Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](B(O)O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[O:1]1[CH2:2][CH2:3][O:4][C:5]2[CH:10]=[C:9]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[N:21][C:22]=4[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=3)[CH:8]=[CH:7][C:6]1=2
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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
Solvent: CCO
Product: CC(C)n1nc(-c2ccc3c(c2)OCCO3)c2c(N)ncnc21
Temperature: 80 °C
Yield: 15 %

Procedure:
A solution of 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (26 mg, 0.14 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA54 (6 mg, 15% yield). ESI-MS (M+H)+ m/z calcd 312.1, found 312.0.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Mg].[CH3:9][O:10][CH2:11][CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O>C(OCC)C>[CH3:9][O:10][CH2:11][CH2:12][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7]
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccsc1Br
Agent: [Mg]
Solvent: CCOCC
Product: COCCc1sccc1C
Temperature: 25 °C
Yield: 36.9 %

Procedure:
Some drops from a solution of 2-bromo-3-methylthiophene (1.5 g, 8.5 mmol) in dry diethyl ether was added to a suspension of magnesium (308 mg, 12.7 mmol, 1.5 equiv.) in dry diethyl ether until the Grignard reagent began to form and the mixture started to reflux. The remaining solution was added dropwise. A solution of toluene-4-sulfonic acid 2-methoxy-ethyl ester (2.9 g, 12.7 mmol, 1.5 equiv.) in dry diethyl ether was added dropwise at room temperature, and the mixture was refluxed for two hours. After cooling to room temperature, the mixture was quenched with saturated ammonium chloride solution and extracted with tert. butylmethyl ether. The combined organic extracts were washed with water, brine, dried over magnesiumsulfate-dihydrate, filtered and evaporated to give a yellow oil. After purification on silica gel, 490 mg of the title compound were obtained as a light yellow oil. GC-MS (EI): M=156
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[C:11]([Cl:19])[C:10]=1[F:20])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO>[C:1]([O:5][C:6](=[O:21])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:28])[C:13]=2[CH:12]=[C:11]([Cl:19])[C:10]=1[F:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2N
Yield: 95.3 %

Procedure:
To a stirred and ice cold solution of (3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (1.32 g, 4.01 mmol) and ammonium acetate (4.7 g, 61.0 mmol) in methanol (21 mL) was added sodium cyanoborohydride (504 mg, 8.02 mmol) under nitrogen. After 10 minutes of stirring at room temperature, the reaction mixture was heated at reflux for 4 hours. The solvent was removed under reduced pressure and to the residue was added saturated sodium bicarbonate solution (10 mL). The resulting solution was extracted with dichloromethane (25 mL×3). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford (5-amino-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (1.26 g, 98%), which is used in the next step without further purification.
Reaction SMILES: CN1CCOCC1.[F:8][C:9]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])=[C:25]([CH2:36][O:37][CH3:38])[CH:24]=3)[O:20][N:19]=2)[CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].Cl.[CH3:40][O:41][C:42](=[O:46])[CH2:43][NH:44][CH3:45].[N-]=C=O>C1COCC1.CN(C=O)C>[F:8][C:9]1[CH:17]=[C:16]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])=[C:25]([CH2:36][O:37][CH3:38])[CH:24]=3)[O:20][N:19]=2)[CH:15]=[CH:14][C:10]=1[C:11]([N:44]([CH3:45])[CH2:43][C:42]([O:41][CH3:40])=[O:46])=[O:12]
Reactant: CNCC(=O)OC
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)Cl)c(F)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Agent: [N-]=C=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCc1cc(-c2nc(-c3ccc(C(=O)N(C)CC(=O)OC)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of example 35 (2 170 mg; 5.2 mmol) in dry DCM (40 mL), oxalyl chloride (1 316 μl; 15.6 mmol) was added followed by dry DMF (40 μl). The reaction mixture was stirred at RT for 2 h and concentrated to afford 2-fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride as a white powder (2300 mg, 100%). In dry THF (1 mL) with a catalytic amount of DMF was swelled morpholinomethyl polystyrene high loading resin (NovaBiochem; 35.77 mg; 0.14 mmol), 3.9 mmol/g). 2-Fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride (25 mg; 0.06 mmol) was added followed by sarcosine methyl ester hydrochloride (15.98 mg; 0.11 mmol). The mixture was stirred overnight at rt. Isocyanate resin Si—NCO (Argonaut, 97 mg; 1.5 eq; 1.7 mmol/g) was added and the mixture stirred for 2 h. It was filtered through a SAX column (2 g) to obtain the title compound as a colorless oil. LC/MS (Method B): 504.2 (M+H)+ HPLC (Method A) Rt: 5.39 min (purity: 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:10]([CH:12]1[CH2:14][CH2:13]1)=O)=[CH:6][N:7](C)C)[CH3:2].Cl.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C(O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:10]([CH:12]3[CH2:14][CH2:13]3)=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:6]=[N:7]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C1CC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C1CC1

