Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[Cl:28])[NH:24][CH:23]=[C:22]3[C:29]([OH:31])=[O:30])=[CH:15][CH:14]=1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[Cl:28][C:27]1[CH:26]=[C:25]2[C:21]([C:22]([C:29]([OH:31])=[O:30])=[CH:23][NH:24]2)=[CH:20][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCCN4)cc3)cc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 92.3 %

Procedure:
To a suspension of 5-{4-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]phenyl}-6-chloro-1H-indole-3-carboxylic acid (140 mg, 0.318 mmol) in ethyl acetate (10 mL) was added hydrogen chloride in ethyl acetate (4 N HCl in EtOAc, 10 mL) under nitrogen. The suspension was stirred for 4.5 hours at room temperature. The mixture was concentrated to afford the desired product (100 mg, 83.5% yield). MS (ES+) 341 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.66 (s, 1H), 7.62 (d, 2H), 7.52 (d, 2H), 4.60 (s, 1H), 3.35 (s, 4H), 2.49 (m, 2 H).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][C:11]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:9]2[NH:10][C:11]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(=O)NCC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCC1(c2ccccn2)COc2cccc(N)c2N1
Reaction time: 2 h
Yield: 109.9 %

Procedure:
N-[(5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide (0.040 g. 0.122 mmol) was dissolved in ethanol (5 mL) in a Parr bottle and degassed with nitrogen, followed by addition of palladium (10% on carbon) (10 mg, 0.09 mmol) catalyst. The reaction vessel was charged to 50 PSI with hydrogen, and shaken for 2 h. The mixture was then filtered and concentrated to give crude N-[(5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide (0.040 g, 80%). LCMS calculated for C16H19N4O2 (M+H)+: m/z=299.1. found: 299.0.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][C:32](Cl)=[O:33].C(Cl)(=O)C>>[CH3:1][N:2]([CH:3]1[CH2:16][CH:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH2:14]2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:32](=[O:33])[CH2:31][C:27]1[S:26][CH:30]=[CH:29][CH:28]=1
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CC(=O)Cl
Product: CC1C2CCC3C4CCC5CC(N(C)C(=O)Cc6cccs6)CCC5(C)C4CCC32CN1C

Procedure:
The title compound was prepared according to procedures described in Example 7C, except substituting Compound 172B for Compound 7B and 2-thiopheneacetyl chloride for acetyl chloride. 1H NMR (CDCl3): δ 0.74 (s, 3 H) 0.95-2.40 (m, 27 H) 2.83 (s, 3 H) 2.88 (s, 3 H) 3.01 (m, 1 H) 3.69 (m, 1 H) 3.90 (d, J=11.53 Hz, 2 H) 4.49 (m, 1 H) 6.92 (m, 2 H) 7.19 (m, 1 H); (M+H)+=469.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](OC(=O)C)(=[O:18])[CH3:17].N1C=CC=CC=1>O1CCOCC1>[C:16]([NH:1][C:2]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(F)(F)F)cc1NC(C)=O
Temperature: 80 °C
Reaction time: 60 h

Procedure:
To a solution of the product from Step 1 (5.34 g) in dioxane (25 ml) was added acetic anhydride (6 ml) and pyridine (4 ml). After 60 hours of stirring at 80° C., the solution was concentrated under reduced pressure and the residue was dissolved into ethyl acetate. The organic layer was washed with 2M sodium carbonate, 10% aqueous HCl, water and brine, dried over sodium sulfate and evaporated. The product was purified by flash chromatography (ISCO, 5%-20% ethyl acetate in hexanes) to provide a beige solid (5.27 g). LRMS (ES+) m/z 262.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:8]=[C:9]([C:13]2([OH:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=O)[CH:10]=[CH:11][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:6][C:7]1[CH:8]=[C:9]([C:13]2([OH:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[NH:1][CH2:2][CH2:3][CH2:4][OH:5])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(F)c1
Reactant: NCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OCCCNC1=Nc2ccccc2C1(O)c1cccc(F)c1

