Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][O-:23].[Na+]>CO.C(OC(=O)C)C>[CH3:22][O:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)c2nc(OC)nc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.167 mmol) in 2 ml methanol was added sodium methoxide (500 μl, 25% by wt. in methanol). The solution was stirred at 80° C. for 1 h, and it was diluted with 50 ml ethylacetate. The solution was washed with water, dried and concentrated. The product was purified using small silica column and isolated as off white solid (22 mg, 54%). 1H NMR (CDCl3): 7.89 (d, J=8.4 Hz, 1H), 7.53 (ddd, J=8.7, 5.4 and 2.4 Hz, 1H), 7.19-7.14 (m, 2H), 6.99-6.93 (m, 2H), 6.90-6.85 (m, 2H), 4.14 (s, 3H), 3.86 (s, 3H), 3.64 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=CC=[CH:16][C:15]=2F)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.[C:39](O)([C:41]([F:44])(F)F)=O>C(Cl)Cl>[F:44][C:41]1[CH:39]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N:31]5[CH:35]=[CH:34][N:33]=[N:32]5)[CH:26]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K81) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (29 mg).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.O.[CH3:26][O:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:33]4[C:28]([O:27][CH3:26])=[N:29][CH:30]=[CH:31][CH:32]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: COc1ncccc1B(O)O
Solvent: O
Product: COc1ncccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 12 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-methoxypyridine-3-boronic acid hydrate (available from Combi-Blocks Inc.; 68 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(2-methoxy-pyridin-3-yl)-benzoic acid (11 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ 12.94 (br s, 1H), 8.47 (s, 1H), 8.41 (d, J=1.9 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.18 (dd, J=5.0, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.1 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.70 (dd, J=7.3, 1.8 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.10 (dd, J=7.2, 5.1 Hz, 1H), 3.78 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:2]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:29][C:30]1[CH:31]=[C:32]([C:36]2[CH:37]=[C:38]([N:42]3[C:47](=[O:48])[C:46]([CH2:49][C:50]4[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=4)=[N:45][C:44]4[CH:56]=[CH:57][CH:58]=[N:59][C:43]3=4)[CH:39]=[CH:40][CH:41]=2)[CH:33]=[CH:34][CH:35]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([NH:29][C:30]3[CH:31]=[C:32]([C:36]4[CH:37]=[C:38]([N:42]5[C:47](=[O:48])[C:46]([CH2:49][C:50]6[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=6)=[N:45][C:44]6[CH:56]=[CH:57][CH:58]=[N:59][C:43]5=6)[CH:39]=[CH:40][CH:41]=4)[CH:33]=[CH:34][CH:35]=3)=[O:14])[N:11]=2)[CH:2]=1
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Reactant: Nc1cccc(-c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)c1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)c1)c1csc(-c2cccnc2)n1
Reaction time: 2 h
Yield: 32.8 %

Procedure:
To a stirred suspension of 2-(3-pyridyl)thiazole-4-carboxylic acid (0.56 g) and triethylamine (0.55 g) in methylene chloride (25 ml) was added pivaloyl chloride (0.33 g) in methylene chloride (5 ml) and the mixture was stirred for 2 hours. After the reaction mixture was cleared, 4-[3-(3-aminophenyl)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.0 g) was added thereto and the mixture was stirred under reflux for 2 hours. The reaction mixture was washed with sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated. Crude residue was chromatographed on silica gel (70 g, chloroform-methanol 100:1 as eluent) to give 4-[3-[3-[2-(3-pyridyl)thiazol-4-ylcarbonylamino]phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine as colorless crystals (0.48 g).
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([Mg]Br)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[Cl:1][CH:2]([CH3:6])[C:3](=[O:4])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: CC(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(Cl)C(=O)CCc1ccccc1

