Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH:16](=[N:15][NH:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: NNc1ccc(Oc2ccccc2)cc1
Solvent: CO
Product: C(=NNc1ccc(Oc2ccccc2)cc1)c1ccccc1

Procedure:
A suspension of (4-phenoxyphenyl)hydrazine (J. Org. Chem. 1956, 395; 1.5 g) in methanol (10 mL) was mixed with benzaldehyde (0.76 mL) and heated to reflux. The crystals which separated out on cooling were filtered off with suction. The product with the molecular weight of 288.35 (C19H16N2O); MS (ESI): 289 ([M+H]+), was obtained in this way.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[CH2:39][C:29]3([C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:28][C:25]2=[N:26][CH:27]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([NH:21][C:22]2[CH:23]=[C:24]3[CH2:39][C:29]4([C:37]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:38])[CH2:28][C:25]3=[N:26][CH:27]=2)=[O:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cn1c(=O)n(-c2ccccn2)c2ccccc21)Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (15 mg, 0.055 mmol, described in Intermediate 7), (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (14 mg, 0.055 mmol, described in Intermediate 4), PyClu (26 mg, 0.072 mmol), and N,N-diisopropylethylamine (0.048 mL, 0.277 mmol) in THF (1 mL) was stirred at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×10 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=504 (M+1). HRMS: m/z=504.1787; calculated m/z=504.1779 for C28H22N7O3.
Reaction SMILES: [CH:1](=[C:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH2:1]([CH:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CC2CCC3(CC2)OCCO3)cc1
Yield: 99.1 %

Procedure:
A solution of 28 g of 8-benzylidene-1,4-dioxa-spiro[4.5]decane and 1 g of 5% palladium on carbon in 250 mL of ethanol was allowed to stir overnight under 1 atm of hydrogen The catalyst was filtered off and the solution concentrated to give 28 g of 8-benzyl-1,4-dioxa-spiro[4.5]decane as an oil.
Reaction SMILES: [C:1]([O:9][CH:10]([C:18](=[O:21])[CH2:19][CH3:20])[C:11](=[O:17])[CH:12]=[CH:13]N(C)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)CC.C(O)(=O)C(O)=O.Cl.S(=O)(=O)(O)O>C(O)(=O)C.C(O)=O>[C:1]([O:9][C:10]1[C:18](=[O:21])[CH:19]=[CH:20][O:17][C:11]=1[CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(OC(=O)c1ccccc1)C(=O)C=CN(C)C
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCC(=O)O
Solvent: O=CO
Product: CCc1occc(=O)c1OC(=O)c1ccccc1

Procedure:
said 4-benzoyloxy-1-dimethylamino-1-heptene-3,5-dione is heated in an acid chosen from the group consisting of formic acid, acetic acid, propionic acid, oxalic acid, dilute hydrochloric acid and dilute sulfuric acid to form 3-benzoyloxy-2-ethyl-4-pyrone, and,
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([CH:13]([O:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21]C)=[O:20])[CH3:14])[CH:10]=[CH:11][CH:12]=1)[CH:4]([CH3:6])[CH3:5].CCOCC.Cl>O1CCOCC1.CO>[CH2:3]([C:7]1[CH:8]=[C:9]([CH:13]([O:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([OH:21])=[O:20])[CH3:14])[CH:10]=[CH:11][CH:12]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)c1cccc(OC(C)c2cccc(CC(C)C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)Cc1cccc(C(C)Oc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
1N aqueous solution of sodium hydroxide (6 ml) was added to a solution of methyl 3-[1-(3-isobutylphenyl)ethoxy]benzoate (1.40 g) in a mixture of 1.4-dioxane (12 ml) and methanol (6 ml). The reaction mixture was stirred at 25° C. for 18 hours,and then poured into a mixture of ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The crystalline residue was washed with hexane to give 3-[1-[3-isobutylphenyl)ethoxy]benzoic acid (1.20 g) as colorless crystals.