Procedure:
Ethyl-2-(cyclopropanecarbonyl)-3-dimethylamino-prop-2-enoate (Intermediate#32) (316 mg, 1.5 mmol) was dissolved in ethanol (5 mL). 4-bromophenylhydrazine hydrochloride (335 mg, 1.5 mmol) and DIPEA (264 μL, 1.5 mmol) were added and the mixture was heated to reflux for 2 h. The reaction mixture was cooled to ambient and evaporated under reduced pressure. The residue was dissolved in DCM (10 mL) washed with water and poured through a phase separating tube. The product was recovered from the filtrate by flash column chromatography (SiO2, elution gradient 0-25% EtOAc in isohexane). Pure fractions were combined and evaporated to give ethyl 1-(4-bromophenyl)-5-cyclopropyl-pyrazole-4-carboxylate as an oil that crystallised on standing. (343 mg, 87%)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[CH3:27])=[C:17]([F:28])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[C:7]=2[CH:6]=1)=[O:4]>C1COCC1.CO.[OH-].[Na+]>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[N:11]([CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH:10]=[N:9][C:8]=3[C:17]=2[F:28])=[C:21]([CH3:27])[CH:22]=1
Reactant: C=CCCCn1cnc2c(F)c(Nc3ccc(Br)cc3C)c(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCCCn1cnc2c(F)c(Nc3ccc(Br)cc3C)c(C(=O)O)cc21
Reaction time: 5 h
Yield: 100 %

Procedure:
6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylic acid methyl ester 9b is dissolved in 1:1 THF/MeOH (10 mL) and 1 N NaOH solution (2.3 mL) is added. After 5 hours, the organic solvents are removed under reduced pressure and the residue diluted with water and 100 mL 1:1 THF:ethyl acetate. The layers are separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to afford 0.39 g (100%) clean desired product as a light yellow solid.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13][CH2:14][CH2:15][NH3+:16].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:13][CH2:14][CH2:15][NH:16][CH2:22][C:18]1[O:17][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccco1
Reactant: [NH3+]CCSc1ccc2ccccc2c1Cl
Agent: [Cl-]
Product: Clc1c(SCCNCc2ccco2)ccc2ccccc12
Yield: 57 %

Procedure:
The reductive amination step of 2-[(1-chloronaphthalen-2-yl)sulfanyl]ethanaminium chloride with furan-2-carbaldehyde was performed as described for compound I to obtain 2-[(1 chloronaphthalen-2-yl)sulfanyl]-N-(furan-2-ylmethyl)ethanamine in 57% yield.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:16]1[CH:17]=[C:18]([NH:23][C:24](=[O:36])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=3)[CH:19]=[CH:20][C:21]=1[CH3:22])[N:9]=2)=[O:4].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(N(CC)CC)C>O1CCCC1>[C:34]([C:31]([C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([O:15][C:10]2[N:9]=[C:8]3[S:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[N:14][C:13]3=[CH:12][CH:11]=2)[CH:17]=1)=[O:36])([CH3:32])[CH3:33])#[N:35]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CCl)sc2n1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CN3CCOCC3)sc2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 42.3 %

