Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH3:36][N:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](O)=[O:43]>C(Cl)CCl>[CH3:36][N:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)=[O:43]
Reactant: Cn1cccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: ClCCCl
Product: Cn1cccc1C(=O)OCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
In an analogous manner to that described in Example 9 (c), by esterifying tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53 (c)] with 1-methyl-pyrrole-2-carboxylic acid in the presence of EDC there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(1-methyl-1H-pyrrol-2-carbonyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 585 (M+H)+.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+].[N+:25]([CH3:28])([O-:27])=[O:26]>>[C:3]1([CH2:2][CH2:1][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:18]=[CH:28][N+:25]([O-:27])=[O:26])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1c[nH]c2ccc(CCc3ccccc3)cc12
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1c[nH]c2ccc(CCc3ccccc3)cc12

Procedure:
The aidehyde 5-phenethyl-3-formylindole (0.15 g, 0.6 mmol), nitromethane (0.9 ml) and ammonium acetate (0.05 g, 0.7 mmol) were heated gently under reflux for 0.5 h. On cooling, crystals slowly separated. Crystallization from methanol gave of 5-(2-phenylethyl)-3-(2-nitroethenyl)indole as crystals.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH:21][C:22]([NH:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[O:23])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:25]1([NH:24][C:22]([NH:21][CH:17]2[CH2:16][C:15]3[CH:14]=[N:13][C:12]4[NH:8][N:9]=[CH:10][C:11]=4[C:20]=3[CH2:19][CH2:18]2)=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(NC(=O)Nc2ccccc2)CC4)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)NC1CCc2c(cnc3[nH]ncc23)C1
Temperature: 65 °C
Yield: 45 %

Procedure:
To 1-[3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl]-3-phenyl-urea (0.093 g, 0.217 mmol) was added trifluoroacetic acid (1 mL). The reaction mixture was heated at 65° C. for 16 hours. On completion of the reaction, toluene (2 mL) was added and the solvent removed under reduced pressure. The crude product was purified using reverse phase HPLC to give the desired product, 1-phenyl-3-(6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl)urea as an off-white solid (0.030 g, 45%). M.p.>216° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.38 (s, 1H), 8.34 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.21 (dd, J1=J2=8.0 Hz, 2H), 6.88 (dd, J1=J2=8.0 Hz, 2H), 6.31 (d, J=8.0 Hz, 1H), 4.04 (m, 1H), 3.19 (m, 1H), 3.05 (m, 2H), 2.80 (m, 1H), 2.10 (m, 1H), 1.88 (m, 1H); LCMS [M+H]: 308.
Reaction SMILES: CON(C)[C:4]([C@@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7])=[O:5].C(=O)=O.[CH3:20][C:21]([CH3:23])=O.C1([Mg]Br)CC1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:21]1([C:4](=[O:5])[C@@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH3:7])[CH2:23][CH2:20]1
Reactant: CC(C)=O
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Br[Mg]C1CC1
Agent: O=C=O
Agent: [Cl-]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
A solution of tert-butyl {(15)-1-[methoxy(methyl)carbamoyl]ethyl}carbamate (10.0 g) in tetrahydrofuran (110 mL) was cooled using dry ice/acetone under a nitrogen atmosphere, and 1.0 mol/L-cyclopropylmagnesium bromide/tetrahydrofuran solution (100 mL) was added. The mixture was warmed to room temperature and stirred for 5 hr, saturated aqueous ammonium chloride solution (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%) to give the title compound as a yellow oil (yield: 3.65 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([Cl:14])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cnc(Cl)cn1
Solvent: ClCCl
Product: O=C(Cl)c1cnc(Cl)cn1
Yield: 104 %

Procedure:
5-Chloropyrazine-2-carboxylic acid (3.15 mmol, 500 mg) was dissolved in DCM (55 ml). Oxalyl dichloride (6.62 mmol, 841 mg) was added slowly and the resulting mixture was refluxed for 2 h. After, the reaction had stopped the mixture was concentrated. 580 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3) δ 8.78 (d, 1H), 9.09 (d, 1H).
Reaction SMILES: [F:1][CH:2]([CH2:15][CH2:16][CH:17]([NH:21]C(OC(C)(C)C)=O)[C:18]([OH:20])=[O:19])[CH:3]([NH:7]C(OC(C)(C)C)=O)[C:4]([OH:6])=[O:5]>CCOCC.Cl>[F:1][CH:2]([CH:3]([C:4]([OH:6])=[O:5])[NH2:7])[CH2:15][CH2:16][C@@H:17]([C:18]([OH:20])=[O:19])[NH2:21]
Reactant: CC(C)(C)OC(=O)NC(CCC(F)C(NC(=O)OC(C)(C)C)C(=O)O)C(=O)O
Agent: Cl
Solvent: CCOCC
Product: NC(C(=O)O)C(F)CC[C@H](N)C(=O)O
Reaction time: 8 h
Yield: 20.9 %

