Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[C:25]([Cl:26])=[C:24]([OH:27])[CH:23]=[CH:22][C:19]=1[CH:20]=O>>[Cl:17][C:18]1[C:25]([Cl:26])=[C:24]([OH:27])[CH:23]=[CH:22][C:19]=1[CH:20]=[CH:15][C:14]([C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: CSc1ccc(-c2ccc(C(C)=O)s2)cc1
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Product: CSc1ccc(-c2ccc(C(=O)C=Cc3ccc(O)c(Cl)c3Cl)s2)cc1

Procedure:
3-(2,3-Dichloro-4-hydroxyphenyl)-1-(5-(4-(methylthio)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(methylthio)phenyl)thien-2-yl)ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is used “as is” for carrying out the next stage.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH:5]([N:27]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH3:28])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH2:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)[CH2:14][C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)=[CH:8][CH:7]=1)C>Cl>[CH2:37]([N:33]([CH2:34][CH2:35][CH3:36])[CH2:32][CH2:31][CH2:30][CH2:29][N:27]([CH:5]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH2:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)[CH2:14][C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)=[CH:8][CH:7]=1)[C:4]([OH:40])=[O:3])[CH3:28])[CH2:38][CH3:39]
Reactant: CCCN(CCC)CCCCN(C)C(C(=O)OCC)c1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Agent: Cl
Product: CCCN(CCC)CCCCN(C)C(C(=O)O)c1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 100 °C
Yield: 123.9 %

Procedure:
The compound (5.1 mg) obtained in Example 100-2 was dissolved in concentrated hydrochloric acid (204 μl) and the whole was refluxed at 100° C. for 20 hours. After completion of the reaction, the solvent was distilled off, thereby obtaining the subject compound (6.0 mg) as a white solid.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:2].Cl.[H][H]>C(O)C.[Pt](=O)=O>[NH2:2][CH2:1][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2n1CC#N
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2n1CCN

Procedure:
A suspension of ethyl 1-cyanomethyl-3-phenyl-5-chloroindole-2-carboxylate (12 grams, 0.035 mole), and 0.15 grams of platinum dioxide in 200 ml absolute ethanol containing 45 ml of concentrated hydrochloric acid is shaken with hydrogen at 45 psi and 45° C, in a standard Parr apparatus. Hydrogenation is stopped after 5.5 lbs. of pressure drop is observed. After removal of catalyst by filtration the filtrate is taken to dryness under reduced pressure. The solid is stirred with water and refiltered and dried. This affords 13 grams of the hydrochloride, m.p. 196°-98° C. A sample is crystallized from ethanol, washed with acetone and dried. This material melts at 205°-206° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1cccc(F)c1
Product: O=Cc1ccc(Oc2cccc(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3-fluorophenol.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[O:19]=[C:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]=O)=[CH:28][C:23]=2[CH2:22][O:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH2:30][CH2:29][C:27]3[CH:26]=[CH:25][C:24]4[C:20](=[O:19])[O:21][CH2:22][C:23]=4[CH:28]=3)[CH2:17][CH2:18]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: CSc1cc(CCN2CCNCC2)ccc1C#N
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1cc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(methylthio)-4-(2-piperazin-1-ylethyl)benzonitrile (0.69 mmol) in 20 mL of DCM was added (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (180 mg, 1.03 mmol) and NaBH(OAc)3 (580 mg, 2.8 mmol), and the mixture was stirred at room temperature overnight. The reaction was diluted with DCM, and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give 2-(methylthio)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.82 (d, J=8.6 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.33˜7.37 (m, 2H), 7.16 (s, 1H), 7.02˜7.05 (m, 1H), 5.27 (s, 2H), 2.49˜3.01 (m, 19H). (0.55 μM)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([F:25])[CH:3]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNC1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C(C)=O)C4=O)cc3F)CC2)c(C)c1
Yield: 46.9 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (500 mg) described in Preparation Example 211 and 1-acetylimidazolidin-2-one (236 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (262 mg) was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.O1CCCC1.[H-].[Na+].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>O.CN(C)C=O>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:23][CH:22]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: Nc1ncccc1-c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncccc1-c1cnn(Cc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.3 %