Procedure:
To a solution of N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide (304 mg, 0.584 mmol) produced in Example C15(i) in tetrahydrofuran (5 mL) were added morpholine (78.8 μL, 0.901 mmol) and triethylamine (125 μL, 0.901 mmol), and the mixture was stirred at 60° C. for 4 hr. The title compound (141 mg, 55%) was obtained as white crystals by operation in the same manner as in Example C88. The present compound was recrystallized from ethyl acetate and tetrahydrofuran.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C=O>[CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1CC(OCc2ccccc2)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CC(OCc2ccccc2)C1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
(3-Benzyloxy-cyclobutyl)-methanol (1.46 g) in N,N-dimethylformamide was treated at 0° C. with imidazole (1.55 g) and tert-butyldimethylsilyl chloride (1.37 g) and allowed to warm to room temperature over 16 hours. The reaction mixture was extracted with ethyl acetate, the organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (0 to 1:9 by volume) to give the title compound (2.24 g).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH2:16][OH:17])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12])=[CH:5][N:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].O>ClCCl.CN(C)C1C=CN=CC=1>[C:31]([O:17][CH2:16][CH2:15][N:7]([C:6]1[C:2]([Cl:1])=[N:3][N:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1)[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CSCC(C)C(=O)N(CCO)c1cn(-c2cccnc2)nc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CSCC(C)C(=O)N(CCOC(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-(2-hydroxyethyl)-2-methyl-3-(methylthio)propanamide (0.045 g, 0.127 mmol) in dichloromethane (1.27 ml) was added N,N-dimethylpyridin-4-amine (0.023 g, 0.190 mmol) and triethylamine (0.019 g, 0.190 mmol) followed by acetyl chloride (0.015 g, 0.190 mmol). The reaction was stirred at room temperature overnight. Water was added and the mixture was extracted with dichloromethane. The combined organic phases were concentrated and chromatographed (0-100% ethyl acetate/hexanes) to give 2-(N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamido)ethyl acetate as a yellow oil (0.015 g, 0.034 mmol, 26.8%): IR (thin film) 1739, 1669 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=2.3 Hz, 1H), 8.64 (dd, J=4.7, 1.4 Hz, 1H), 8.15 (s, 1H), 8.04 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.47 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 4.50-3.40 (m, 4H), 2.84 (dd, J=12.7, 8.9 Hz, 1H), 2.78-2.63 (m, 1H), 2.46 (dd, J=12.7, 5.4 Hz, 1H), 2.03 (s, 3H), 2.01 (s, 3H), 1.16 (d, J=6.6 Hz, 3H); ESIMS m/z 398 ([M+H]+).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH3:13])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[S:24])=[CH:18][CH:17]=1>>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[S:24])=[CH:7][C:6]=1[O:12][CH3:13])=[O:2]
Reactant: COc1cc(N)ccc1NNC=O
Reactant: COc1ccc(N=C=S)cc1
Product: COc1ccc(NC(=S)Nc2ccc(NNC=O)c(OC)c2)cc1

Procedure:
Procedure (18.) was employed with 1-formyl-2-(4-amino-2-methoxyphenyl)hydrazine (1.2g, 0.006 mole) and 4-methoxyphenyl isothiocyanate (1.1 g, 0.0066 mole). Yield 1.6 g (70%), m.p. 160°-162° C.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:20]([C:23]1[S:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>C(N(CC)CC)C>[C:20]([C:23]1[S:27][C:26]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: CCOC(=O)CCCNc1ccc2ncc(Br)n2n1
Reactant: CC(=O)c1ccc(B(O)O)s1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1ccc2ncc(-c3ccc(C(C)=O)s3)n2n1
Yield: 74 %

