Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=CC(N(CC=C(C)C)C2CCN(C(C3CC(C)CCN3CCC(C)C)=O)CC2)=CC=1)C1C=CC=CC=1.C[CH:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[CH:44]([C:53]([OH:55])=[O:54])[CH2:43]1>>[CH3:51][CH:50]([CH3:52])[CH2:49][CH2:48][N:45]1[CH2:46][CH2:47][CH2:42][CH2:43][CH:44]1[C:53]([OH:55])=[O:54]
Reactant: CC(C)CCN1CCC(C)CC1C(=O)O
Agent: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)C2CC(C)CCN2CCC(C)C)CC1
Product: CC(C)CCN1CCCCC1C(=O)O
Yield: 14 %

Procedure:
The preparation of Example 17: {4-[(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl }-[4-methyl-1-(3-methyl-butyl)-piperidin-2-yl]-methanone was made in accordance with the process of Example 11 (Step 3), except that 4-Methyl-1-(3-methyl-butyl)-piperidine-2-carboxylic acid was used instead of 1-(3-Methyl-butyl)-piperidine-2-carboxylic acid (14% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:33])([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=3)[NH:13][C:12](=[O:34])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].Cl[C:36]1C=C(C2C3C(=CC=C(C(C4C=C(Cl)N=CC=4)(O)C4N(C)C=NC=4)C=3)NC(=O)C=2)C=CC=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([OH:33])([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:18]=3)[N:13]([CH3:36])[C:12](=[O:34])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: Cn1cncc1C(O)(c1ccnc(Cl)c1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Reactant: CCOc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4cccnc4)c4cccnc4)cc23)c1
Product: CCOc1cccc(-c2cc(=O)n(C)c3ccc(C(O)(c4cccnc4)c4cccnc4)cc23)c1
Yield: 13 %

Procedure:
The same procedure was used as that in example 2, except that 4-(3-ethoxy-phenyl)-6-(hydroxy-di-pyridin-3-yl-methyl)-1H-quinolin-2-one (91 mg, 0.202 mmol) was used in the place 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-4-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1H-quinolin-2-one to give the title compound of example 37C as a white solid (12 mg, 13% yield).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].[OH-].[Li+]>>[CH3:28][C:26]1[CH:27]=[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:22])[F:21])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])[N:24]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[N:25]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cccc(-n2nc(C)cc2N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)c1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(5-methyl-2-m-tolyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid. MS (ESI): m/z=494.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[C:38]3[C:33](=[CH:34][C:35]([F:40])=[C:36](F)[CH:37]=3)[C:32](=[O:41])[N:31]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]2=[O:50])[CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[C:38]3[C:33](=[CH:34][C:35]([F:40])=[C:36]([N:11]4[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]4)[CH:37]=3)[C:32](=[O:41])[N:31]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:30]2=[O:50])[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)c1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Product: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCC(NC(=O)OC(C)(C)C)C4)cc32)c1
Yield: 86.7 %

Procedure:
Using General Method 4, the reaction of 3-t-butoxycarbonylamino-pyrrolidine (0.162 g, 0.9 mmol), triethylamine (0.12 mL, 0.9 mmol), and 1-(3-methoxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example E-1, 0.12 g, 0.3 mmol) provided 0.15 g of the title compound as a solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[CH:10]3)=[O:34])=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1
Reaction time: 6 h

