Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:30](=[O:31])[CH2:29][O:28][C:27]3[CH:33]=[CH:34][C:24]([F:23])=[CH:25][CH:26]=3)[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Reactant: O=C(O)COc1ccc(F)cc1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(F)cc3)CC2)c2nc(-c3cccnc3)sc2n1
Yield: 67 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-fluorophenoxyacetic acid in a yield of 67%, according to the procedure for the synthesis of example 50
Reaction SMILES: Br[C:2]1[CH:22]=[N:21][C:5]2[NH:6][C:7](=[O:20])[CH2:8][N:9]([CH2:10][C:11]3[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=3[Cl:19])[C:4]=2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:19][C:12]1[C:13]([F:18])=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH2:10][N:9]1[CH2:8][C:7](=[O:20])[NH:6][C:5]2[N:21]=[CH:22][C:2]([C:33]3[CH:32]=[N:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)=[CH:3][C:4]1=2
Reactant: O=C1CN(Cc2c(F)ccc(F)c2Cl)c2cc(Br)cnc2N1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCO
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3c(F)ccc(F)c3Cl)CC(=O)N4)cn2)CC1
Temperature: 130 °C
Yield: 28.9 %

Procedure:
A mixture of 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-one (42 mg, 0.11 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (40 mg, 0.13 mmol), palladium (II) acetate (4 mg) and triphenylphosphine (14 mg) in n-propanol (1.0 mL) was degassed with argon while adding a 1.26 M aqueous solution of Na2CO3 (0.12 mL) followed by water (0.38 mL). This mixture was heated in a microwave for 10 minutes at 130° C., cooled to room temperature and extracted into CH2Cl2. The organic phase was passed through a plug of Na2SO4, absorbed onto florisil and evaporated to dryness. This material was purified by silica gel chromatography by eluting with increasing amounts of 5% NH4OH/methanol in dichloromethane. The isolated material was recrystallized from methanol to give the title compound (15.4 mg, 29%). m.p. 235-236° C. (dec); LCMS: m/z=485/487 (M+H+); 1H-NMR (CDCl3-d6, 400 MHz) δ 8.22 (d, J=2.4 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.49-7.46 (m, 1H), 7.16 (s, 1H), 7.15-7.06 (m, 1H), 7.05-6.93 (m, 1H), 6.69 (d, J=8.8, 1H), 5.43, (s, 2H), 4.81 (s, 1H), 4.24 (s, 2H), 3.61-3.59 (m, 4H), 2.55-2.52 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:47]([C:49]1[CH:50]=[C:51]([CH:53]=[CH:54][CH:55]=1)[NH2:52])#[CH:48].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C=O>[C:47]([C:49]1[CH:50]=[C:51]([NH:52][C:11](=[O:13])[C@@H:9]([N:8]([CH3:14])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH3:10])[CH:53]=[CH:54][CH:55]=1)#[CH:48]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: C#Cc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To N-Boc-N-methyl-L-alanine (2.03 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.81 g) and 1-hydroxybenzotriazole monohydrate (2.70 g), N,N-dimethylformamide (20 mL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, N,N-diisopropylethylamine (5.2 mL) and 3-ethynylaniline (1.17 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 80 to 50% hexane in ethyl acetate) to obtain (S)-tert-butyl (1-((3-ethynylphenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (G1, 626 mg) as white solid.
Reaction SMILES: Cl[CH:2]([C@H:7]([OH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+]>CO>[O:15]1[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C@H:2]1[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCCCCCC[C@@H](O)C(Cl)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCC[C@H]1O[C@@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To 500 ml of a methanol solution of 90 g (0.384 mol) of the methyl (3R)-2-chloro-3-hydroxydecanoate (VIII) obtained in (2) above was added dropwise 78 g (0.4 mol) of a 28% methanol solution of sodium methoxide at 0 to 5° C., followed by stirring at room temperature for 1 hour. After confirming disappearance of the methyl (3R)-2-chloro-3-hydroxydecanoate (VIII) by TLC, methanol was evaporated. The concentrate was cooled, adjusted to pH 8 to 9 with 500 ml of a phosphate buffer (prepared by dissolving 5.55 g of sodium dihydrogen phosphate (NaH2PO4.2H2O) and 21.5 g of sodium hydrogenphosphate (Na2HPO4.12H2O) in 1 l of water), and extracted with 1 of isopropyl ether. The isopropyl ether was evaporated, and the residue was distilled to obtain 65.3 g (0.326 mol; yield: 85.0%) of the title compound (V-1) (boiling point: 135° C./0.3 mmHg).
Reaction SMILES: I[C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].CC1(C)C(C)(C)OB([C:43]2[CH:47]=[CH:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[N:44]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:18]([O:17][C:16]([NH:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:7]1[N:6]=[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[C:4]2[C:31](=[O:34])[NH:32][CH2:33][C:3]=2[C:2]=1[C:47]1[CH:43]=[N:44][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH:46]=1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)n1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(I)c3c2C(=O)NC3)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(-c3cnn(C(=O)OC(C)(C)C)c3)c3c2C(=O)NC3)c1
Temperature: 80 °C

