21])[CH:5]=1
Reactant: CI
Reactant: CCOC(=O)c1sc(-n2ccc(O)cc2=O)nc1C
Product: CCOC(=O)c1sc(-n2ccc(OC)cc2=O)nc1C
Yield: 54 %

Procedure:
Following the procedure as described in Example 15, making variations only as required to use methyl iodide in place of (bromomethyl)cyclopropane to react with ethyl 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a yellowish solid in 54% yield: mp 163-165° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=8.1 Hz, 1H), 6.16 (dd, J=8.1, 2.7 Hz, 1H), 6.00 (d, J=2.7 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 2.68 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 168.3, 162.9, 162.2, 156.6, 155.7, 131.3, 119.7, 103.8, 96.3, 60.9, 56.0, 17.3, 14.3; MS (ES+) m/z 295.2 (M+1).
Reaction SMILES: [CH:1](Br)=[CH2:2].[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[NH4+].[Cl-]>C1COCC1.BrBr.O>[OH:10][CH:9]([C:8]1[CH:11]=[CH:12][C:5]([OH:4])=[CH:6][CH:7]=1)[CH:1]=[CH2:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=CBr
Agent: BrBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A 2.5 l sulfonation flask equipped with stirrer, thermometer, reflux condenser, addition funnel and bubble counter connected to an argon flask is charged with 92.2 g Mg turnings, (4.0 mol) and 150 ml THF. After the system has been flushed with argon one iodine crystal is added followed by 30 drops of a solution of 192.6 g vinyl bromide (1.8 mol) in 300 ml THF. Using an oil bath, the reaction flask is heated to 70° and one drop of bromine is added. After ignition of the Grignard-reaction the oil bath is removed and the vinyl bromide-THF solution is added steadily at ambient temperature over a period of 6 hours. Stirring is continued for another 30 minutes and the cloudy, black-grey mixture obtained is cooled to 0° with an ice bath. After dilution with 600 ml THF, a solution of 61.05 g 4-hydroxy-benzaldehyde (0.5 mol) in 150 ml THF is added under efficient cooling (ice bath) over a period of 30 minutes. The thick, but stirrable suspension obtained is stirred at room temperature overnight and then cooled to 0° C. Under vigorous stirring a solution of 133.7 g NH4Cl (2.5 mol) in 350 ml H2O is added very carefully over a period of 1.5 hours. The suspension obtained is stirred for another 1.5 hours, the precipitated solids are separated by filtration and the reaction vessel is rinsed several times with a total of 600 ml MTBE. The combined organic layers are washed 2× with 500 ml water, 2× with 500 ml aq. NaHSO3 (10%), 2× with 500 ml H2O, 1× with 500 ml satd. NaHCO3 and 2× with 500 ml brine/water ca 2:1. Each aqueous phase is extracted 1× with 500 ml MTBE, the combined organic phases are dried over MgSO4 and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel 60, Merck Flash; 30 cm column with 7.5 cm diameter; solvent:hexane/MTBE 1:1) to give 56.0 g (75%) 4-(1-hydroxyallyl)-phenol in form of a yellowish, viscuous oil that slowly crystallizes.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5]C(=O)OC(C)(C)C)[CH2:2]1.CC1C=CC(S(O[C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][C:29]4([CH2:37][CH2:36][CH2:35][CH2:34]4)[C:28]=3[N:27]=[C:26]([NH2:38])[N:25]=2)(=O)=O)=CC=1>>[NH2:5][CH:3]1[CH2:2][N:1]([C:24]2[C:33]3[CH2:32][CH2:31][CH2:30][C:29]4([CH2:37][CH2:36][CH2:35][CH2:34]4)[C:28]=3[N:27]=[C:26]([NH2:38])[N:25]=2)[CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Product: Nc1nc(N2CC(N)C2)c2c(n1)C1(CCCC1)CCC2

Procedure:
The title compound was prepared according to the procedures of Examples 1G and 1H, substituting tert-butyl azetidin-3-ylcarbamate for the product from Example 1D. 1H NMR (300 MHz, CDCl3) δ 4.49 (br, 2H), 3.33 (m, 4H), 2.38-2.52 (m, 3H), 2.02-2.22 (m, 4H), 1.79-1.93 (m, 2H), 1.53-1.68 (m, 6H). MS (DCI+) m/z 274 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[N:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>O1CCCC1>[I:15][C:13]1[C:12]([O:16][CH3:17])=[CH:11][C:10]([CH:18]([CH3:20])[CH3:19])=[C:9]([CH:14]=1)[O:8][C:7]1[C:2]([NH:1][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[N:3][C:4]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[N:5][CH:6]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc(C(C)C)c(Oc2cnc(NC(=O)C(C)C)nc2N)cc1I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)C(C)C)nc2NC(=O)C(C)C)cc1I
Reaction time: 1 h
Yield: 21.7 %

Procedure:
To N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-isobutyramide (386 mg, 0.82 mmol), dissolved in anhydrous tetrahydrofuran, was added triethylamine (0.13 mL, 0.90 mmol) and isobutyryl chloride (0.09 mL, 0.90 mmol). After stirring one hour, the reaction was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (50 mL), and the dichloromethane layer was washed with water, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by preparatory TLC plates (98/2/0.5 dichloromethane/methanol/ammonium hydroxide) yielded 96 mg (22%) of N-[5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-4-isobutyrylamino-pyrimidin-2-yl]-isobutyramide as white solid, MS (M+H)=541.