Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[OH:1][C:2]1[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(O)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(O)c1O
Temperature: 25 °C

Procedure:
A solution of commercially available 2,3-dihydroxy-4-methoxybenzoic acid (11.6 g, 63 mmol) in anhydrous MeOH (150 mL) was cooled in an ice-bath and conc. H2SO4 (8 mL) added dropwise. The reaction mixture was refluxed for 12 h, then cooled to rt and the solvent was removed under reduced pressure. H2O (100 mL) and sat aq NaHCO3 (50 mL) were added and extracted with EtOAc (3×100 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford compound 513 as a pale yellow solid, which was used in the next step without further purification. LC-MS: RT=2.31 min.; m/z 197.3 (M−H)−. 1H NMR (CDCl3): δ 10.83 (1H, s), 7.41 (1H, d, J 9.0), 6.50 (1H, d, J 8.9), 5.45 (1H, s), 3.94 (3H, s), 3.93 (3H, s).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:18]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH2:17][N:16]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:15][CH:14]2[OH:40])=[CH:9][CH:8]=1)[CH:4]=[CH2:5].Cl[CH2:42][C:43]1[CH:44]=[CH:45][C:46]2[O:51][CH2:50][C:49](=[O:52])[N:48]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:47]=2[CH:58]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:18]([O:19][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:27]([CH3:29])[CH3:28])[CH:21]([CH3:22])[CH3:23])[CH2:17][N:16]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:15][CH:14]2[O:40][CH2:42][C:43]2[CH:44]=[CH:45][C:46]3[O:51][CH2:50][C:49](=[O:52])[N:48]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:47]=3[CH:58]=2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5]
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: C=CCOc1ccc(C2C(O)CN(C(=O)OCc3ccccc3)CC2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C2C(OCc3ccc4c(c3)N(CCCOC)C(=O)CO4)CN(C(=O)OCc3ccccc3)CC2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 10 °C
Reaction time: 18 h