Reaction SMILES: C(OC1([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)C2C(=CC=C(C)C=2)N(CC)C1=O)(=O)C1C=CC=CC=1.[C:36]([O:44][CH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([Cl:54])[CH:52]=2)[N:47]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:46]1=[O:63])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:44][C:45]1([CH2:23][C:24]2[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=2)[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([Cl:54])[CH:52]=2)[N:47]([CH2:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:46]1=[O:63])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(OC1C(=O)N(CCc2ccccc2)c2ccc(Cl)cc21)c1ccccc1
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: COc1cc(CC2(OC(=O)c3ccccc3)C(=O)N(CCc3ccccc3)c3ccc(Cl)cc32)cc(OC)c1OC

Procedure:
This compound was made in an analogous fashion to 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate using 5-chloro-2-oxo-1-phenethylindolin-3-yl benzoate.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.[CH3:29][N:30]([CH3:37])[CH2:31][CH2:32][CH2:33][C:34](O)=[O:35]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21]([C:34](=[O:35])[CH2:33][CH2:32][CH2:31][N:30]([CH3:37])[CH3:29])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2
Reactant: CN(C)CCCC(=O)O
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Product: CN(C)CCCC(=O)N1Cc2ccccc2C2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)C1

Procedure:
The title compound was prepared from N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide and 4-(dimethylamino)butanoic acid following the procedure of Example 110 Step 1. LC-MS Method 1 tR=2.4 min, m/z=493.38; 1HNMR (CD3OD) δ=1.55-1.73 (m, 4H), 1.80-1.94 (m, 8H), 1.95-2.10 (m, 8H), 2.66-2.72 (m, 2H), 2.82-2.92 (s, 6H), 3.05-3.19 (m, 2H), 3.19-3.28 (m, 2H), 3.80-3.92 (m, 1H), 3.92 (s, 3H), 3.93-4.04 (m, 1H), 4.72-4.80 (m, 2H), 5.78-5.95 (m, 1H), 7.15-7.30 (m, 3H), 7.40-7.47 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Cl[CH2:21][O:22][CH3:23]>CCN(C(C)C)C(C)C>[CH3:21][O:22][CH2:23][O:1][C:2]1[C:3]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: COCCl
Reactant: CCC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of 1-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1-one (Intermediate 13, 2.6 g, 10 mmol)) in i-Pr2NEt (28 mL) was added chloromethylmethyl ether (4.8 mL, 63 mmol). The mixture was stirred at ambient temperature for overnight, was quenched with 1M HCl, and extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3% EtOAc-hexane) to give the title compound as a white solid (2.79 g, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13].C(N(CC)C(C)C)(C)C.O.[C:45]([O:48]CC)(=[O:47])C>O1CCOCC1.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>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([N:5]2[C:6]([C:7]3[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[C:12]=3[CH3:13])=[C:2]([C:45]([OH:48])=[O:47])[CH:3]=[N:4]2)=[CH:28][CH:29]=1)#[N:32]
Reactant: CCOC(C)=O
Reactant: Cc1c(-c2c(Br)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2c(C(=O)O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-bromo-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 93) (139.8 mg) in 1,4-dioxane (2.0 ml) were added tetrakis(triphenylphosphine)palladium (30.7 mg),N,N-diisopropylethylamine (46.8 μl) and water (0.5 ml) and the resulting mixture was stirred at 100° C. under carbon monoxide atmosphere for four hours. To the reaction mixture was added ethyl acetate (100 ml) and the mixture was washed with 1M hydrochloric acid (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylic acid (24.5 mg) as brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([C:16]([OH:18])=O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].S([O:26][CH3:27])(OC)(=O)=O.[CH3:28]N(C)C=O>>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]1([C:16]([O:26][CH3:27])=[O:18])[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)[CH3:28])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COS(=O)(=O)OC