Procedure:
To an oven dried vial was added tert-butyl (1S,2R)-2-(7-iodo-3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (40 mg, 0.069 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (30.6 mg, 0.104 mmol), and sodium carbonate (0.104 mL, 0.208 mmol) in DMF (1 mL). The resulting tan mixture was degassed 15 min. Bis(triphenylphosphine) palladium(II) chloride (4.86 mg, 6.93 μmol) was added and the mixture was degassed an additional 5 min. The vial was capped and was heated at 80° C. for 12 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was collected, dried with Na2SO4 and concentrated to give a brown residue, which was used without further purification (55 mg). LCMS indicated the desired mass less one of the Boc protecting groups. [M+H-Boc] calc'd for C33H43N7O5, 518. found, 518.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:30]([CH2:34][C:35]([OH:37])=O)([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:35](=[O:37])[CH2:34][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)CC(=O)O
Product: CN(C(=O)CC(C)(C)C)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3,3,N-trimethyl-butyramide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using tert-butylacetic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 536.3 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[C:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22])(=[O:18])[CH3:17]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:17]/[C:16]([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])=[O:18])=[CH:5][C:4]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccccc1C(=O)O
Product: COc1ccc(/C=C/C(=O)c2ccccc2C(=O)O)cc1-c1cccs1
Yield: 44 %

Procedure:
The title compound was prepared by condensing 4-methoxy-3-(thiophen-2-yl)-benzaldehyde (Ex-41A) and 2-acetylbenzoic acid in a similar manner as described in Ex-3. Beige solid with green tint, mp 79–81° C., 44% yield. 1H-NMR (DMSO-D6) δ 8.07 (d, J=2 Hz, 1H), 7.91 (d, J=8 Hz, 1H), 7.73 (dd, J=2, 4 Hz, 1H), 7.67–7.70 (m, 2H), 7.63 (dd, J=2, 7 Hz, 1H), 7.57 (dd, J=2,5 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.22 (d, J=2 Hz, 2H), 7.19 (d, J=8 Hz, 1H), 7.12 (dd, J=4, 5 Hz, 1H), 3.96 (s, 3H). HRMS m/z=calc. 365.0848, found 365.0853.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:17][C:3]1([C:1]#[C:2][C:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][CH:26]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Ic1cccc2ccccc12
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cccc3ccccc13)O2

Procedure:
rac-3,4-dihydro-2,5,7,8-tetramethyl-2-[(1-naphthyl)ethynyl]-2H-1-benzopyran-6-ol was prepared by coupling rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 1-iodonaphthalene under the conditions described in Example 1. It was isolated by chromatography over 40 fold amount of silica gel using methylene chloride. The combined clean fractions were crystallized from hexane and recrystallized from petroleum ether to give colorless crystals with m.p. 127°-128°.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH:3]=[CH2:4].ClC1C=C(C=CC=1)C(OO)=[O:21].C([O-])(O)=O.[Na+]>ClCCl>[O:21]1[CH2:4][CH:3]1[CH2:2][CH2:1][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: C=CCCN1C(=O)c2ccccc2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCC1CO1
Temperature: 0 °C

Procedure:
70 g (350 mmol) 2-(but-3-enyl)-isoindolin-1,3-dione are dissolved in dichloromethane. The solution is cooled to ca. 0° C. and a suspension of 120.8 g (350 mmol) 50% 3-chloro-peroxy-benzoic acid in dichloromethane is added under cooling. The mixture is left standing without further cooling at room temperature for two days. After addition of 250 ml saturated NaHCO3 solution the organic phase is separated and washed three times each with 200 ml saturated NaHCO3 solution and once with water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum: yield 80 g.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[NH:21][C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:12].Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2[CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1.O>CC(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C@@H:10]([NH:9][C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][N:34]3[CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[CH3:28])=[C:15]([NH:21][C:22]2[N:23]=[CH:24][CH:25]=[CH:26][N:27]=2)[CH:16]=1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1ncccn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1Nc1ncccn1
Temperature: 80 °C