Procedure:
1.61 g of sodium hydride dispersion (60%) are added to a solution of 19.76 g of benzyl 4-(4-allyloxyphenyl)-3-hydroxy-5 -triisopropylsilanyloxypiperidine-1-carboxylate and 9.95 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benz[1,4]-oxazin-3-one in 285 ml of N,N-dimethylformamide while the reaction mixture is stirred at 10° C. for 1 hour and at room temperature for 18 hours. The mixture is poured into 1M aqueous sodium bicarbonate solution (700 ml) and extracted with tert-butyl methyl ether 2×800 ml). The organic phases are washed successively with water (2×500 ml) and brine (1×500 ml), dried with sodium sulphate and evaporated. The title compound is obtained from the residue by flash chromatography (SiO260 F). Rf (EtOAc/heptane 2:3)=0.30, Rt=7.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:23][CH3:24])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34].C[O-].[Na+:38]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[O:23][CH3:24])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:38]
Reactant: COC(CNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(CNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To a solution of 6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.056 g, 0.108 mmol) in methanol (2 ml) was added 0.5M sodium methanolate in methanol (0.228 ml, 0.114 mmol), and the reaction was stirred for 16 hours. The reaction was concentrated, and the residue was taken up in dichloromethane and hexanes, and concentrated to yield 56 mg of the title compound (95.9% yield). MS (apci) m/z=515.8 (M-Na+2H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH:41]1([CH2:47][C@H:48]([NH:81][C:82]([O:84][CH2:85][C:86]2[CH:91]=[CH:90][C:89]([N+:92]([O-:94])=[O:93])=[CH:88][CH:87]=2)=[O:83])[C@@H:49]([OH:80])[CH2:50][C:51]([NH:53][C@H:54]2[CH2:58][CH2:57][N:56]([C:59]([C@@H:61]3[CH2:65][C@H:64]([SH:66])[CH2:63][N:62]3[C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([N+:77]([O-:79])=[O:78])=[CH:73][CH:72]=3)=[O:68])=[O:60])[CH2:55]2)=[O:52])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:66][C@@H:64]3[CH2:63][N:62]([C:67]([O:69][CH2:70][C:71]4[CH:72]=[CH:73][C:74]([N+:77]([O-:79])=[O:78])=[CH:75][CH:76]=4)=[O:68])[C@H:61]([C:59]([N:56]4[CH2:57][CH2:58][C@H:54]([NH:53][C:51](=[O:52])[CH2:50][C@H:49]([OH:80])[C@@H:48]([NH:81][C:82]([O:84][CH2:85][C:86]5[CH:91]=[CH:90][C:89]([N+:92]([O-:94])=[O:93])=[CH:88][CH:87]=5)=[O:83])[CH2:47][CH:41]5[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]5)[CH2:55]4)=[O:60])[CH2:65]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C(C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)C[C@H](O)[C@H](CC5CCCCC5)NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 72.6 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-diphenylphosphoryloxy-1-carbapen-2-em-3-carboxylate (1.53 g) and (2S,4S)-2-[(3S)-3-[(3S,4S)-5-cyclohexyl-3-hydroxy-4-(4-nitrobenzyloxycarbonyl)aminopentanoylamino]pyrrolidin-1-ylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.00 g), reaction and purification were carried out in a similar manner to that described in Example 1-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[(3S)-3-[(3S,4S)-5-cyclohexyl-3-hydroxy-4-(4-nitrobenzyloxycarbonyl)aminopentanoylamino]pyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (2.10 g) was obtained as an amorphous substance.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:19][CH2:20][CH2:21][O:22][Si](C(C)(C)C)(C)C>>[CH:1]1([CH2:4][N:5]([CH2:19][CH2:20][CH2:21][OH:22])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:15])([F:16])[F:17])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(NCC2CC2)cc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Product: N#Cc1ccc(N(CCCO)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1B from 4-[(cyclopropylmethyl) amino]-2-(trifluoromethyl)benzonitrile and [(3-bromopropyl)oxy](1,1-dimethylethyl)dimethylsilane: 1H NMR (300 MHz, CD3OD) δ 7.63 (d, J=8.7 Hz, 1H), 7.11 (d, J=2.6 Hz, 1H), 7.02 (dd, J=9.0, 2.7 Hz, 1H), 3.66-3.56 (m, 4H), 3.37 (d, J=6.4 Hz, 2H), 1.83 (tt, J=7.2, 6.2 Hz, 2H), 1.13-0.98 (m, 1H), 0.64-0.53 (m, 2H), 0.37-0.28 (m, 2H); MS (APCI) m/z 299 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Br>CN(C)C=O>[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH2:19][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(F)cc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 51.4 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 2,4-difluoro-benzyl bromide (62 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(2,4-difluoro-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (82 mg, 51%) as an off-white solid. APCI-MS (M+H) 333.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[NH:24][C:25]2[C:26]3[C:33]([CH3:34])=[C:32]([C:35]([NH2:37])=[O:36])[S:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[F:23][C:21]1[CH:20]=[CH:19][C:18]([NH:24][C:25]2[C:26]3[C:33]([CH3:34])=[C:32]([C:35]([NH2:37])=[O:36])[S:31][C:27]=3[N:28]=[CH:29][N:30]=2)=[C:17]([O:16][C@H:13]2[CH2:14][CH2:15][C@H:10]([NH:9][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:11][CH2:12]2)[CH:22]=1
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](N)CC3)c12
Reactant: CN1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](NC4CCN(C)CC4)CC3)c12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
0.019 g 1-methyl-4-piperidone in 1.5 ml MeOH followed by 1 drop acetic acid were added to a mixture of 0.070 g 4-(2-(trans-4-aminocyclohexyloxy)-4-fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxamide (cpd.15.2) in 2 ml methanol. Sodium cyanoborohydride was added when the mixture was stirred at rt for 40 min. After stirring at 50° C. for 3 h further 0.010 g 1-methyl-4-piperidone and 0.010 g sodium cyanoborohydride were added and heating was continued overnight.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[B:20](OC)([O:23]C)[O:21]C.Cl>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][C:12]([B:20]([OH:23])[OH:21])=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCn2cccn2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccn(COCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-benzyloxymethyl-1H-pyrazole (200 mg, 1.06 mmol) in THF (5 mL) at 0° C. is added n-BuLi (0.51 mL of 2.5M in THF, 1.28 mmol) and the mixture is stirred at 0° C. for 30 min. To this is added trimethyl borate (551 mg, 5.3 mmol) dropwise then the mixture is allowed to warm to RT overnight. The light yellow solution is acidified with 1N HCl (12.8 mL) and the THF is removed under reduced pressure. The aqueous phase is purified by reverse phase MPLC using a gradient of 0-60% MeCN/water as eluent. The solvent is concentrated until a precipitate forms. The mixture is cooled to 0° C. and the solid filtered to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:12]([O:14]C)=O.C(O)(=O)C.[CH:20](=[NH:22])[NH2:21].[H-].[Na+]>O1CCOCC1>[OH:14][C:12]1[C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]=2[N:21]=[CH:20][N:22]=1
Reactant: COC(=O)c1cncc(C(=O)OC)c1Cl
Reactant: N=CN
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1cncc2c(O)ncnc12
Temperature: 25 °C
Yield: 56.1 %