Procedure:
A mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine (60 mg, 0.26 mmol), (4-benzyloxy-phenyl)-acetic acid (63 mg, 0.26 mmol), ethyldimethylpropylcarbodiimide hydrochloride (60 mg g, 0.31 mmol), N-hydroxybenzotriazole (42 mg, 0.31 mmol), and N-methyl morpholine (66 mg, 0.62 mmol) in 2 mL of DMF was shaken for 6 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in 1.5 mL of a 1:1 mixture of dimethyl sulfoxide/methanol and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.61 (m, 4H), 2.43 (m, 4H), 2.86 (t, 2H, J=6.78), 3.56 (s, 2H), 4.45 (t, 2H, J=6.78), 5.08 (s, 2H), 6.97 (m, 2H), 7.25–7.31 (m, 6H), 7.27 (m, 2H), 7.59 (m, 1H), 7.97 (s, 1H), 8.08 (s, 1H), 10.10 (s, 1H); MS (DCI/NH3) m/z 455 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C(N(CC)CC)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([NH:8][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)c1ccccc1
Temperature: 23.5 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
To a mixture of benzylamine (75.0 g, 0.700 mol), THF (300 mL) and triethylamine (70.8 g, 134 g, 0.700 mol) was added dropwise benzoyl chloride (98.4 g, 0.700 mol) at 2° C. or lower, and the mixture was allowed to warm, and stirred at 12-35° C. for 3 hr. The progress of the reaction was confirmed by TLC (eluent: toluene/ethyl acetate (4:1)). To the reaction mixture was added water (165 mL) at 16° C. or lower, the mixture was extracted with ethyl acetate (60 mL), and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed successively with 5% aqueous citric acid solution (50 mL×2) and 20% brine (75 mL×3), and dried over magnesium sulfate (20 g). The silica gel (12 g) was added to the solution, and the mixture was filtered through silica gel. The filtrate was concentrated under reduced pressure at 40° C. until the beginning of the precipitation. To the concentrate (263 g) was added ethyl acetate (41.5 g), and the resulting solid was dissolved at 60° C. The solution was cooled over 2 hr to 20° C., and ethyl acetate (40 mL) was added thereto. Then, the mixture was cooled to 5° C., and the resulting crystals were collected by filtration, and washed with cold ethyl acetate (75 mL). The obtained crystals were dried under reduced pressure at 40° C. to give N-benzylbenzamide (116 g, yield 78.5%) as white crystals.
Reaction SMILES: O[CH2:2][C@H:3]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6]2[C@H:4]1[CH2:5]2.C([N:21](CC)CC)C.CS(Cl)(=O)=O.[N-]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[NH2:21][CH2:2][C@H:3]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6]2[C@H:4]1[CH2:5]2
Reactant: CCN(CC)CC
Reactant: O=C(OCc1ccccc1)N1C[C@H]2C[C@H]2[C@H]1CO
Agent: CS(=O)(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: NC[C@@H]1[C@@H]2C[C@@H]2CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of racemic 7-2 (9.6 g, 38.8 mmol) in dichloromethane (190 mL) at 0° C. was added triethylamine (7.86 g, 78.0 mmol) followed by methanesulfonyl chloride (6.67 g, 58.2 mmol) and the reaction mixture was slowly warmed to ambient temperature over 24 h. The mixture was then quenched with water and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to an oil. The residue was dissolved in dimethylformamide (100 mL) and to this mixture was added sodium azide (10.1 g, 155 mmol). The reaction mixture was heated to 90° C. for 15 h. The reaction was cooled and partition between EtOAc (300 mL) and water (100 mL). The organic phase was washed with water (3×100 mL), and the organic phase was dried over MgSO4 and concentrated to an oil. The oil was dissolved in THF (370 mL) and to this was added polymer-bound triphenylphosphine (18.4 g, 40.4 mmol, 2.2 mmol/g loading) and water (6.6 g, 367 mmol). The reaction was heated to 50° C. for 2 h and the reaction was complete. The reaction was cooled to ambient temperature dried over MgSO4 and concentrated to yield >80% pure product as an oil which was used as is in the next reaction. ESI+ MS: [M+H]+ 247.4.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:36])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:26][C:18]=2[C:19]([O:21]C(C)(C)C)=[O:20])=[CH:12][CH:11]=1>>[CH3:8][N:9]([CH3:36])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:26][C:18]=2[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=1
Reactant: CN(C)c1ccc(Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(Nc2cc(-c3ccccc3)ccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 2-((4-(dimethylamino)phenyl)amino)-4-phenylbenzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, ethyl acetate and water were added to the obtained residue, and it was adjusted to pH6.5 with saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Ethyl acetate was added to the obtained residue, and solid matter was filtrated to give 2-((4-(dimethylamino)phenyl)amino)-4-phenylbenzoic acid 61 mg of a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24]OS(C)(=O)=O)=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:30])[CH2:4][CH3:5])[CH3:2].[CH2:31]([CH2:33][NH2:34])[OH:32]>>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:34][CH2:33][CH2:31][OH:32])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:30])[CH2:4][CH3:5])[CH3:2]
Reactant: NCCO
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCOS(C)(=O)=O)cc3)no2)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCNCCO)cc3)no2)cc1C
Yield: 13 %