Procedure:
Triethylamine (518 μl, 3.72 mol) was added to (S)-2-amino-N-[4-fluoro-2-(pyrimidin-2-ylamino)phenyl]propionamide hydrochloride salt 161b (289 mg, 0.93 mmol) and 6-chloro-9-(tetrahydropyran-2-yl)purine (265 mg, 1.10 mol) in IPA (5.0 ml) and heated to 80° C. overnight. The reaction was poured into water and the aqueous layer extracted into EtOAc (×3). The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by chromatography (SiO2, 0-10% 2M ammonia methanol/DCM) to yield the title compound as a 1:1 mixture of diastereomers (236 mg, 0.50 mmol, 53%). LCMS RT 2.63 min [M+H]+ 478.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([OH:15])=O>O>[F:1][C:2]1[CH:18]=[CH:17][C:16]2[C:13](=[O:15])[CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4]=2[CH:3]=1
Reactant: O=C(O)Cc1ccccc1Oc1cccc(F)c1
Solvent: O
Product: O=C1Cc2ccccc2Oc2cc(F)ccc21
Reaction time: 1 h

Procedure:
2-(3-Fluorophenoxy)benzeneacetic acid (22 g.) was added to 90 g. of polyphosphoric acid at 125°. The reaction mixture was stirred 1 hour at 125°. It was then cooled; water (300 ml) was added with stirring; a solid product was filtered and extracted with toluene several times. The combined toluene extracts were washed successively with water, dilute alkali, and water, then dried over magnesium sulfate and evaporated to yield the title compound as a solid product, which was purified upon treatment with hexane. ##STR15##
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29](=[O:31])[CH3:30])=[CH:26][C:25]=2[CH:32]=1>CN(C=O)C>[C:29]([C:27]1[O:28][C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:2]3[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:32][C:25]=2[CH:26]=1)(=[O:31])[CH3:30]
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(=O)c1cc2cc(N)ccc2o1
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(Nc2ccc3oc(C(C)=O)cc3c2)=C(c2ccccc2)S1(=O)=O
Yield: 34.5 %

Procedure:
A solution of 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.245 g, 0.81 mmol) and 1-(5-amino-1-benzofuran-2-yl)ethanone (0.285 g, 1.63 mmol) in DMF (4 mL) was heated at 130° C. for 4 h in a microwave reactor. The product was purified by preparative HPLC [0.1M NH4OAc/MeCN, gradient A:B (8:2 to 3:7)]. The product fractions were evaporated and the residue was extracted with DCM. The organic layer was washed with saturated NaHCO3, dried through a phase separator and evaporated to give the title compound (0.123 g, 34%) as a solid; 1H NMR (500 MHz, CD3CN): δ 7.32 (ds, 1H), 7.24 (d, 1H), 7.02-7.16 (m, 7H), 3.93 (t, 2H), 3.73 (t, 2H), 3.38 (s, 3H), 2.49 (s, 3H); Mass Spectrum: M+H+ 441.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:10]=[CH:11]2)=[CH:6][CH:5]=1.C(OCC)(=O)C.C(O)C>[Pd]>[CH2:3]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:10]=[CH:11]2)=[CH:6][CH:5]=1)[CH:2]([CH3:20])[CH3:1]
Reactant: CC(C)=Cc1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)Cc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To a solution of N-(7-(2-methylprop-1-enyl)isoquinolin-3-yl)cyclopropanecarboxamide (100.0 mg, 0.2891 mmol) in ethyl acetate (10.0 mL, 102 mmol) was added palladium (30.6 mg, 0.0288 mmol) (10 wt % on carbon). The reaction vessel was purged first with nitrogen and then with hydrogen, and stirred at room temperature under a hydrogen balloon for 2 hours. Ethanol (5.0 mL, 86 mmol) and palladium (41.9 mg, 0.0394 mmol) were added, and the reaction maintained at room temperature for 19 hours. The reaction mixture was then filtered through celite and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 54.4 mg (70%) of N-(7-isobutylisoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=5.079, M+H=269.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.06 (s, 1H), 8.41 (s, 1H), 7.86-7.70 (m, 2H), 7.54 (dd, J=8.6, 1.3 Hz, 1H), 2.62 (d, J=7.1 Hz, 2H), 2.13-2.01 (m, 1H), 1.94 (dp, J=13.4, 6.7 Hz, 1H), 0.90 (d, J=6.6 Hz, 6H), 0.86-0.75 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][CH:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30]>CN(C=O)C>[CH2:16]([N:15]1[C:11]([O:10][C:4]2[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([S:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[CH:3]=2)=[CH:12][CH:13]=[N:14]1)[CH3:17]
Reactant: CCn1nccc1Oc1cc(Br)cnc1C#N
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1C#N
Reaction time: 1 h
Yield: 93.3 %