Procedure:
Reaction of 3-aminopropanol with 3-(m-fluorophenyl)-3-hydroxy-3H-indol-2-one in presence of toluene-p-sulphonic acid by a procedure analogous to that of Example 1 gives 3-(m-fluorophenyl)-2-(3-hydroxypropylamino)-3H-indol-3-ol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:17].N1C=CC=CC=1.[S:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]2[CH2:32][CH2:33][CH2:34][CH2:35][C:25]1=2>C(Cl)Cl>[CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:17][C:29]([C:28]1[S:24][C:25]2[CH2:35][CH2:34][CH2:33][CH2:32][C:26]=2[CH:27]=1)=[O:30]
Reactant: O=C(Cl)c1cc2c(s1)CCCC2
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (7) (1.20 g, 5.16 mmol, 1.0 equiv) and pyridine (0.42 mL, 25.8 mmol) are dissolved in DCM (40 mL) at 0° C. under a nitrogen atmosphere. 4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carbonyl chloride (8) (1.03 g, 5.16 mmol) is then added in portions over 5 min and allowed to react warming to RT over 60 min. All solvent is then removed under reduced pressure, and the resultant oil is reduced from toluene (3×20 mL) to remove residual pyridine. The residue is then dissolved in ethyl acetate and washed with sodium hydroxide (1N, 1×100 mL), then washed with saturated sodium chloride (1×100 mL) and dried over sodium sulfate. The solution is then filtered and concentrated under reduced pressure to give 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid [2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]diaxaborolan-2-yl)-phenyl]-amide (9) as an off-white solid (1.87 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[I-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C.C(OCC)(=O)C>[CH3:25][O:24][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6]([C:5]3[CH:26]=[CH:27][N:28]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:3](=[O:2])[CH:4]=3)=[O:7])[S:10][C:11]=2[C:17]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccn(Cc4ccccc4)c(=O)c3)nc12
Temperature: 25 °C
Yield: 32 %

Procedure:
To a stirred solution of 85 mg (0.21 mmol) 2-methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in 2 ml acetonitrile were added 73 mg (0.43 mmol) sodium iodide and 0.05 ml (0.43 mmol) benzyl bromide. The mixture was heated at reflux for 16 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed sequentially with water and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. Flash chromatography (2/1 EtOAc/toluene) afforded 32 mg (32%) 1-benzyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide as a yellow crystalline solid. ES-MS m/e (%)): 499 (M+Na+, 14), 477 (M+H+, 100).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:34])([F:33])[C:8]1[N:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[CH2:15][CH2:16][C:11]2=[N:10][N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:30][CH2:29][CH2:28][O:27][C:26]1[CH:31]=[CH:32][C:23]([CH:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH2:15][CH2:16][C:11]4[N:12]([C:8]([C:7]([F:6])([F:33])[F:34])=[N:9][N:10]=4)[N:13]=3)[CH2:18][CH2:19]2)=[CH:24][CH:25]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of methanesulfonyl chloride (0.158 mL, 2.04 mmol) in DCM (1 mL) was added dropwise to a stirred solution of 2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (695 mg, 1.70 mmol) and triethylamine (0.473 mL, 3.40 mmol) in DCM (7 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes, then warmed to room temperature and stirred for a further 15 minutes. The reaction mixture was diluted with DCM (50 mL), and washed with water (50 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 2-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (796 mg, 96%).
Reaction SMILES: [OH-].[K+].[CH:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]([C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)(=[O:15])[CH3:14]>CO>[CH3:21][C:16]1([C:13](=[O:15])[CH:14]=[CH:3][CH:4]=[CH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:20][CH2:19][CH2:18][O:17]1
Reactant: CC(=O)C1(C)OCCO1
Reactant: O=CC=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C(=O)C=CC=Cc2ccccc2)OCCO1
Reaction time: 4 h