Procedure:
The title compound (6 mg) is prepared in analogy to Example 160 starting from methanesulfonic acid 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl ester (50 mg, 111 μmol) and ethanolamine (34 mg, 556 μmol); LC-MS: tR=0.63 min; [M+1]+=415.07; 1H NMR (CDCl3): δ1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.63 (q, J=7.0 Hz, 4H), 2.80-2.86 (m, 2H), 2.87-2.93 (m, 2H), 2.94-3.00 (m, 2H), 3.62-3.67 (m, 2H), 3.73 (s, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.67 (s, 1H), 8.09 (d, J=8.0 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C(O)(=O)C.[I:25]C1C=CC=CC=1.II>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCCl>[C:1]([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:14]([I:25])=[C:10]([CH:9]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Ic1ccccc1
Reactant: CC(C)(C)OC(=O)c1cccc(C(=O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)c1ccc(I)c(C(=O)O)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
A 100 mL flask was charged with 3-(tert-butoxycarbonyl)benzoic acid (Matrix, 1.75 g, 7.87 mmol), palladium(II) acetate (0.177 g, 0.787 mmol), iodobenzene diacetate (2.54 g, 7.87 mmol), iodine (2.00 g, 7.87 mmol), and tetrabutylammonium iodide (2.91 g, 7.87 mmol). DCE (30 mL) was added and the dark reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was concentrated in vacuo, diluted with 2M aq. sodium carbonate solution, and then extracted with ether (2×). The aqueous layer was made acidic with concentrated HCl and then extracted with EtOAc (2×). The pooled EtOAc extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give crude 5-(tert-butoxycarbonyl)-2-iodobenzoic acid (1.7 g, 62%) which was used directly without further purification. A 200 mL round bottom flask was charged with crude 5-(tert-butoxycarbonyl)-2-iodobenzoic acid (1.7 g, 4.88 mmol) and HATU (2.23 g, 5.86 mmol). THF (30 mL), DMF (30.0 mL), and 2,6-lutidine (1.1 mL, 9.77 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Next, 1,2,3,4-tetrahydroisoquinoline (0.93 mL, 7.3 mmol) was then added. After stirring at room temperature 1 h, the reaction mixture was suspended in EtOAc, and then washed with sat. aq. sodium bicarbonate solution, 10% aq. LiCl solution, and then sat. aq. bicarbonate solution again. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Isco 120 g column eluting with 0-40% EtOAc/hexanes) to give the title compound (1.46 g, 65%) as a white foam. 1H NMR (CDCl3) δ 7.96-7.90 (m, 1H), 7.81-7.80 (m, 1H), 6.70-6.67 (m, 1H), 7.27-7.13 (m, 4H), 5.09-4.83 (m, 1H), 4.45-4.33 (m, 1H), 4.06-4.01 (m, 1H), 3.50-3.44 (m, 1H), 3.05-2.83 (m, 2H), 1.58 (s, 9H); MS(ESI+) m/z 464.1 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:15]2[CH2:27][CH2:26][C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([Cl:28])[CH:23]=4)[N:18](COC)[C:17]=3[CH2:16]2)([CH3:14])[CH2:11][O:12][CH3:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+]>CO.C1COCC1.Cl>[C:1]1([S:7]([C:10]([CH:15]2[CH2:27][CH2:26][C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([Cl:28])[CH:23]=4)[NH:18][C:17]=3[CH2:16]2)([CH3:14])[CH2:11][O:12][CH3:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCn1c2c(c3cc(Cl)ccc31)CCC(C(C)(COC)S(=O)(=O)c1ccccc1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCC(C)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 6 h
Yield: 13.2 %

