Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=2[N:19]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[N:20]2)(=O)=O)=CC=1.[OH-].[K+]>C(O)C.O>[CH3:25][C:21]1[CH:22]=[C:23]([CH3:24])[N:19]([C:13]2[C:14]([OH:18])=[CH:15][CH:16]=[CH:17][C:12]=2[OH:11])[N:20]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(O)c2-n2nc(C)cc2C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)n(-c2c(O)cccc2O)n1
Yield: 58.9 %

Procedure:
To 62 mg of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxyphenyl 4-methylbenzene sulfonate was added a solution in which 97 mg of potassium hydroxide was dissolved in 1.5 ml of ethanol and 1.5 ml of water, and heated at reflux for 3.5 hours. To the reaction mixture, 20 ml of water was added, and extracted with 20 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using preparative thin-layer silica gel column chromatography (hexane:ethyl acetate=1:1) to yield 20.8 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH:25]=[CH:24][C:23]([O:26][CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:1])([CH3:13])[CH:3]3[OH:12])=[N:22]2)=[CH:19][CH:20]=1
Reactant: CC1(C)Oc2ccncc2C2OC21
Reactant: O=c1ccn(-c2ccc(Cl)cc2)[nH]1
Product: CC1(C)Oc2ccncc2C(Oc2ccn(-c3ccc(Cl)cc3)n2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 1-(4-chloro-phenyl)-1,2-dihydro-pyrazol-3-one as starting materials, the title compounds were prepared as pale yellow solids.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[C:51](Cl)(=[O:53])[CH3:52]>C1COCC1>[C:17]1([C@H:15]([NH:14][C:12](=[O:13])[NH:11][C:9]2[N:8]=[CH:7][C:6]3[C:2]([NH:1][C:51](=[O:53])[CH3:52])=[N:3][N:4]([C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:5]=3[CH:10]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (900 mg, 1.671 mmol) and DIEA (0.584 mL, 3.34 mmol) in THF (16 mL) at 0° C. was treated drop-wise with a solution of acetyl chloride (0.131 mL, 1.838 mmol) in THF (0.5 mL). The reaction was stirred at 0° C. for 10 min, then allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated in vacuo and purified by flash chromatography (0-30% EtOAc/DCM) to afford (R)—N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd. For C36H32N6O2 [M+1]+ 581. found 581.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH3:24])[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[H-].[Na+].[C:29](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:29])[C@@:9]1([CH3:24])[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)[C@@]1(C)CCN(C(=O)OCc2ccccc2)C1
Reaction time: 2 h
Yield: 88 %

Procedure:
Benzyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-methylpyrrolidine-1-carboxylate (I-346) (400 mg, 1.20 mmol) and methyl iodide (112 μl, 1.79 mmol) were dissolved in dimethylformamide (12 ml), and with cooling with ice, sodium hydride (55% w/w) (62.6 mg, 1.44 mmol) was added, followed by stirring for 2 hours with cooling with ice. With cooling with ice, aqueous 10% citric acid solution was added to the reaction liquid, followed by extraction with ethyl acetate, and the obtained organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (367 mg, 88%) as a colorless oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH3:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][C:7]=12)#[CH:2].Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH3:12][C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[C:7]2[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)cc3)cnn12

Procedure:
The title compound was prepared from 3-ethynyl-7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.12) (75 mg, 0.25 mmol) and 4-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (62 mg, 54%). MS (ISN) 454.9 [(M−H)−]; mp 282-284° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][C:21]2[CH:25]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=3)[O:23][N:22]=2)=[CH:18][CH:17]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>O>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][C:19]3[CH:33]=[CH:34][C:16]([OH:15])=[CH:17][CH:18]=3)[CH:25]=2)=[CH:27][CH:28]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.3 %