Procedure:
To a mixture of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (150 mg, 0.94 mmol) described in Manufacturing Example 32-1-4 and tetrahydrofuran (2 mL) was added sodium hydride (12 mg, 0.24 mmol, 50% in oil) at 0° C., and then N,N-dimethylformamide (2 mL) was added. The reaction mixture was stirred for 10 minutes at room temperature, after which 4-bromobenzyl bromide (260 mg, 1.0 mmol) was added at 0° C. to this mixture, which was stirred for 1 hour at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:1) to obtain the title compound (270 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[C:4]([F:18])[CH:3]=1.[CH3:19][C:20]([O:22][CH2:23][C@H:24]1[O:29][C@H:28](Br)[C@H:27]([O:31][C:32]([CH3:34])=[O:33])[C@@H:26]([O:35][C:36]([CH3:38])=[O:37])[C@H:25]1[O:39][C:40]([CH3:42])=[O:41])=[O:21].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:32]([O:31][C@@H:27]1[C@@H:26]([O:35][C:36](=[O:37])[CH3:38])[C@@H:25]([O:39][C:40](=[O:41])[CH3:42])[C@@H:24]([CH2:23][O:22][C:20](=[O:21])[CH3:19])[O:29][C@H:28]1[O:17][C:10]1[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:18])=[C:13]([CH:14]([CH3:16])[CH3:15])[NH:12][N:11]=1)(=[O:33])[CH3:34]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(Br)cc1F
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2F)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 12 using 4-[(4-bromo-2-fluorophenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[O:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:25][CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)[C:10]=2[N:11]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: NC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc2ncnc(NC3CCOCC3)c2n1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.05 g, 0.250 mmol), tetrahydro-2H-pyran-4-amine (0.029 ml, 0.275 mmol), PdCl2(dppf)-CH2Cl2Adduct (2.041 mg, 2.500 μmol) and sodium tert-butoxide (0.048 g, 0.500 mmol) in dioxane (1.250 ml) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=2:1) to give 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine (0.027 g, 41%) as a yellow solid.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16]C[C:14]2=[O:20])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(=O)NCCCC1>>[C:1]1([C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][C:14]2=[O:20])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCCCN1C(=O)c1cccc2ccccc12
Agent: O=C1CCCCN1
Product: O=C1CCCCN1C(=O)c1cccc2ccccc12

Procedure:
Synthesized as for N-(1-naphthoyl)caprolactam (Example XVII) using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: FC1C=C(F)C=CC=1CO[C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:8](=[O:20])[CH:7]=1.[I:26]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>CC#N>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:9]1[CH:10]=[CH:11][CH:6]=[C:7]([I:26])[C:8]1=[O:20]
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1cc(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Agent: O=C(O)C(Cl)Cl
Solvent: CC#N
Product: O=c1c(I)cccn1Cc1cccc(F)c1
Temperature: 60 °C
Yield: 106 %

Procedure:
To a mixture of 4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one (0.15 g, 0.43 mmol) and N-iodosuccinimide (0.10 g, 0.46 mmol) in CH3CN (3 mL) was added dichloroacetic acid (13 mg, 0.10 mmol), and the reaction mixture was heated to 60° C. for 4 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The organic solution was washed with a saturated solution of NaHCO3 and then brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 90:10 methylene chloride/hexanes to 99:1 methylene chloride/methanol) provided 4-(2,4-difluorobenzyloxy)-[(3-fluorobenzyl)-3-iodo-1H-pyridin-2-one as a white solid (0.15 g, 77%): mp 164-167° C.; 1H NMR (300 MHz, CDCl3) δ 7.65-7.55 (m, 1H), 7.35-7.26 (m, 2H), 7.15-6.80 (m, 5H), 6.05 (d, J=6 Hz, 1H), 5.22 (s, 2H), 5.16 (s, 2H) ES HRMS m/z 472.0033 (M+H C19H14F31NO2 requires 472.0018).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:47]=[CH:46][C:36]([O:37][C:38]3[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=3[C:40]#[N:41])=[CH:35][CH:34]=2)O1.COCCOC.O.C(=O)([O-])[O-].[Na+].[Na+]>O.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:33]3[CH:47]=[CH:46][C:36]([O:37][C:38]4[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=4[C:40]#[N:41])=[CH:35][CH:34]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3C#N)cc2)OC1(C)C
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: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5C#N)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 85 °C
Yield: 67.8 %