Procedure:
95 mg (0.20 mmol) of (RS,SR)-2-(1-benzenesulfonyl-2-methoxy-1-methyl-ethyl)-6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazole were dissolved in 8 mL of MeOH/THF 1:1, and 5 drops of HCl 12M were added. The temperature was raised to 55° C. and the solution was stirred for 6 hours. By adding 2M NaHCO3 the solution was neutralized to pH=7, and the mixture was extracted with EtOAc. Column chromatography on silica gel with heptane/EtOAc 2:1 yielded 11 mg (13%) of (RS,SR)-2-(1-benzenesulfonyl-2-methoxy-1-methyl-ethyl)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole as a white solid, MS: 418 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([N:11]1[CH2:14][C:13]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:12]1)[CH2:6][CH2:5]2.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[OH-].[Na+].Cl[C:53]1[CH:58]=[C:57]([CH3:59])[N:56]=[CH:55][N:54]=1.Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:59][C:57]1[N:56]=[CH:55][N:54]=[C:53]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C@H:7]([N:11]2[CH2:12][C:13]4([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]4)[CH2:14]2)[CH2:6][CH2:5]3)[CH:58]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(Br)ccc31)C2
Reactant: Cc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Product: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)ncn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a 50 mL flask charged with (R)-tert-butyl 2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (4.0 g, 9.49 mmol) was added bis(triphenylphosphine)palladium(II) chloride (0.17 g, 0.24 mmol), potassium acetate (3.73 g, 37.97 mmol), bis(pinacolato)diboron (2.65 g, 10.44 mmol) followed by degassing via vacuum then backfilling with nitrogen 5 times. De-oxygenated (nitrogen stream for 30 minutes prior to addition) toluene (40 mL) was added to the mixture and the reaction was heated at 100° C. for 1.5 hours. The reaction was monitored for completion by HPLC. Upon formation of the boronic ester intermediate, the reaction was cooled to 40° C. and charged with a degassed solution of 4 M sodium hydroxide (11.87 mL, 47.46 mmol) followed by addition of 4-chloro-6-methylpyrimidine (1.53 g, 11.87 mmol). The resulting mixture was then heated to 90° C. for 5 hours under nitrogen. The reaction was cooled to room temperature and charged with water (25 mL). After stirring for 20 minutes, the mixture was filtered to remove black solids. The organic layer was extracted to an aqueous solution containing 1.5 equiv of HCl (40 mL). The organic layer was removed and the resulting solution was treated with (4 g) ISOLUTE® Ultra Pure Si-Thiol silica gel for 1.5 hours and filtered. The aqueous solution was adjusted to pH 7.8 with 4N NaOH and extracted with toluene (40 mL). The toluene layer was concentrated to approximately 15 mL under vacuum at 45° C. and heptane (75 mL) was added slowly and the mixture was stirred at 20° C. for 1 hour. The product was filtered and dried under vacuum at 45° C. for 8 hours to afford the title compound as a white solid (3.56 g, 86%). MS (ES+) 435.5 (M+H)+. 1H NMR (CDCl3) δ 1.46 (s, 9H), 1.70-1.74 (m, 4H), 1.90-2.01 (m, 1H), 2.13-2.26 (m, 1H), 2.59 (s, 3H), 2.84-2.93 (m, 1H), 3.04-3.21 (m, 5H), 3.30-3.38 (m, 4H), 3.95-4.02 (m, 1H), 7.40 (d, 1H), 7.56 (s, 1H), 7.87 (d, 1H), 7.95 (s, 1H), 9.12 (s, 1H).
Reaction SMILES: C(O[C:4]1(OCC)[CH2:8][CH2:7][CH2:6]O1)C.[CH3:12][O:13][C:14](=[O:26])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH2:23])=[C:17]([O:24][CH3:25])[CH:16]=1>C(O)(=O)C>[CH3:12][O:13][C:14](=[O:26])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([N:23]2[CH:4]=[CH:8][CH:7]=[CH:6]2)=[C:17]([O:24][CH3:25])[CH:16]=1
Reactant: CCOC1(OCC)CCCO1
Reactant: COC(=O)c1cc(OC)c(N)c(OC)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(-n2cccc2)c(OC)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9 g. of diethoxy-tetrahydrofuran and 5 ml. of glacial acetic acid was added dropwise at room temperature to a solution of 10.5 g. of 4-amino-3,5-dimethoxy-benzoic acid methyl ester in 50 ml. of glacial acetic acid with stirring. The mixture was stirred at 100° C. for an additional 30 minutes, cooled with ice, filtered under vacuum, dried and recrystallized from cyclohexane, whereby there was obtained 3,5-dimethoxy-4-(pyrrol-1-yl)-benzoic acid methyl ester having a melting point of 145°-146° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH:35]=O>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[O:22])=[CH:35][C:31]3[S:30][CH:34]=[CH:33][CH:32]=3)[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Reactant: O=Cc1cccs1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2cccs2)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2cccs2)c1