Procedure:
To a trifluoroacetic acid (5 mL) solution of 5-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (270 mg, 0.755 mmol) described in Example 28 was added thioanisole (355 μL, 3.02 mmol) at 0° C., which was stirred for 1 hour and 20 minutes at room temperature. Sodium hydrogencarbonate and water were added to the reaction mixture at 0° C., which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (150 mg, 74%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].FC(F)(F)S(N(C1C=CC(Cl)=CN=1)S(C(F)(F)F)(=O)=O)(=O)=O.[CH2:44]([O:46][C:47]([C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1)=[O:48])[CH3:45].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(#N)C>[F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][C:6]([C:52]2[CH:53]=[CH:54][C:49]([C:47]([O:46][CH2:44][CH3:45])=[O:48])=[CH:50][CH:51]=2)=[CH:5][CH2:4]1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1CCC(C(F)(F)F)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(N(c1ccc(Cl)cn1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)c1ccc(C2=CCC(C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of 4-trifluoromethyl cyclohexanone (3.00 grams, 18.1 mmol) in anhydrous THF (100 mL) was added lithium bis(trimethylsilyl)amide (19.9 mL, 1.0 M in THF, 19.9 mmol) dropwise. After 10 min, a solution of 2-[N,N-bis(trifluoromethylsulfonyl)amino]5-chloropyridine (7.09 g, 18.1 mmol) in THF (20 mL) was added, and the resulting mixture was allowed to warm slowly to ambient temperature overnight, at which point it was quenched by pouring into sat. aq. NaHCO3. The mixture was extracted with EtOAc. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting enol triflate was used without further purification. To a flask containing the unpurified enol triflate were added 4-ethoxycarbonylphenylboronic acid (3.68 g, 18.69 mmol) and trans-dichlorobis(triphenylphosphine) palladium (II) (633 mg, 0.903 mmol). Acetonitrile (90 mL) and sodium carbonate (45 mL, 1.0 M aqueous, 45.0 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70° C. for 1.5 h, then was allowed to cool to room temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 10% EtOAc in hexanes, then 10 to 100% EtOAc) provided the title compound: LCMS m/z 299.5 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 6.20-6.18 (m, 1H), 4.37 (q, J=7.0 Hz, 2 H), 2.61-2.18 (m, 6H), 1.74-1.68 (m, 1H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH:8]1([C@H:14]2[C:47](=[O:48])[N:46]3[CH2:49][C@@H:43]([CH2:44][C@H:45]3[C:50](=[O:67])[NH:51][C@:52]3([C:57](=[O:66])[NH:58][S:59]([C:62]4([CH3:65])[CH2:64][CH2:63]4)(=[O:61])=[O:60])[CH2:54][C@H:53]3[CH:55]=[CH2:56])[O:42][C:26]3=[N:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]([O:35][CH:36]4[CH2:41][CH2:40][NH2+:39][CH2:38][CH2:37]4)=[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[CH2:68][C@H:18]3[O:17][C:16](=[O:69])[NH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.[CH:79]([S:81]([CH3:84])(=[O:83])=[O:82])=[CH2:80]>C(Cl)Cl>[CH:8]1([C@H:14]2[C:47](=[O:48])[N:46]3[CH2:49][C@@H:43]([CH2:44][C@H:45]3[C:50]([NH:51][C@:52]3([C:57](=[O:66])[NH:58][S:59]([C:62]4([CH3:65])[CH2:63][CH2:64]4)(=[O:61])=[O:60])[CH2:54][C@H:53]3[CH:55]=[CH2:56])=[O:67])[O:42][C:26]3=[N:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]([O:35][CH:36]4[CH2:37][CH2:38][N:39]([CH2:80][CH2:79][S:81]([CH3:84])(=[O:83])=[O:82])[CH2:40][CH2:41]4)=[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[CH2:68][C@H:18]3[O:17][C:16](=[O:69])[NH:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C=CS(C)(=O)=O
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CC[NH2+]CC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCN(CCS(C)(=O)=O)CC1)O2)C(=O)NS(=O)(=O)C1(C)CC1
Reaction time: 16 h

Procedure:
To a solution of the product from Step 1, Example 236 (50 mg, 0.057 mmol) in CH2Cl2 (3 ml) was added DIPEA (0.030 ml, 0.171 mmol) followed by methyl vinyl sulfone (12.10 mg, 0.114 mmol). The reaction was stirred in a sealed vial for 16 h at which stage LCMS indicated complete conversion to one peak corresponding to a product with desired mass. After removing the solvent the crude mixture was purified by PTLC (5% MeOH in CH2Cl2) and then repurified by PTLC using 40% acetone in hexane to furnish the title compound. LRMS m/z 981.6 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[S:25][C:24]([C:26]([OH:28])=O)=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:31][O:32][C:33](=[O:36])[CH2:34][NH2:35]>CN(C=O)C>[CH3:31][O:32][C:33](=[O:36])[CH2:34][NH:35][C:26]([C:24]1[S:25][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:29])=[O:28]
Reactant: COC(=O)CN
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc(C)c(C(=O)O)s2)cc1C
Agent: Cl
Solvent: CN(C)C=O
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc(C)c(C(=O)NCC(=O)OC)s2)cc1C
Yield: 97 %