Procedure:
A mixture of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.29 g, 5.19 mmol, 1 equiv), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]benzonitrile (2.0 g, 6.2 mmol, 1.2 equiv), tetrakis(triphenylphosphine)palladium (0.329 g, 0.311 mmol, 0.06 equiv), DME (21 mL), and sodium carbonate monohydrate (1.54 g, 12.5 mmol, 2.4 equiv) in water (16 mL) was heated at 85° C. for 60 h. Additional tetrakis(triphenylphosphine)palladium (0.100 g, 0.02 equiv) was added and the reaction mixture was heated at 85° C. for 6.5 h. The reaction mixture was allowed to cool to ambient temperature and was partitioned between saturated aqueous sodium bicarbonate solution (25 mL) and EtOAc (25 mL). The organic extract was dried over MgSO4, filtered, and concentrated. The residue was triturated from Et2O and purified by column chromatography on silica gel (elution with 1 L of 5% MeOH/CH2Cl2, 1L of 10% MeOH/CH2Cl2, 1 L of 20% MeOH/CH2Cl2, and 1 L of 25% MeOH/CH2Cl2) to give cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile as a pale yellow solid (1.79 g, 3.52 mmol): 1H NMR (d6 DMSO, 400 MHz): δH 8.24 (1H, s), 7.94 (1H, d, J=7.7 Hz), 7.68-7.73 (3H, m), 7.31-7.34 (3H, m), 7.18 (1H, d, J=8.5 Hz), 4.78-4.83 (1H, m), 2.21-2.51 (11H, m), 2.19 (3H, s), 2.05-2.08 (2H, m), 1.56-1.71 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.16 min. MS: MH+ 509.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([F:11])=[C:6]([CH:10]=1)/[CH:7]=[N:8]/O>C(OC(=O)C)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7]#[N:8]
Reactant: Cc1cc(Br)cc(/C=N/O)c1F
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1cc(Br)cc(C#N)c1F

Procedure:
A stirred solution of (E)-5-bromo-2-fluoro-3-methylbenzaldehyde oxime (0.5 g, 2.2 mmol) in acetic anhydride (5.0 mL) was heated to reflux for 18 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound as a light brown gummy material (0.4 g, crude): ESIMS m/z 213.82 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][N:21]=3)[C:7]=2[CH:27]=1)#[N:2].[Cl:28][CH2:29][C:30]#[C:31][CH2:32]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][O:13][CH3:14])([CH2:15][O:16][CH3:17])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:32][C:31]#[C:30][CH2:29][Cl:28])[N:21]=3)[C:7]=2[CH:27]=1)#[N:2]
Reactant: ClCC#CCCl
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)[nH]n2)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)n(CC#CCCl)n2)[C@@H]1O
Yield: 24.8 %