Procedure:
The reaction of hydroxylamine 55 (0.80 g, 2 mmol) with 2-thiophenecarboxaldehyde (64) (0.224 g, 2 mmol) afforded, after workup, a light yellow oil. The crude product was purified by flash chromatography with 2:1 ethyl acetate/hexane as the eluant to obtain 0.86 g (1.73 mmol, 86%) of 75 as a yellow gum: IR (CH2Cl2) 3440, 2940, 1698, 1625, 1560, 1472, 1375, 1298, 1215, 1105, cm-1 ; 1H NMR (CDCl3) δ 1.09 (d, J=6.2 Hz, 3H), 1.21 (d, J=6.2 Hz, 3H), 2.28 (s, 6H), 3.32 (s, 3H), 3.56 (t, J=4.8 Hz, 2H), 4.18 (m, 2H), 4.94 (septet, J=6.2 Hz, 1H), 5.09 (s, 1H), 6.99-8.52 (m, 8H); 13C NMR (CDCl3) δ 19.32, 19.44, 21.99, 22.22, 40.12, 58.85; 62.81, 67.18, 70.74, 102.75, 103.53, 118.83, 120.88, 127.19, 128.53, 129.34, 130.21, 130.29, 131.42, 133.00, 145.12, 145.91, 146.37, 149.97, 167.09, 167.55. Anal. calcd for C26H30N2O6S: C, 62.65; H, 6.02. Found: C, 62.47; H, 6.10.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:24](O)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl.CN(C=O)C>[CH2:24]([O:5][C:4](=[O:6])[C:3]([CH3:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: CCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCOC(=O)C(C)(C)C(F)(F)F
Reaction time: 2 h

Procedure:
3,3,3-Trifluoro-2,2-dimethyl-propionic acid (3.0 g, 19.2 mmol) and a drop of DMF are dissolved in 30 mL of DCM and treated dropwise at RT with oxalyl chloride (1.85 mL, 21.1 mmol). After 2 h gas evolution ceases and the mixture is treated slowly with triethyl amine (5.36 mL, 38.4 mmol) followed by n-butanol (2.1 mL, 23 mmol). The mixture is stirred over night, the solvent evaporated and the residue stirred with hexanes. The solid is filtered off and the filtrate is evaporated to a brown-red oil. Kugelrohr distillation (10 mbar, 60-80° C. oven temperature) gives the title compound a colorless liquid.
Reaction SMILES: Cl.Br[C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([CH3:11])[C:8]([Cl:12])=[N:7][N:6]2[CH:13]=1.[CH3:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1.CC([O-])(C)C.[K+]>C1COCC1>[Cl:12][C:8]1[C:9]([CH3:11])=[C:10]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH3:14])=[CH:22][CH:21]=2)[C:5]2[N:6]([CH:13]=[CH:3][N:4]=2)[N:7]=1
Reactant: CCOc1ccc(N)cc1
Reactant: Cc1cc2nc(Br)cn2nc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc(Nc2c(C)c(Cl)nn3ccnc23)cc1

Procedure:
(1d variation 2) To a mixture of bromo-6-chloro-7-methylimidazo[1,2-b]pyridazine HCl salt (102 mg, 0.36 mmol) from 1c, in THF (1.5 ml) was added p-Phenetidine (49 mg, 0.36 mmol) and a 1.0 M solution of KOt-Bu in THF (3.0 eq, 1.08 ml, 1.08 mmol). The mixture was allowed to heat at 50 C for 1 hour. The solution was then concentrated in vacuo to dryness to provide 6-chloro-N-(4-ethoxyphenyl)-7-methylimidazo[1,2-b]pyridazin-8-amine as a solid. m/e 303 (MH+).