Procedure:
In two self assembled multi-injection microreactors having 2 to 6 reaction regions assembled from separate injection points, mixing zones and reaction zones (each reaction comprising one injection point, one mixing zone and one reaction zone), 2-chloro propionic chloride (13.5 wt %) in tetrahydrofuran (THF, 86.5 wt %) as flow A and phenethylmagnesium bromide (1 eq., 10 wt %) in THF (1 eq., 90 wt %) as flow B were reacted. The microreactors were placed in a bath at 20° C. Temperature adjustment of the microreactors depended on heat exchange on the outer surface of the single parts of the modules. The microreactor of examples 1.1 to 1.5 comprised reaction zones of about 0.2 mL internal volume allowing almost no cooling between the injection points. The microreactor of examples 1.6 to 1.10 comprised reaction zones of about 2.0 mL internal volume allowing at least a low effective cooling (LEC) between the injection points. Flow rates of 20 and 40 g/min were performed. The 2nd reactant was fed to the 1st reactant in equimolar ratio. The yields of the product 4-chloro-1-phenyl-pentan-3-one collected after the respective reaction zone are shown in table 1 and 2 in relation to feed rate and cooling conditions.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[NH:8][C:9](=[O:23])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:11]=2[CH3:12])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:39][C:40]1[O:44][C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH:42][CH:41]=1>CN(C)C=O.CO>[C:28]([C:27]1[CH:26]=[CH:25][C:24]([CH:7]2[N:8]([CH2:39][C:40]3[O:44][C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH:42][CH:41]=3)[C:9](=[O:23])[N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[C:11]([CH3:12])=[C:6]2[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:31][CH:30]=1)#[N:29]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)C3CC3)C2c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 4-{5-(cyclopropylcarbonyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 22) (150 mg, 0.35 mmol) and potassium carbonate (98 mg, 0.71 mmol) in dimethylformamide (3 ml) is added methyl 5-(chloromethyl)-2-furoate (92 mg, 0.53 mmol). The suspension is stirred at room temperature overnight (16 h), then additional methyl 5-(chloromethyl)-2-furoate (6.1 mg, 0.35 mmol) and potassium carbonate (49 mg, 0.35 mmol) are added, and the suspension is stirred an additional 72 hours. The reaction mixture is diluted with methanol (5 ml) and purified directly by preparative HPLC (RP 18 column; eluent: acetonitrile/water 10:90→90:10). The title compound is isolated as a brownish amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>COCCOC.C(=O)(O)[O-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:24]=[O:25])[CH:31]=3)[S:22][C:13]=12
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4cccc(C=O)c4)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), 3-formylphenylboronic acid (330 mg, 2.2 mmol) and 65 mg of tetrakis(triphenylphosphine)palladium(0) in 70 mL of ethylene glycol dimethyl ether and 40 mL of saturated aqueous sodium bicarbonate is heated at reflux for 1.5 hours. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 hexane:ethyl acetate. The fractions containing product are combined and concentrated in vacuo. The residue is recrystallized from ethyl acetate to provide 62 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(3-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 262-263° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.39 (s, 1H), 7.69-7.82 (m, 2H), 7.98 (s, 1H), 8.03-8.14 (m, 2H), 8.23 (s, 1H), 8.64 (s, 1H), 9.80 (s, 1H), 10.08 (s, 1H); MS 452.0, 453.9 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[C:19]([CH3:20])=[C:18]([CH2:21]Cl)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH:27]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[C:19]([CH3:20])=[C:18]([CH2:21][N:29]4[CH2:30][CH2:31][CH2:32][C@@H:28]4[C@@H:27]([OH:26])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)C1CCCN1
Reactant: Cc1c(CCl)sc2c1c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Product: Cc1c(CN2CCC[C@@H]2[C@@H](O)c2ccccc2)sc2c1c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C