Procedure:
The ethyl 4-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)butanoate was subjected to Suzuki coupling with (5-acetylthiophen-2-yl)boronic acid, using triethylamine as the base and the procedure described in example 5.6.19 to give 74% yield of the product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:14][C:13]=1[CH3:19]
Reactant: Cc1cc(O)ccc1N
Reactant: N#Cc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Oc2ccc(F)cc2C#N)ccc1N
Temperature: 25 °C
Yield: 98.6 %

Procedure:
In a 3 L, 4-necked flask that had been evacuated and back-filled with argon, 2,5-difluorobenzonitrile (295.3 ml, 812.0 mmol) and 4-amino-3-methylphenol (100.0 g, 812.0 mmol) were dissolved in dry DMSO (2.75 M) with rapid stirring at room temperature. The solution was evacuated/backfilled with argon (3×). Potassium carbonate (185.2 g, 1340 mmol) (−325 mesh) was added. The reaction mixture was evacuated/backfilled with argon (3×) and warmed to 80° C. (internal probe) for 16 hours. TLC indicated complete conversion. The reaction mixture was cooled to room temperature and poured slowly into 2 L of ice water with rapid stirring. The residue in the round bottom flask was taken up in water repeatedly and poured into the ice water until a total volume of 3 L was achieved and all solids were in the ice water. The suspension was stirred rapidly for 2 hours as it came to room temperature. The brown solids were collected by filtration, washed with water (3 L), air dried, dried with latex dam, and dried under high vacuum at 40° C. for 44 hours to provide 194 g (99%) of the desired product as a tan solid. MS (APCI+) m/z 243 (M+1) was detected. 1H NMR (400 MHz, CDCl3) δ 7.38 (m, 1H), 7.18 (m, 1H), 6.65-6.85 (m, 5H), 3.60 (br, 2H), 2.17 (s, 3H).
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=[O:2].[C:13]12(O)[CH2:21][CH:17]([C:18]1([CH3:20])[CH3:19])[CH2:16][CH2:15][C:14]2([OH:23])[CH3:22].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.C1COCC1>[OH:23][C:14]1([CH3:22])[C:15](=[O:2])[CH2:16][CH:17]2[CH2:21][CH:13]1[C:18]2([CH3:20])[CH3:19]
Reactant: CC1(O)CCC2CC1(O)C2(C)C
Reactant: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(O)C(=O)CC2CC1C2(C)C
Yield: 86 %

Procedure:
o-Iodoxybenzoic acid I (420 mg; 1.5 mmol) was added under stirring in one portion to a solution of pinanediol (170 mg; 1 mmol) in DMSO (3.4 ml) and THF (2.9 ml) at 0° C. After 3 h the reaction was poured in 20 ml of a solution of Na2CO3 (10%) and extracted with diethyl ether (3×10 ml). The combined organic layers were dried over sodium sulfate. The organic solvent was distilled under vacuum. The residue was purified by chromatography (SiO2, dichloromethane) to give after trituration with n-hexane, 145 mg (86%) of 2-hydroxy-pinanone, mp 30°-32° C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([OH:12])[C:4]=1[C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([OH:12])[C:4]=1[C:13](=[N:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:2]
Reactant: Nc1ccccc1
Reactant: N#Cc1c(C(=O)c2ccccc2)n(O)c2ccccc12
Solvent: Cc1ccccc1
Product: N#Cc1c(C(=Nc2ccccc2)c2ccccc2)n(O)c2ccccc12

Procedure:
A mixture of 3-cyano-2-benzoyl-1-hydroxy-indole (2.62 g, 10.0 mmole) and aniline (1.0 g, 10.8 mmole) were heated at reflux in toluene (50 ml) under a trap for 16 hours. Concentration in vacuo afforded a solid. Recrystallization from methylcyclohexane provided dark crystals, m.p. 188°-190° C. Analysis (dry 25° C.): Fd(calculated) N, 12.2 (12.4), C, 78.2 (78.3) H, 4.7 (4.5).
Reaction SMILES: O=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([OH:21])=O)[CH2:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[NH2:23][NH2:24]>C(O)C>[C:5]1([C:4]2[CH:3]=[C:2]3[C:12]4[C:13]([CH2:18][C:19](=[O:21])[N:24]3[N:23]=2)=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: O=C(O)Cc1ccccc1C(=O)CC(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: O=C1Cc2ccccc2-c2cc(-c3ccccc3)nn21
Yield: 81.5 %