Procedure:
3-fluoro-2,6-di-tert.-butoxycarbonylaminopimelic acid (940 mg, 2.3 mmoles) is dissolved in ether saturated with HCl gas, and the mixture is stirred overnight. The white crystals are filtered off and dissolved in isopropanol/ethanol. After filtration through a membrane filter (Millipore), propylene oxide (0.6 mL) is added. The precipitate is stirred with isopropanol and filtered off again. Crystallization from water/ethanol/isopropanol gives the pure title compound (100 mg) containing 0.2 moles of HCl.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].C(OCC)(=O)C.[ClH:25]>C(O)(=O)C.[Cu](Cl)Cl>[Cl:25][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: Cl
Reactant: COC(=O)c1ccc(C(=O)O)cc1N
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)O)cc1Cl
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To 3-amino-4-methoxycarbonylbenzoic acid (0.98 g, 5 mmol) suspended in 12 M hydrochloric acid (25 mL) and acetic acid (25 mL), an aqueous solution (10 mL) of sodium nitrite (0.35 g, 5 mmol) was added at −10° C., and the resulting solution was stirred for 30 minutes. The solution was added to copper chloride (I) (0.99 g, 10 mmol) in 12 M hydrochloric acid (25 mL) at −10° C., and the resulting reaction mixture was stirred at room temperature for 1 hour. After addition of ethyl acetate, the reaction mixture was washed with water, dried over magnesium sulfate, filtered through celite and purified by silica gel column chromatography to give 0.44 g of the desired product as a colorless solid (yield 39%).
Reaction SMILES: [C:1]([C:3]1[C:14]2=[C:15]3[N:10]([CH:11]([CH3:16])[CH2:12][CH2:13]2)[CH:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7](=[O:22])[C:6]3=[CH:5][CH:4]=1)#[N:2].[C:23]([O-])(=[O:25])[CH3:24].[Na+]>[Ni].C(OC(=O)C)(=O)C>[C:23]([NH:2][CH2:1][C:3]1[C:14]2=[C:15]3[N:10]([CH:11]([CH3:16])[CH2:12][CH2:13]2)[CH:9]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7](=[O:22])[C:6]3=[CH:5][CH:4]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1cn2c3c(c(C#N)ccc3c1=O)CCC2C
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cn2c3c(c(CNC(C)=O)ccc3c1=O)CCC2C
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 5.0 g (16.9 mmole) of ethyl 8-cyano-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate, 10 g of sodium acetate, 2 g of Raney nickel and 100 ml of acetic anhydride was stirred under hydrogen gas on a Paar apparatus at 50 psi and 50° C. for six hours. The catalyst was removed by filtration, and the filtrate was evaporated. The residue was dissolved in isopropyl alcohol and slowly crystallized to provide white crystals of ethyl 8-acetamidomethyl-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate. The structural assignment was supported by infrared spectral analysis.
Reaction SMILES: [OH:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:35]=[CH:34][C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27](O)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:18]([F:36])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:15][C:16]1[CH:35]=[CH:34][C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:1][CH2:2][CH:3]=[CH:4][C:5]4[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:18]([F:36])[CH:17]=1
Reactant: OC=CCc1ccncc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC=Cc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.6 %