Procedure:
4.0 g of a 15% strength by weight potassium hydroxide solution were added dropwise to a solution of 26.4 g of cinnamaldehyde and 26.0 g of 2-acetyl-2-methyl -1,3-dioxolan in 100 ml of methanol in the course of 10 minutes at from 20° to 25° C., and the mixture was stirred for a further 4 hours at from 20° to 25° C. Thereafter, the solvent was distilled off, the residue was taken up in 200 ml of tert-butyl methyl ether and the solution was washed with water and dried over sodium sulfate After the solvent had been distilled off, the crude product was distilled at from 150° to 155° C. and at 0.04 mbar.
Reaction SMILES: [SH:1][CH2:2][CH:3]([SH:6])[CH2:4][SH:5].O=[C:8]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][C:8]1([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:6][CH:3]([CH2:4][SH:5])[CH2:2][S:1]1)[CH3:15]
Reactant: CCOC(=O)CCC(=O)CCC(=O)OCC
Reactant: SCC(S)CS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCC1(CCC(=O)OCC)SCC(CS)S1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
A stirred solution of 1,2,3-trimercaptopropane (10.0 g, 0.071 mol) and diethyl 4-oxopimelate (16.43 g, 0.071 mol) in methylene chloride (300 ml) under nitrogen atmosphere was treated with boron trifluoride etherate (2 ml). After stirring for 3 days at room temperature, the reaction was quenched by addition of 200 ml of 5% sodium bicarbonate solution. The organic phase was separated and dried over anhydrous sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel using 5% ethyl acetate/hexane to give 10 g (40%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.O.[NH2:24][NH2:25]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:24][NH:25]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCCCC3)nc(N)n2)cc1F
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCCC2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
In a 25 mL sealable tube under argon were combined 4-[2-amino-6-(1-piperidinyl)-4-pyrimidinyl]-2-fluorobenzonitrile (0.106 g, 0.258 mmol), hydrazine monohydrate (0.51 mL, 10.3 mmol) and EtOH (5 mL). The vial was sealed and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and concentrated. The resulting solid was sonicated on a mixture of EtOH (1 mL) and water (9 mL). The mixture was filtered and the solid was washed with water and dried under vacuum at 40° C. to afford the title compound (66 mg, 80%) as a white solid. LC-MS (ES) m/z=310 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.53 (m, 4H), 1.64 (m, 2H), 3.47-3.79 (m, 4H), 5.37 (s, 2H), 6.03 (s, 2H), 6.58 (s, 1H), 7.57 (dd, J=8.3, 1.3 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: C(OC([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9]C1)=O)C=C.[C:22]([O:31][CH2:32]Cl)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[NH2:7][C@@:11]1([C:10]([OH:9])=[O:21])[C@@H:16]([F:17])[CH2:15][C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20][CH2:32][O:31][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:19]
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Reactant: CCCCCCCC(=O)OCCl
Product: CCCCCCCC(=O)OCOC(=O)[C@H]1[C@@H]2C[C@H](F)[C@@](N)(C(=O)O)[C@@H]21
Yield: 26.4 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 300 mg) and chloromethyl octanoate (483 mg) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (A-6, 95 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]#[N:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:32])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]#[N:34])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([C:28]([F:30])([F:31])[F:29])[CH2:26][CH2:27]3)[C:17]([OH:19])=[O:18])[C:10](=[O:32])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
295 mg (594 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoate (racemate) in 6 ml of dichloromethane and 915 μl (11.9 mmol) of TFA were reacted according to General Method 6A. Yield: 258 mg (purity 92%, 91% of theory)
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[N:19]([O-])=[O:20].[Na+]>O>[N:1]1([CH2:7][CH:8]2[CH2:13][N:12]([N:19]=[O:20])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)NCC(CN1CCOCC1)O2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CC(CN2CCOCC2)Oc2ccccc21

Procedure:
Similarly 8 g (0.034 mole) of racemic 2-(4-morpholinylmethyl)-3,4-dihydro-2H-1,4-benzoxazine in about 130 ml. of 2N aqueous hydrochloric acid was treated with 1.3 g (0.019 mole) of sodium nitrite in about 100 ml of water at 0° C. to produce racemic 2-(4-morpholinylmethyl)-4-nitroso-3,4-dihydro 2H 1,4-benzoxazine, which was used as such in the next synthetic step without further purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28]>CO>[C:27]([NH:31][CH2:20][CH:19]([OH:21])[CH2:18][O:17][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[CH:15]=[C:6]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=3)[O:7]2)=[CH:12][CH:11]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)c1
Reactant: CC(C)(C)N
Solvent: CO
Product: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC(O)CNC(C)(C)C)cc3o2)c1