Procedure:
Analogous to the procedures described in Example 2, N-(4-chlorobenzyl)-2-(chloromethyl)-3,7-dimethyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 30) is treated with 2-(hydroxy(phenyl)methyl)pyrrolidine (Preparations 2) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O:19][C:20]1[C:21](=[O:36])[O:22][CH:23]([CH2:33][CH2:34]O)[C:24]=1[O:25]CC1C=CC=CC=1)C1C=CC=CC=1>>[OH:19][C:20]1[C:21](=[O:36])[O:22][CH:23]([CH2:33][CH2:34][O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[C:24]=1[OH:25]
Reactant: Oc1ccc2ccccc2n1
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Product: O=C1OC(CCOc2ccc3ccccc3n2)C(O)=C1O
Yield: 17.4 %

Procedure:
Mitsunoble coupling of 0.17 g (1.2 mmol) of 2-hydroxyquinoline with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 50 mg (17% yield) of 3,4-dihydroxy-5-[2-(quinoline-2-oxy)ethyl]-2(5H)-furanone as a fluffy white solid after recrystallization from ether and hexanes: 1H NMR (acetone-d6) δ 8.25-8.17 (m, 1H); 7.88-7.38 (m, 4H), 7.01-6.93 (m, 1H); 4.97 (dd, J=4.9, 8.7 Hz, 1H), 4.81-4.55 (m, 2H); 2.62-2.45 (m, 1H), 2.20-1.95 (m, 1H). Anal Calcd for C15H13NO5 +0.5 H2O: C, 60.81; H, 5.10; N, 4.72. Found: C, 61.04; H, 5.04; N, 4.32.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:13]1([C:2]2[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N1CCNCC1
Yield: 59.8 %

Procedure:
68 g (0.3 mol) of 2,4,5-Trichloronitrobenzene and 77.4 g (0.9 mol) of piperazine were stirred in 100 ml of a dimethylformamide in the presence of 31 g of anhydrous potassium carbonate for one hour at a room temperature of 25° C. to 40° C. and then for one hour at 70° to 80° C. to obtain 49.5 g of 2-piperazino-4,5-dichloronitrobenzene. This compound was reacted with 2-ethylhexanoyl chloride in a solvent of acetonitrile in the presence of pyridine to obtain 2-[N-(2-hexanoyl)piperazino]-4,5-dichloronitrobenzene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(C(C)(C)C)cc2)CC1
Yield: 34 %

Procedure:
To 1-bromo-4-tert-butyl-benzene (639 mg; 3.0 mmol), [1,4]diazepane-1-carboxylic acid tert-butyl ester (500 mg; 2.5 mmol), tris-(dibenzylidenacetone)-dipalladium (0) (45 mg; 0.049 mmol), sodium tert-butoxide (360 mg; 3.75 mmol) and (±)-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (92 mg; 0.147 mmol) is added toluene (5 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 2 hours at 100° C. Further tris-(dibenzylidenacetone)-dipalladium (0) (45 mg; 0.049 mmol) and (±)-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (92 mg; 0.147 mmol) are added and microwave irradiation at 120° C. is continued for another hour. The reaction mixture is then diluted with ethyl acetate and filtered. The filtrate is concentrated under high vacuum and the obtained residue is purified by column chromatography on silica gel (hexanes/dichloromethane 50:50 v/v to 100) to afford the desired compound (284 mg; 0.85 mmol).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH2:24][NH2:25]>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH:25][CH2:24][CH:23]([O:26][CH3:27])[O:22][CH3:21])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(CN)OC
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CNC(=O)c1ccc(OC(C)=O)cc1)OC
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of 4-(chlorocarbonyl)phenyl acetate (110 g, 553.87 mmol) in CH2Cl2 (500 mL) was cooled in an ice bath and treated with triethylamine (115 mL, 830 mmol, 1.5 equiv.) and 2,2-dimethoxyethanamine (63.36 mL, 581.56 mmol, 1.05 equiv.). The reaction mixture was allowed to warm to ambient temperature and the reaction was followed by TLC (CH2Cl2). The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and filtered. The filtrate was washed with water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with water, dilute mono-potassium phosphate (pH=5.4, pH of solution about 7), water, and brine, dried, and concentrated to give 120 g (81% th.; 109% pract.) of 4-(2,2-dimethoxyethylcarbamoyl)phenyl acetate as a light brown waxy solid with no further purification; 1H NMR (CDCl3) δ 7.79 (d, 2H), 7.15 (d, 2H), 6.32 (br. t, 1H), 4.47 (t, 1H), 3.58 (d, 2H), 3.41 (s, 6H), 2.30 (s, 3H) ppm.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][OH:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:30]I.O>O1CCCC1>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][O:27][CH3:30])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: O=C(C=Cc1c(-c2ccccc2)nn2ccccc12)N1CCCCC1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-hydroxymethylpiperidine (trans isomer) (0.30 g) was added to a stirred solution of tetrahydrofuran (2 ml) and sodium hydride (62.8%, 0.04 g) with ice-cooling. After 30 minutes, a solution of methyl iodide (0.14 g) in tetrahydrofuran (2 ml) was added to that stirred solution at 0° C. The reaction mixture was stirred for 4 hours at room temperature, then poured into water (20 ml), extracted with chloroform (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-methoxymethylpiperidine (trans isomer) (0.30 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Li+]>O1CCCC1.O>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(Cc2noc(-c3cccc(C(F)(F)F)c3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cc2noc(-c3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 50 °C
Yield: 52 %