Procedure:
A mixture of 4-(3-hydroxyprop-2-en-1-yl)pyridine (180 mg, 1.3 mmol) and thionyl chloride (0.3 ml) in toluene (10 ml) was stirred at room temperature for 2 hours. The volatiles were removed by evaporation to give crude 4-(3-chloroprop-2-en-1-yl)pyridine hydrochloride (180 mg, 0.94 mmol)) This product was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (500 mg, 1.6 mmol) and potassium carbonate (500 mg, 4.9 mmol) in DMF (20 ml) and the mixture stirred at 100° C. for 1 hour. The reaction mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (100/0 increasing to 95/5) and then by reverse phase (C18) HPLC eluting with methanol/water (30/7 increasing to 50/50) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(pyrid-4-yl)prop-2-en-1-yloxy)quinazoline (15 mg, 4%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[Br-].[NH4+].[C:10]([C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)#[N:11].O.[C:20](O)(=[O:22])[CH3:21]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:10]([C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)#[N:11].[C:1]([O:4][CH:5]([O:7][C:20](=[O:22])[CH3:21])[C:6]1[CH:15]=[CH:16][CH:17]=[C:12]([C:10]#[N:11])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: Cc1cccc(C#N)c1
Agent: [Br-]
Solvent: O
Product: CC(=O)OC(OC(C)=O)c1cccc(C#N)c1

Procedure:
A glass three-neck flask was charged with 106.3 g of acetic anhydride, 0.67 g of cerous (III) acetate monohydrate, 0.88 g of zinc (II) acetate dehydrate and 0.78 g of ammonium bromide, and the mixture was stirred at 500 rpm using stirring blades, while air was bubled in at 150 ml/min at atmospheric pressure. In succession, the three-neck flask was heated in an oil back, to be kept at 90° C., and 14.9 g of m-cyanotoluene was added at a time from a dropping funnel, to start reaction. After initiation of reaction, 0.1 g of ammonium bromide was added every hour 8 times. The reaction solution was sampled at predetermined time intervals and analyzed by high performance liquid chromatography. The m-cyanotoluene conversion and m-cyanobenzylidene diacetate yield were calculated from the following formulae:
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:31]1([C:37]2[CH:46]=[CH:45][C:40]([C:41](=[O:44])[CH2:42]Br)=[CH:39][CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:42][C:41]([C:40]3[CH:45]=[CH:46][C:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:38][CH:39]=3)=[O:44])=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCC(=O)c5ccc(-c6ccccc6)cc5)cc4)cc3)n(C)c(=O)c12
Yield: 37.2 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (398 mg), 4-phenylphenacyl bromide (290 mg) and potassium carbonate (440 mg) in DMF (7 ml) was stirred at room temperature for 72 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane: ether =10:1) and recrystallized from chloroform-ethyl acetate to provide the title compound as colorless solid (217 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C@H:13]([C@@H:16]([OH:18])[CH3:17])[C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1>CN(C=O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][C@H:13]([C@H:16]([O:18][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)[CH3:17])[C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: Clc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccc(Cl)cn1)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
A mixture of 69 mg (1.7 mmol) NaH (55% suspension in mineral oil), 359 mg (1.08 mmol) (S)-1-[(3S,4S)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol and 225 mg (1.52 mmol) 2,5-dichloropyridine in 2 mL DMF was stirred for 20 h at 40° C. Further 0.2 eq. 2,5-dichloropyridine was added and stirring was continued for 20 h at 60° C. After evaporation the residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to afford after evaporation of the product containing fractions 205 mg (43%) of the title compound as colorless viscous oil. MS (m/e): 441.1 [(M+H)+]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35](O)=[O:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:31]4[O:30][CH:34]=[CH:33][N:32]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1ncco1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ncco2)c1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 28 mg, 0.07 mmol) and oxazole-2-carboxylic acid (8 mg, 0.07 mmol). Yield 24 mg (69%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]2[C:16]([I:17])=[CH:15][NH:14][C:10]=2[N:11]=[CH:12][N:13]=1.Br[CH2:19][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:21]=[CH2:22].O>CN(C=O)C.C(OCC)(=O)C>[Si:24]([O:23][CH:20]([CH:21]=[CH2:22])[CH2:19][N:14]1[C:10]2[N:11]=[CH:12][N:13]=[C:8]([Cl:7])[C:9]=2[C:16]([I:17])=[CH:15]1)([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:25])[CH3:26]
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: C=CC(CBr)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC(Cn1cc(I)c2c(Cl)ncnc21)O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 36.8 %