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CCOCC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1(CN(C)C(=O)OC(C)(C)C)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{[(tert-Butoxycarbonyl)amino]methyl}tetrahydro-2H-pyran-4-carboxylic acid (729 mg, 2.81 mmol) was dissolved in N,N-dimethylformamide (7.3 mL) and cooled with an ice bath. To the solution was added sodium hydride, 60% in mineral oil (337 mg, 8.43 mmol), and the solution was warmed to room temperature. Dimethyl sulfate (612 μL, 6.47 mmol) was added, and the mixture was heated at 50° C. After 30 minutes, the reaction was cooled to room temperature, and additional 60% sodium hydride in mineral oil (56.2 mg, 1.40 mmol) and dimethyl sulfate (133 μL, 1.40 mmol) were added: The mixture was then heated at 50° C. for 1 hour. The reaction was cooled with an ice bath and quenched into a cold (ice bath temperature) mixture of 1 N hydrogen chloride (19.7 mL) and saturated sodium chloride (19.7 mL). The product was extracted with ethyl acetate (3 times). The organic solution was dried over anhydrous sodium sulfate and filtered. Concentration of the organic solution gave the title compound, which was used crude in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([F:41])=[CH:22][N:21]=1>>[F:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: COc1cc2c(cc1N)CCN(CC(N)=O)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1F
Product: COc1cc2c(cc1Nc1ncc(F)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CC(N)=O)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.013 g, 14%). MP: 98-140° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.27 (d, 1H, J=8.6 Hz), 8.16 (s, 1H), 7.92 (d, 1H, J=2.8 Hz), 7.40 (s, 1H), 7.25-7.17 (m, 2H), 6.64 (s, 1H), 6.56-6.54 (m, 1H), 6.53-6.49 (m, 1H), 5.52-5.41 (m, 1H), 3.93-3.84 (m, 10H, 3.16-3.10 (m, 6H), 2.90-2.82 (m, 4H), 2.76-2.68 (m, 4H). MS: 552.28 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:18](OC(=O)C)(=[O:20])C>C(O)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH:16][CH:18]=[O:20])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(C(=O)OCC)c1csc(N)n1
Solvent: O=CO
Product: CCOC(=O)C(C(=O)OCC)c1csc(NC=O)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 2-(2-amino-4-thiazolyl)malonic acid diethyl ester in a mixture of acetic anhydride (6 parts) and formic acid (6 parts) is stirred at 0° C. for 1 hour. The reaction mixture is concentrated in vacuum, diluted with ethyl acetate, washed with diluted hydrochloric acid, aqueous sodium hydrogen carbonate, and water, dried, and concentrated in vacuum to give 2-(2-formamido-4-thiazolyl)malonic acid diethyl ester. Yield: 70%.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:17][N:16]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: NO
Reactant: COC(=O)c1cc(C=O)ccc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(C=NO)ccc1OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Methyl 5-formyl-2-methoxybenzoate 1.0 g, 5.15 mmol), hydroxylamine hydrochloride (1.8 g, 25.75 mmol) and sodium acetate (2.1 g, 25.75 mmol) were combined in a ethanol/water mixture (1:1, 40 mL) and stirred at 50° C. for 1 h. After cooling to room temperature, the reaction mixture was poured in to ice water and extracted with methylene chloride (2×). The combined organic layers were washed with brine (2×), dried over sodium sulfate and concentrated to afford 1.04 g (97%) which was used without purification. LC/MS (HPLC method 3): tR=1.63 min, 210.06 (MH)+.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][CH:21]2[NH2:24])=[CH:17][CH:16]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][CH:21]2[NH:24][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([NH:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: NCc1cccnc1
Reactant: COc1ccc2c(c1)C(N)CC2
Product: COc1ccc2c(c1)C(Nc1ccc3c(NCc4cccnc4)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=397.1 (M+H+), was prepared in accordance with the general method of example 6 from 5-iodo-2-chloroquinoline, 6-methoxyindan-1-ylamine (CAS 103028-81-5) and 3-(aminomethyl)-pyridine.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](SC)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:29][C:30]1[N:35]=[CH:34][C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][N:31]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.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>[CH3:29][C:30]1[N:35]=[CH:34][C:33]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]4)=[CH:13][C:14]=3[N:15]=2)=[CH:32][N:31]=1