Procedure:
(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (556 mg, 1.5 mmol) obtained in Example 8 and 1,4-dichloro-2-butyne (2.9 ml, 30 mmol) were dissolved in dimethylformamide (10 ml). Potassium carbonate (413 mg) was added and the mixture was reacted at 120° C. overnight. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The residue obtained was purified by silica gel column chromatography (methanol:chloroform=1:30) to give 171 mg of crude (3S,4R)-6-cyano-4-[(1-(4-chloro-2-butyn-1-yl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino]-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol. The compound was dissolved in dimethylformamide (3 ml), added with diethylamine and stirred at 70° C. for 2.5 hours. Water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 71 mg of the title compound (38%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[Mg].C1O[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=O)[O:17]C1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:21]2[CH2:22][CH2:23][C:18](=[O:17])[CH2:19][CH2:20]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Reactant: O=C1CCCCC12OCCO2
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C1CCC(c2ccc(OC(F)(F)F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To Grignard reagent prepared from 3-fluoro-4-trifluoromethoxy bromobenzene 70.0 g (270 mmol) and magnesium in dried THF 300 ml at room temperature, a THF (200 ml) solution of cyclohexanedione monoethyleneketal 42.1 g (270 mmol) was added dropwise at room temperature, and the mixture was stirred for 3 hours at room temperature. The reactant was added to one liter of 6N-hydrochloric acid, and the product was extracted with diethylether. The extract was washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue, para-toluene sulfonic acid 5 g and toluene 500 ml were added. The mixture was refluxed with heating for 3 hours while removing water formed with Dien-Stark. The reactant was washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=4/1). Such obtained purified material was hydrogenated in the presence of 5% palladium carbon 5 g as a catalyst in ethanol 300 ml. The catalyst was filtered off, the solvent was distilled off under reduced pressure, formic acid 20 g and toluene 200 ml were added to the residue, and the mixture was refluxed for 3 hours. After cooling, water 300 ml was added to the reactant, and the organic layer was fractionated, washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1) to obtain 4-(3-fluoro-4-trifluoromethoxyphenyl)cyclohexanone 22.0 g (84.5 mmol). The yield was 31.3% from 3-fluoro-4-trifluoromethoxybromobenzene.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[S:6](=[O:8])(=[O:7])[CH:5]2[CH2:9][C:10](=[O:11])[N:4]2[CH:3]1[C:12]([O-:14])=[O:13].[Na+].O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[S:6](=[O:7])(=[O:8])[C@@H:5]2[CH2:9][C:10](=[O:11])[N:4]2[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: CC1(C)C(C(=O)[O-])N2C(=O)CC2S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2.55 g. of sodium penicillanate 1,1-dioxide in 20 ml. of water was added 3.80 g. of tetrabutylammonium bisulfate. Stirring was continued for 5 minutes and then 20 ml. of chloroform was added. The pH was adjusted to 6.8 with saturated aqueous sodium bicarbonate and then the aqueous layer was saturated with sodium sulfate. The layers were separated and the aqueous layer was extracted with chloroform. The combined chloroform solutions were dried using sodium sulfate and then evaporated in vacuo to give the tetrabutylammonium salt of penicillanic acid 1,1-dioxide.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.S(Cl)(Cl)=O.[NH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22]>C(Cl)Cl.CCOCC>[OH:22][CH2:21][C:20]([NH:19][C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:14])[F:13])=[CH:12][CH:11]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
To a 100 ml round bottom flask was loaded 4-(trifluoromethoxy)benzoic acid (4.85 g, 23.5 mmol). Thionyl chloride (5.15 ml, 70.6 mmol) was added at 0° C. The reaction mixture was allowed to warm up to room temperature and then heated at 80° C. for 1 hour. After cooling down to room temperature, the volatiles were removed. The residue was diluted with 50 ml methylene chloride, and 2-amino-2-methylpropan-1-ol (7.34 g, 82 mmol) was added at 0° C. The reaction mixture was allowed to warm up to room temperature. It was diluted with 150 ml ether, washed sequentially with 100 ml 1N HCl, 100 ml 5% KOH and 50 ml brine. The organics were dried over sodium sulfate, filtered and concentrated to give 4.2 g desired product. It was used for the next step directly without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.S(Cl)(Cl)=O.C(N(CC)CC)C.[NH2:27][C:28]1[N:33]=[C:32]([C:34]2[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=2)[C:37]([O:39]C(C)(C)C)=[O:38])[C:31]([CH3:47])=[CH:30][CH:29]=1.FC(F)(F)C(O)=O>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:27][C:28]4[N:33]=[C:32]([C:34]5[CH:35]=[C:36]([CH:44]=[CH:45][CH:46]=5)[C:37]([OH:39])=[O:38])[C:31]([CH3:47])=[CH:30][CH:29]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)CCO3)CC1
Reactant: Cc1ccc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: O=S(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1-c1cccc(C(=O)O)c1
Reaction time: 0.5 h

Procedure:
1-(2,3-Dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (24.0 mg, 0.118 mmol) was placed in an oven-dried flask which was allowed to cool under nitrogen. Thionyl chloride (0.3 mL) and N,N-dimethylformamide (0.03 mL) were added and the solution was allowed to stir for 30 minutes. The excess thionyl chloride was removed under vacuum and the resulting oil was re-dissolved in dichloromethane containing triethylamine (0.0495 mL, 0.353 mmol). tert-Butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate (33.4 mg, 0.118 mmol) was added and the reaction mixture was allowed to stir for 3 hours. Trifluoroacetic acid (1 mL) was added and the solution was allowed to stir for an additional 3 hours. The mixture was evaporated to dryness, dissolved in a minimum of N,N-dimethylformamide and then purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 3-(6-(1-(2,3-dihydrobenzofuran-5-yl)cyclo-propanecarboxamido)-3-methylpyridin-2-yl)benzoic acid. ESI-MS m/z calc. 414.2, found; 415.0 (M+1)+ Retention time 1.64 minutes.