Procedure:
Potassium carbonate (2.2 g) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.7 g) obtained in Step 1 and 1-bromo-2-(tert-butyldimethylsilyloxy)-3-butene (3.5 g) obtained in Step 2 in DMF (26 ml) at room temperature, and the mixture was stirred at 80° C. for 5 hours. After cooling the reaction mixture, water and ethyl acetate were added thereto, and the generated insoluble matter was filtered off. The organic layer was separated, washed with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow solid (2.25 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:19](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:21])=[O:20])=[C:15]([F:18])[CH:16]=2)[N:11]=[CH:10][CH:9]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.[Cl-].[NH4+]>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:19]([NH:1][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)(=[O:21])=[O:20])=[C:15]([F:18])[CH:16]=2)[N:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1cc2nccc(Cl)c2cc1F
Reactant: Nc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1cc2nccc(Cl)c2cc1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A flask containing a solution of 2-aminothiazole (0.039 g, 0.386 mmol) and perfluorophenyl 4-chloro-6-fluoroquinoline-7-sulfonate (0.150 g, 0.351 mmol) in THF (1.754 ml) was cooled to −78° C. for 10 minutes, and then lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (0.701 ml, 0.701 mmol) was added drop wise (conversion from colorless solution to yellow-orange). After 20 minutes, the reaction was diluted with sat. aq ammonium chloride solution, and was extracted with DCM:MeOH (90:10) (×3). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The material was taken forward crude. m/z (ESI) 344.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8](O)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[NH2:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cccnc1CO
Temperature: 15 °C
Reaction time: 8 h

Procedure:
3-Aminopicolinic acid (145 mg, 1.05 mmol) was carefully added in 3 aliquots to a slurry of LiAlH4 (143 mg, 3.78 mmol) in dry tetrahydrofuran (6 ml). The resulting mixture was stirred at 15° C. overnight. After cooling in an ice bath, the reaction mixture was quenched with careful addition of water (1 ml) dropwise, followed by 15% aqueous NaOH (1 ml), and then water (3 ml). The resulting solid was filtered and washed several times with tetrahydrofuran. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel using 5% CH3OH(NH3)/ethyl acetate as eluent to yield the title compound as a yellow oil. 110 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:17]([F:24])=[CH:18][C:19]([F:23])=[C:20]([CH:22]=1)[NH2:21].CCN(C(C)C)C(C)C.[C:34]([C:38]1[O:42][N:41]=[C:40]([NH:43][C:44](=O)[O:45]C2C=CC=CC=2)[CH:39]=1)([CH3:37])([CH3:36])[CH3:35].O>C1COCC1.CN(C1C=CN=CC=1)C>[C:34]([C:38]1[O:42][N:41]=[C:40]([NH:43][C:44]([NH:21][C:20]2[CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[C:17]([F:24])=[CH:18][C:19]=2[F:23])=[O:45])[CH:39]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: COc1cc2ncnc(Oc3cc(N)c(F)cc3F)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc2ncnc(Oc3cc(NC(=O)Nc4cc(C(C)(C)C)on4)c(F)cc3F)c2cc1OC
Temperature: 70 °C
Yield: 25.1 %

Procedure:
To a solution of 5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline (100 mg, 0.3 mmol) in THF (10 mL), DIEA (58 mg, 0.45 mmol), DMAP (20 mg, 0.16 mmol), and phenyl 5-tert-butylisoxazol-3-ylcarbamate (117 mg, 0.32 mmol) were added and the mixture heated overnight at 70° C. The mixture was poured into water and extracted with EtOAc three times. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified using silica gel chromatography eluting with EtOAc/Hexane (3-80%). The appropriate fractions were concentrated to afford 1-(5-tert-butylisoxazol-3-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)urea (37.56 mg, 25% yield). 1H NMR (300 MHz, CDCl3) δ 1.35 (s, 9H), 4.05 (s, 6H), 6.09 (s, 1H), 6.85 (s, 1H), 7.28 (s, 1H), 7.35 (s, 1H), 8.28 (m, 1H), 8.70 (s, 1H), 9.50 (s, 1H). LC-MS (ESI) m/z 500 (M+H)+
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:17]=[N:18][CH:19]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:22](=[O:23])/[CH:21]=[CH:20]/[C:16]1[CH:17]=[N:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=1)[CH2:4]2
Reactant: COc1cncc(/C=C/C(=O)O)c1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: COc1cncc(/C=C/C(=O)N[C@H]2CN3CCC2CC3)c1

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(5-methoxy-3-pyridyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 288 (MH+).