Procedure:
3′,5′-Dimethoxy-7-(2,3-epoxy-propoxy)-flavone, 32 (500 mg, 1.41 mmol) and tert-butyl amine (0.6 mL, 5.64 mmol) in dry methanol (100 mL) were reacted in a similar manner to that described under 34 to afford 43. Yield 400 mg (66%); mp 145-146° C.; MS (FAB) 428 (M+1); IR (KBr) 3431, 1631; 1H NMR (200 MHz, DMSO-d6) δ 7.93 (d, J=8.8 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 7.15 (d, J=2.0 Hz, 2H), 7.08 (dd, J=8.9 Hz, 2.0 Hz, 1H), 6.92 (s, 1H), 6.68 (s, 1H), 4.17-4.01 (m, 3H), 3.82 (s, 6H), 2.77-2.59 (m, 2H), 1.08 (s, 9H). Analysis Calcd for C24H29NO6: C, 67.43; H, 6.84; N, 3.28. Found: C, 67.59; H, 6.73; N, 3.39.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](F)=[O:26].Cl>CCOCC>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:26]
Reactant: O=C(F)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(NCCCCCCCC(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(N(CCCCCCCC(=O)O)C(=O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6.1 g (23 mmol) of 8-(4-Methoxyphenylamino)-caprylic acid are dissolved in 40 cc. of 0.2 n soda lye. A solution of 4.4 g (23 mmol) of 3-(Trifluoromethyl)-benzoic acid fluoride in 50 cc. of ether are added thereto within 20 minutes with vivid stirring dropwise at 25° C., holding the pH at between 7.2 and 8 by the dropwise addition of 0.2 n soda lye. After the addition, vivid stirring is continued for 30 minutes. The mixture is then acidified to pH 3 by the addition of 2 n hydrochloric acid. The aqueous and ethereal layers are separated. The aqueous phase is extracted several times with ether and then is rendered alkaline by the addition of calcium hydroxide. The separated calcium fluoride is filtered off with suction and is discarded. The purified ethereal phase is shaken with water, dried over MgSO4 and the solvent is distilled off. The residue is purified chromatographically on silicic acid gel using chloroform as eluant.
Reaction SMILES: C1(O[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)C=CC=CC=1.[BrH:23].C(O)(=O)C>O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][Br:23])=[CH:10][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Fc1ccc(COc2ccccc2)cc1Oc1ccccc1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(CBr)cc1Oc1ccccc1

Procedure:
A mixture of 14.7 g (0.05 mol) of 4-fluoro-3-phenoxybenzyl phenyl ether, 50 ml of 32% strength aqueous hydrobromic acid and 60 ml of glacial acetic acid was heated to the reflux temperature for 10 hours, while stirring. The reaction mixture was then poured into 200 ml of water and extracted twice with 200 ml of methylene chloride each time. The combined methylene chloride phases were then extracted twice by shaking with 100 ml of 10% strength sodium hydroxide solution each time. The organic phase was subsequently dried over magnesium sulphate and the solvent was then stripped off under a waterpump vacuum. The residue was freed from the last residues of solvent by incipient distillation at a bath temperature of 60° C./3 mbars. 4-Fluoro-3-phenoxy-benzyl bromide was thus obtained as a viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][CH2:26][O:27][CH3:28])=[CH:19][CH:18]=2)=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:35]([O:42][C@@H:43]1[C@@H:49]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:48]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[O:46][C:44]1=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:35]([O:42][C@@H:43]1[C@@H:49]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:48]([O:58][CH2:59][C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[O:46][C:44]1([C:10]1[CH:11]=[C:12]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][O:25][CH2:26][O:27][CH3:28])=[CH:21][CH:22]=2)[C:13]([Cl:15])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:45])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: COCOCCc1ccc(Cc2cc(Br)c(OCc3ccccc3)cc2Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOCCc1ccc(Cc2cc(C3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCc3ccccc3)cc2Cl)cc1
Reaction time: 0.08 h
Yield: 21.8 %

Procedure:
To a tetrahydrofuran solution (3 mL) of 1-(benzyloxy)-2-bromo-5-chloro-4-[4-[2-(methoxymethoxy)ethyl]benzyl]benzene (290 mg, 0.609 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.6 M hexane solution of n-butyllithium (234 μL, 0.609 mmol), and the mixture was stirred for 5 minutes at the same temperature. Then a tetrahydrofuran solution (3 mL) of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (328 mg, 0.609 mmol) was added dropwise, and the mixture was stirred for an hour at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (124 mg, 22%) as a colorless oily compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[Cl:22])[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Reactant: NCCc1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1nc(NCCc2ccccc2Cl)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 160 °C
Yield: 39.9 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(2-chlorophenyl)ethanamine (300 mg, 1.94 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (150 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.99 (t, J=8 Hz, 2H), 3.52-3.53 (m, 2H), 5.39 (s, 2H), 6.03 (s, 2H), 6.29 (s, 1H), 7.03 (s, 1H), 7.24-7.46 (m, 5H), 7.71 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 11.53 (s, 1H).