Reactant: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C)nc1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CSC
Product: Cc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (100 mg) in 1,2-dimethoxyethane (10 mL) was added 2-methyl-5-tributylstannanyl-pyrimidine (176 mg) and copper(I)bromide-dimethyl sulfide (94 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (13 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 411. NMR: (CDCl3): 2.69-2.72 (4 H, m), 2.83 (3 H, s, Me), 2.84 (3 H, s, Me), 3.31-3.34 (4 H, m), 3.90-3.93 (6 H, m), 4.06-4.08 (4 H, m), 7.37 (1 H, Ar) and 9.58 (1 H, Ar). MS: (ESI+): MH+=490.15
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41].O>O1CCCC1>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=1[C:40]([C:36]1[O:35][CH:39]=[CH:38][CH:37]=1)=[O:41]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Reactant: O=C(Cl)c1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccco3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 33 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.35 ml) was added to the cooled solution, and the mixture was stirred at −78° C. for 20 min. 2-Furancarbonyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 7 hr. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (34 mg, yield 33%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][C@@:11]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[CH2:13][C@H:12]2[C:14]([OH:16])=O)=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1.C(N(CC)C(C)C)(C)C.CCOC(C)=O.CCCCCCC>C(OCC)(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][C@@:11]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[CH2:13][C@H:12]2[C:14]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=2)=[O:16])=[CH:4][N:3]=1
Reactant: Nc1ccc(F)cn1
Reactant: Cc1ncc(OC[C@@]2(c3cccc(F)c3)C[C@H]2C(=O)O)c(C)n1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCCC
Product: Cc1ncc(OC[C@@]2(c3cccc(F)c3)C[C@H]2C(=O)Nc2ccc(F)cn2)c(C)n1
Temperature: 2.5 °C
Reaction time: 0.42 h

Procedure:
(1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-cyclopropanecarboxylic acid (13, 12.80 g, 0.040 mol, 1.0 equiv.), and 2-amino-5-fluoropyridine (4.76 g, 0.0425 mol, 1.05 equiv.) were dissolved in ethyl acetate (102.4 mL), under nitrogen. The solution was cooled to 0-5° C., and N,N-diisopropylethylamine (14.10 mL, 0.081 mol, 2.0 equiv.) was added to the reaction mixture while maintaining the internal temperature at 0-15° C. The reaction mixture was stirred at 0-10° C. for 20-30 minutes. n-Propylphosphonic anhydride (T3P; 50% w/w solution in ethyl acetate, 36.1 g, 1.4 equiv.) was added to the reaction mixture while maintaining the internal temperature at 0-15° C., The reaction was stirred at 20-25° C. for at least 20-24 hour and monitored by HPLC and TLC (EtOAc/Heptane=1/1), Upon completion of the reaction, the reaction mixture was cooled to 0-5° C. and then was quenched with water (64.0 mL) while maintaining the internal temperature below 10-15° C. The aqueous layer was back extracted once with MTBE (76.8 mL). The organic layers were combined and washed once with saturated aqueous NaHCO3 solution (38.4 mL) and once with water (38.4 mL). The organic layer was polish filtered and the filter rinsed with MTBE (12.8 mL). The organic layer was then concentrated under reduced pressure to a minimum stirrable volume. Ethyl acetate (60.8 mL) was added to the reaction mixture and the mixture was heated to no more than 50° C. to achieve a clear solution. n-Heptane (86.3 mL) was added slowly with agitation. The reaction mixture was cooled to 20-25° C., and the suspension was stirred for at least 1 h at 20-25° C. and then stirred at least for 1 h at 0-5° C. The suspension was filtered and the cake was washed two times with 5:1 heptane/ethyl acetate (2× 12.8 mL). The cake was dried under nitrogen and/or vacuum to provide the title compound, (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide, (14, 12.54 g, >99% ee) as a white to off white solid.