Procedure:
Using a procedure analogous to Example 38, 5-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 51) (0.3 g, 0.72 mmol), glycine methyl ester hydrochloride, and DMF (2 mL) as reaction solvent to give the title compound (0.34 g, 0.69 mmol, 97%). 1H NMR (CDC3), δ 0.71 (t, J=7.1 Hz, 6H), 0.95 (t, J=7.1 Hz, 6H), 1.63-1.72 (m, 4H), 2.04-2.14 (m, 4H), 2.21 (s, 3H), 2.48 (s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 4.15 (d, J=5.2 Hz, 2H), 6.20 (t, J=5.2 Hz, 1H), 6.63 (s, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.98-7.01 (m, 1H), 7.01-7.06 (m, 1H). LC/MS (m/z): calcd. for C27H38NO5S (M−H)−: 488.7; found: 488.5.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][C:19]=3[F:31])[C@H:12]([C:33](O)=[O:34])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.Cl.[CH3:37][NH2:38]>>[CH3:37][NH:38][C:33]([C@@H:12]1[CH2:11][C@@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:14][N:13]1[CH2:15][C:16](=[O:32])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=[O:30])=[CH:20][C:19]=1[F:31])=[O:34]
Reactant: CN
Reactant: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)O)Nc1ccc(-n2ccccc2=O)cc1F
Agent: Cl
Product: CNC(=O)[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1CC(=O)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
Using general procedure D (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid (example 12) was coupled with methylamine hydrochloride to give (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid methylamide. White solid. MS 532.3 ([M+H]+)
Reaction SMILES: O[C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12](=[O:17])[N:13]([CH2:15][CH3:16])[CH3:14])[CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:25]([NH2:28])[C:26]#[CH:27]>ClCCl>[CH2:25]([NH:28][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12](=[O:17])[N:13]([CH2:15][CH3:16])[CH3:14])[CH:9]=2)[CH2:4][CH2:3]1)[C:26]#[CH:27]
Reactant: C#CCN
Reactant: CCN(C)C(=O)Oc1ccc2c(c1)[C@H](O)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN[C@H]1CCc2ccc(OC(=O)N(C)CC)cc21
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Methanesulfonyl anhydride (1.544 g, 8.9 mmol) as a solution in dichloromethane (7.5 mL+2.5 mL) was added to a stirred solution of (R)-ethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester (1.04 g, 4.4 mmol) and triethylamine (2.5 mL, 17.7 mmol) in dichloromethane (10 mL) at −35° C. (external) over 10 minutes. The reaction was maintained at this temperature for 45 minutes before propargylamine (3.0 mL, 44.3 mmol) was added. The reaction was allowed to warm slowly to room temperature overnight before being partitioned between ethyl acetate (100 mL) and ice-water (100 mL). The organic material was concentrated under reduced pressure to afford a brown oil which was partitioned between methyl tert-butyl ether (50 mL) and aqueous hydrochloric acid (1M, 50 mL). The aqueous layer was basified by addition of aqueous sodium hydroxide solution (2M, 40 mL) before being extracted with ethyl acetate (50 mL). This final organic extract was dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (842 mg, 70%). 1H NMR (400 MHz, CDCl3) δ ppm 7.19 (1H, d, J 8, Ar), 7.09 (1H, s, Ar), 6.94 (1H, brd, J, 8, Ar), 4.39 (1H, dd, J 6 and 6, NHCH), 3.55 (1H, Dd, J 17 and 2, NCHH), 3.49 (1H, Dd, J 17 and 2, NCHH), 3.46 (rotamer A, 1H, q, J 8, MeCHHN), 3.40 (rotamer B, 1H, q, J 7, MeCHHN), 3.06 (rotamer A, 1.5H, s, MeN), 3.03-2.95 [2.5H, m, NCHCH2CHH and rotamer B, Me, incl. at 2.98 (rotamer B, 1.5H, s, MeN)], 2.83-2.75 (1H, m, NCHCH2CHH), 2.48-2.39 (1H, m, NCHCHH), 2.25 (1H, t, J 2, ≡CH), 1.92-1.83 (1H, m, NCHCHH), 1.23 (rotamer A, 1.5H, t, J 7, MeN) and 1.18 (rotamer B, 1.5H, t, J 7, MeN). Analysis of this material by chiral LC indicated it to be 62% e.e.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][N:15]1[C:19]([CH2:20][OH:21])=[CH:18][C:17]([C:22]([F:25])([F:24])[F:23])=[N:16]1.[CH2:26]([O:28][C:29](=[O:41])[CH2:30][C:31]1[C:35]2[CH:36]=[CH:37][C:38](O)=[CH:39][C:34]=2[S:33][CH:32]=1)[CH3:27].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:26]([O:28][C:29](=[O:41])[CH2:30][C:31]1[C:35]2[CH:36]=[CH:37][C:38]([O:21][CH2:20][C:19]3[N:15]([CH3:14])[N:16]=[C:17]([C:22]([F:23])([F:24])[F:25])[CH:18]=3)=[CH:39][C:34]=2[S:33][CH:32]=1)[CH3:27]
Reactant: Cn1nc(C(F)(F)F)cc1CO
Reactant: CCOC(=O)Cc1csc2cc(O)ccc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc2cc(OCc3cc(C(F)(F)F)nn3C)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a mixture of tri-n-butylphosphine (0.165 mL), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (110 mg), ethyl(6-hydroxy-1-benzothiophen-3-yl)acetate (120 mg), and THF (5.0 mL) was added ADDP (167 mg) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) and then silica gel column chromatography (EtOAc/hexane) to give the title compound (173 mg). The solid was crystallized from EtOH-hexane to give the title compound.
Reaction SMILES: [C:1]([C@H:5]1[C:32](=[O:33])[N:31]2[CH2:34][C@@H:28]([CH2:29][C@H:30]2[C:35]([O:37][CH3:38])=[O:36])[O:27][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([OH:26])=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:39][C@H:9]2[O:8][C:7](=[O:40])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][N:42]1[CH2:47][CH2:46][CH:45](O)[CH2:44][CH2:43]1>>[C:1]([C@H:5]1[C:32](=[O:33])[N:31]2[CH2:34][C@@H:28]([CH2:29][C@H:30]2[C:35]([O:37][CH3:38])=[O:36])[O:27][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([O:26][CH:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:39][C@H:9]2[O:8][C:7](=[O:40])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Reactant: CN1CCC(O)CC1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCN(C)CC1)O2
Temperature: 40 °C