Procedure:
The compound (1.2 g) obtained in Example 201b was dissolved in tetrahydrofuran (32 mL) and water (8 mL), and lithium hydroxide (0.56 g) was added. The reaction mixture was heated at 40-60° C. for 48 hr, stirred and concentrated under reduced pressure. The residue was diluted with water and adjusted with 2.5N hydrochloric acid to pH 5-6. The resulting precipitate was collected by filtration and dried. The obtained solid was recrystallized from ethyl acetate to give the title compound (0.60 g) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]([O:25]C)=[O:24])[CH:17]=[CH:16]2)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+]>O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:17]=[CH:16]2)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cn1ccc2cc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(c1ccc2c(ccn2CC(=O)O)c1)S(C)(=O)=O
Yield: 90 %

Procedure:
To a solution of methyl 2-(5-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetate (520 mg, 1.360 mmol) in a 1:1 mixture of THF and water (20 ml), lithium hydroxide (326 mg, 13.60 mmol) was added, and the mixture was reacted for 2 hours at room temperature. The organic layer was evaporated and 1N HCl was added to the reaction mixture (pH 5); the resulting solid was filtered off affording 2-(5-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetic acid that was used in the next step without any additional purification (450 mg, 1.221 mmol, 90% yield). MS/ESI+ 369.2 [MH]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:23][C:24]1([NH2:28])[CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:26]4[CH2:27][C:24]([CH3:23])([NH2:28])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC1(N)CNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(N)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A mixture of 0.23 g (0.82 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 0.26 g (1.64 mmoles) of 3-methyl-3-aminoazetidine dihydrochloride and 0.5 ml of triethylamine is refluxed in 10 ml of pyridine for 2 hours. Filtering and washing with water and ethanol yield 0.250 g (87%) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-3-amino-1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid having a melting point and spectroscopic data identical to those of the derivative obtained by Method E.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11](OCC)=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:6]=1[C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:7]2[C:6]([C:23]#[C:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[N:9]([CH2:10][CH2:11][OH:12])[N:8]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cn1nc(-c2ccc(F)cc2)c(C#Cc2ccccc2)c1NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(=O)Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a solution of ethyl 2-(5-acetamido-3-(4-fluorophenyl)-4-(phenylethynyl)-1H-pyrazol-1-yl)acetate (1 g, 2.5 mmol) in ethanol (40 mL) and methanol (10 ml) was added sodium borohydride (466 mg, 12.3 mmol and the reaction stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 and washed with a dilute NH4Cl solution. The aqueous was extracted with CH2Cl2 and the combined organic extracts were dried over MgSO4, filtered and evaporated. The crude product was suspended in CH2Cl2 (20 ml), heated to reflux, allowed to cool and the product was filtered and dried in vacuo to give N-(3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide as a white solid (659 mg), which was used as such in the subsequent step.