Procedure:
To ethanol (10 ml), there were added 2-(1,3-dioxo-3-phenylpropyl) phenylacetic acid (1.42 g) and hydrazine hydrate (0.25 g), followed by heating under reflux for 2 hours. Thereafter, the reaction mixture was cooled to give 2-phenyl-5,6-dihydropyrazolo-[5,1-a]isoquinolin-5-one (1.06 g). Mp. 181°-183° C.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[NH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[NH2:26][C:27]1[CH:32]=[C:31]([C:3]2[C:2]([F:1])=[CH:10][CH:9]=[C:8]3[C:4]=2/[C:5](=[CH:12]/[C:13]2[NH:17][CH:16]=[N:15][C:14]=2[CH3:18])/[C:6](=[O:11])[NH:7]3)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(-c3cccc(N)c3)c21

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 3-aminobenzeneboronic acid (52.5 mg, 0.339 mmol) (Lancaster) in a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 4 days. The reaction mixture was concentrated and the crude material was purified by C18 reverse phase chromatography to give (Z)-4-(3-Aminophenyl)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 18 mg, 40%).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][N:3]=1.[NH2:15][CH2:16][C@@H:17]([OH:20])[CH2:18][OH:19]>C(O)(C)C>[C:9]([O:8][C:6]([C:5]1[CH:4]=[N:3][C:2]([NH:15][CH2:16][C@@H:17]([OH:20])[CH2:18][OH:19])=[CH:14][CH:13]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: NC[C@@H](O)CO
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)c1ccc(NC[C@@H](O)CO)nc1
Temperature: 100 °C

Procedure:
A mixture of t-butyl 6-chloronicotinate (4.69 g, 0.0220 mol) and (R)-3-amino-1,2-propanediol (5.00 g, 0.0549 mol) in isopropanol (20 ml) was heated at 100° C. overnight. Solvent was removed under vacuum, and the residue taken up in ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated to give nearly pure product as a yellow oil. Yield 5.90 g (99%). 1H NMR. MS: 269 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:12][O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.[CH3:29][N:30]1CCCC1=O>[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.O.O.O.[K+].[K+].[K+].[K+].[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:29]#[N:30])=[CH:17][CH:16]=2)[CH2:12][O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: Brc1ccc(C2COCCN(Cc3ccccc3)C2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Product: N#Cc1ccc(C2COCCN(Cc3ccccc3)C2)cc1
Temperature: 120 °C
Reaction time: 10 h
Yield: 79 %

Procedure:
A mixture of 4-benzyl-6-(4-bromo-phenyl)-[1,4]oxazepane (2.4 g, 6.9 mmol), potassium hexacyanoferrate(II) trihydrate (1.48 g, 3.5 mmol), palladium(II) acetate (1.6 mg, 0.007 mmol), diphenylphosphinoferrocene (7.8 mg, 0.014 mmol) and sodium carbonate (0.74 g, 7.0 mmol) in N-methylpyrrolidone (NMP) (7 mL) was prepared in a round bottom flask at room temperature under nitrogen atmosphere and the mixture was heated to 120° C. After stirring for 10 hours, the reaction mixture was cooled to room temperature and poured into water. The organic materials were extracted with ethyl acetate and wash with brine. The organic layer was separated and dried over anhydrous sodium sulfate. After concentration, the residual oil was passed through flash column chromatography on silica gel (hexane/ethyl acetate=90/10 to 50/50 as an eluant) to obtain pure 4-(4-benzyl-[1,4]oxazepan-6-yl)-benzonitrile (1.6 g, 5.5 mmol, 79%) as light yellow oil.