Procedure:
Methyl (1aR,55,8S,10R,22aR)-5-tert-butyl-17-hydroxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-8-carboxylate synthesized in example 113, step 5 was reacted with 1-methylpiperidin-4-ol using the procedure described for Example 137 (heating was required: 40° C. for 18 hours). LRMS (ES+) m/z 651.55 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:9]=1[C:10](O)=[O:11].[OH-].[K+]>C1COCC1.O>[OH:11][CH2:10][C:9]1[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:8]=1[NH2:7]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N)c(CO)c1

Procedure:
1.3 l of a 1.3 molar lithium aluminium hydride solution in THF are added dropwise under reflux to a solution of 100 g (0.66 mol) of 2-amino-5-methylbenzoic acid in 400 ml of anhydrous tetrahydrofuran. After addition is complete, the mixture is additionally heated under reflux for 1.5 h and hydrolysed at this temperature using a solution of 36 g of potassium hydroxide in 145 ml of water. After boiling under reflux for a further 15 min, the hydroxide precipitate is filtered off while hot, the precipitate is washed with ethyl acetate, the organic solution is concentrated in vacuo, the residue is dissolved in ethyl acetate and the solution is washed with dilute sodium hydroxide solution and water. After drying with sodium sulphate and concentrating the solution, the residue is recrystallised from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1.C1(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)C=CC=CC=1.C12CCCCC1CCCNN=2.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:25]=[N+:26]=[N-:27])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ncccc1CO
Agent: C1CCC2CCCNN=C2C1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ncccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.4 g of 2-methoxy-3-hydroxymethylpyridine was dissolved in 100 ml toluene, and 13.8 ml diphenyl phosphoryl azide and 9.5 ml diazabicyclo[5.4.0]undecene were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction product which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 9.5 g of [(2-methoxy-3-pyridyl)methyl]azide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][CH:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2=O.C(=O)([O-])[O-].[K+].[K+].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:5]1[C:4]2[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C1C=Nc2cc(F)c(F)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cnc2cc(F)c(F)cc2c1Cl
Temperature: 95 °C
Yield: 84.7 %

Procedure:
A suspension of 58.3 g of ethyl 6,7-difluoro-4-oxoquinoline-3-carboxylate in 490 g of phosphorus oxychloride was heated at 95° C. for 5 hours with stirring. After evaporation to dryness under reduced pressure (5.2 kPa), the viscous residue obtained was supplemented with 500 cm3 of ice-cold water and decomposed by slow addition of a saturated aqueous potassium carbonate solution up to pH 8. The insoluble material formed was extracted twice with 400 cm3 of dichloromethane. The organic extracts obtained were dried over sodium sulphate in the presence of animal charcoal, filtered, and concentrated under reduced pressure (5.2 kPa). The residue obtained was recrystallized from 800 cm3 of hexane. 53 g of ethyl 4-chloro-6,7-difluoroquinoline-3-carboxylate was obtained in the form of white crystals, which melted at 111° C.