Procedure:
5-Bromo-3-(1-ethyl-1H-pyrazol-5-yloxy)picolinonitrile (16.1 g, 55 mmol) and cesium carbonate (17.9 g, 55 mmol) were combined with DMF (160 ml) and pyridine-2-thiol (6.1 g, 55 mmol) dissolved in DMF (40 ml) was added dropwise over 30 minutes. The mixture was then agitated for 1 hour, quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and evaporated. The residue was purified over silica gel (20-35% ethyl acetate/hexanes) to afford 3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (16.6 g, 93% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:30]([O:32][CH3:33])=[O:31])#[N:2].[CH3:34][C:35]1[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:23]=[C:24]([C:36]4[CH:37]=[CH:38][CH:39]=[C:40]([CH3:41])[C:35]=4[CH3:34])[CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:30]([O:32][CH3:33])=[O:31])#[N:2]
Reactant: Cc1cccc(B(O)O)c1C
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(I)c4)cc3)c(C#N)cc21
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: Cc1ccccc1
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5cccc(C)c5C)c4)cc3)c(C#N)cc21
Temperature: 100 °C
Reaction time: 17 h
Yield: 64 %

Procedure:
In a vial were placed methyl 6-cyano-7-(4-(3-iodophenylcarbamoyl)phenoxy)chroman-4-carboxylate (Preparation 3) (56 mg, 0.101 mmol), 2,3-dimethylphenylboronic acid (19.70 mg, 0.131 mmol), Na2CO3 (32.12 mg, 0.303 mmol), toluene (1 ml), and water (0.1 ml). The mixture was degassed with Argon for few minutes. Tetrakis(triphenylphosphine)palladium(0) (5.836 mg, 0.0050 mmol) was added and the vial was sealed. The mixture was stirred for 17 hours at 100° C. The crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 34.4 mg of the title compound as a thin film (64%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][CH2:24][OH:25])[C:15]=2[F:26])[C:11]([NH2:13])=[S:12])=[CH:5][CH:4]=1)#[N:2].F[B-](F)(F)F.[CH3:32][O+](C)C.C1(C)C=CC=CC=1>C(#N)C.[O-2].[O-2].[Mn+4]>[CH3:32][S:12][C:11](=[NH:13])[C:10](=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH2:23][CH2:24][OH:25])[C:15]=1[F:26]
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)cc2)C(N)=S)c1
Reactant: C[O+](C)C
Agent: [Mn+4]
Agent: F[B-](F)(F)F
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COc1cc(OCCO)c(F)c(C(=Nc2ccc(C#N)cc2)C(=N)SC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(4-cyanophenylamino)-2-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxypheny l]thioacetamide (100 g, 267 mmol) in acetonitrile (600 mL), under water cooling, trimethyloxonium tetrafluoroborate (39.5 g, 267 mmol) was added over 20 minutes, and the resulting mixture was stirred at room temperature for 0.5 hours. To the solution, under water cooling, manganese dioxide (139 g, 1.602 mmol) was added over 10 minutes, and the resulting mixture was stirred at room temperature for 1 hour. Toluene (500 mL) was added to the reaction mixture, and the resulting mixture was filtered, after which the resulting filter cake was washed with ethyl acetate. The filtrate obtained and a washing solution were combined, and the resulting mixture was sequentially washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated saline, dried over anhydrous magnesium sulfate, and then filtered. The filtrate obtained was concentrated under reduced pressure to obtain a crude product of the captioned compound as an oily product.
Reaction SMILES: [C:1]([C:3]1[C:11]2[O:10][C:9]([CH3:12])=[N:8][C:7]=2[C:6]([N+:13]([O-])=O)=[CH:5][CH:4]=1)#[N:2]>CCOC(C)=O.[Fe]>[NH2:13][C:6]1[C:7]2[N:8]=[C:9]([CH3:12])[O:10][C:11]=2[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: Cc1nc2c([N+](=O)[O-])ccc(C#N)c2o1
Agent: [Fe]
Solvent: CCOC(C)=O
Product: Cc1nc2c(N)ccc(C#N)c2o1
Temperature: 65 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
Compound 477C (0.156 g, 0.77 mmol) was dissolved in a 1:1 mixture of EtOAc/10% HOAc (20 mL) and heated to 65° C. Iron powder (325 mesh, 0.214 g, 3.83 mmol) was added and the reaction was stirred for 4 h. The cooled mixture was filtered through Celite and the resulting filtrate was washed with water (25 mL), brine (25 mL), dried over MgSO4, and concentrated to give compound 477D (0.118 g, 89%) as an orange solid. HPLC: 87% at 2.03 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 174.05 [M+H]+.