Procedure:
To the mixture of dimethyl 4-chloropyridine-3,5-dicarboxylate (0.6 g, 2.6 mmol) and formimidamide acetate (0.82 g, 7.8 mmol) in dioxane (20 mL) was added NaH (0.31 g, 7.8 mmol). The resulting mixture was refluxed for 48 hours, cooled to RT. The precipitate was filtered, and washed with EA to afford the title compound as grey solid (yield 56.1%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([C:30]2[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=2)=[C:25]([CH:29]=1)[C:26](O)=[O:27].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:26](=[O:27])[C:25]2[CH:29]=[C:21]([CH3:20])[CH:22]=[CH:23][C:24]=2[C:30]2[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=2)[C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19]
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.66 g, 2.55 mmol), 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid (0.5 g, 2.318 mmol), diisopropylethylamine (0.7 mL, 6.954 mmol) and HATU (0.881 g, 2.318 mmol) in DCM was stirred at rt for 1 h. The reaction mixture was diluted with DCM and washed with satd. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hexanes) to afford the title compound. ESI-MS (m/z): 457 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][C:31]#[C:32][CH3:33])[CH:15]=2)=[CH:9][C:8]=1[CH3:34])C.[OH-].[Na+].Cl>C(O)C>[CH2:30]([O:29][C:16]1[CH:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([CH3:34])[CH:9]=2)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:17]=1)[C:31]#[C:32][CH3:33]
Reactant: CC#CCOc1cc(C#CCN2CCOCC2)cc(Sc2ccc(OCC(=O)OCC)c(C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC#CCOc1cc(C#CCN2CCOCC2)cc(Sc2ccc(OCC(=O)O)c(C)c2)c1
Reaction time: 1 h

Procedure:
{4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 140 mg. HPLC-MS: m/z: 466.0 (M+); Rt: 1.60 min.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][C:20]1[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[CH3:31])[CH:21]=1.[OH-].[K+]>C(#N)C>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:19][C:20]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([O:29][C@@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:39])[F:40])[CH3:31])[CH:21]=3)[CH:3]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)c1sc(N)cc1O[C@H](C)c1ccccc1C(F)(F)F
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 50.7 %

Procedure:
A solution of 1-[(3-fluoro-4-nitrophenyl)methyl]-4-methylpiperazine (0.733 g, 2.90 mmol) in acetonitrile (5 mL) was added dropwise to a mixture of methyl 5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (1.00 g, 2.90 mmol) and KOH (0.325 g, 5.79 mmol) in acetonitrile (10 mL) at 0° C. The reaction mixture was allowed to warm to room temperature overnight and then heated to 40° C. for 1 h until analysis by HPLC showed complete consumption of starting materials. The reaction mixture was partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was washed with saturated aqueous NaHCO3 (10 mL), concentrated under reduced pressure and then purified by flash column chromatography (DCM:MeOH 98:2 to 85:15, then EtOAC:MeOH 99:1 to 85:15) to give the title compound (0.85 g, 50%) as a red amorphous solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9](Cl)([CH3:11])[CH3:10].[SH-:16].[Na+]>CO>[CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9]([SH:16])([CH3:11])[CH3:10]
Reactant: [SH-]
Reactant: COC(CC(C)CCCC(C)(C)Cl)OC
Agent: [Na+]
Solvent: CO
Product: COC(CC(C)CCCC(C)(C)S)OC

Procedure:
A solution of 10 g. of 1,1-dimethoxy-7-chloro-3,7-dimethyloctane, 1.1 equivalents of sodium hydrosulfide and 100 ml. of methanol is refluxed for 24 hours. After cooling, solvent is evaporated under reduced pressure and the concentrate taken up in ether. The ether solution is washed with water, dried over magnesium sulfate and then evaporated to give 1,1-dimethoxy-7-mercapto-3,7-dimethyloctane.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[C:13]([C:16]1[S:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:9]([O:8][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([C:19]2[S:20][C:16]([C:13](=[O:15])[CH3:14])=[CH:17][CH:18]=2)[CH:7]=1)[CH3:10]
Reactant: CCOc1cc(Cl)nc(SC)n1
Reactant: CC(=O)c1ccc(B(O)O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2ccc(C(C)=O)s2)nc(SC)n1
Temperature: 80 °C
Yield: 27.9 %

Procedure:
The crude product of Preparation 27, 4-chloro-6-ethoxy-2-methylsulfanylpyrimidine, (525 mg, 2.56 mmol) was dissolved in DMF (4 mL). To this solution was added 5-acetyl-2-thiopheneboronic acid (523 mg, 3.08 mmol), PdCl2dppf (209 mg, 0.26 mmol), potassium carbonate (1.06 g, 7.69 mmol) and water (0.4 mL). The reaction mixture was heated at 80° C. under nitrogen atmosphere for overnight. The reaction mixture was cooled and poured into 30 mL of water and was then extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo. The resulting crude product was purified by flash silica column chromatography (20% ethyl acetate in hexane) to give product 1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone (210 mg, 28% yield over two steps). 1H-NMR (CDCl3): δ 7.67 (m, 2H), 6.68 (s, 1H), 4.46 (q, J=7.1 Hz, 2H), 2.60 (s, 3H), 2.59 (s, 3H), 1.40 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[S:13][C:14]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[C:15]([C:17]([O:19]CC)=O)[N:16]=1.[CH3:30][NH2:31]>C1COCC1.O>[CH3:30][NH:31][C:17]([C:15]1[N:16]=[C:12]([NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[S:13][C:14]=1[NH:22][C:23]([C:25]1[CH:29]=[CH:28][S:27][CH:26]=1)=[O:24])=[O:19]
Reactant: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccsc1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of ethyl 2-(naphthalen-2-ylamino)-5-(thiophene-3-carboxamido)thiazole-4-carboxylate (50 mg, 0.118 mmol) in THF (5 mL) was added 40% methylamine in water (0.5 mL) at rt, and the mixture was stirred overnight at rt. To complete the reaction, an additional 40% methylamine in water (0.5 mL) was added to the mixture, and stirring was continued at rt overnight. The solvent was removed, and the residue was triturated with water. The resulting solids were collected by filtration, and the solids were washed successively with water and EtOAc to give 28 mg (58% yield) of the titled compound.
Reaction SMILES: [N:1]1([C:6]2([C:16]#N)[CH2:15][CH2:14][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Mg]Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[CH2:16]([C:6]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: N#CC1(N2CCCC2)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(CC2(N3CCCC3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 40.0 g 8-pyrrolidin-1-yl-1,4-dioxaspiro[4.5]decane-8-carbonitrile in 150 ml analytical grade tetrahydrofuran was added dropwise to 127 ml 2.0 molar benzylmagnesium chloride solution in THF under a nitrogen atmosphere and the mixture was stirred overnight at room temperature. For working up, 50 ml saturated ammonium chloride solution were added, while cooling with ice, the phases were separated, the aqueous phase was extracted three times with 50 ml diethyl ether each time, the combined organic phases were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. The crude 1-(8-benzyl-1,4-dioxaspiro[4.5]dec-8-yl)pyrrolidine obtained (54.0 g of yellow solid) was stirred, without further purification, with a mixture of 128 ml conc. hydrochloric acid (32 per cent by weight) and 74 ml water for 24 hours at room temperature. The reaction mixture was then first washed twice with 50 ml diethyl ether each time and then rendered alkaline by addition of sodium hydroxide solution (32 per cent by weight), while cooling with ice, and extracted three times with 100 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 40.3 g 4-benzyl-4-pyrrolidin-1-yl-cyclohexanone were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH2:11])[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[N:24]=[C:23]([CH3:25])[C:22]([C:26](O)=[O:27])=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([NH:11][C:26]([C:22]2[C:23]([CH3:25])=[N:24][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=3)=[N:20][CH:21]=2)=[O:27])[CH:3]=1
Reactant: Cc1cn(N)c2cccnc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2ncccc21
Reaction time: 1 h
Yield: 44 %

Procedure:
A mixture of 3-methyl-pyrrolo[3,2-b]pyridin-1-yl amine (75% pure) (240 mg, <1.63 mmol), 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (379 mg, 1.63 mmol), HATU (744 mg, 1.96 mmol) and DIPEA (388 mg, 4.89 mmol) in DMF (5 mL) is heated at 1500 C. for 1 h. The reaction is quenched with water, extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 10% MeOH in DCM. The resulting product is recrystallized with ether to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (197 mg, 44%). MS: 362 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.14 (s, 1H), 8.40 (d, 1H), 8.36 (d, 1H), 8.22 (d, 1H), 7.85(d, 1H), 7.55 (q 1H), 7.47 (s, 1H), 7.25-7.34 (m, 2H), 2.83 (s, 3H), 2.42(s, 3H). IC50=2 nM.