Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:20]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[C:32](O)=[O:33])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:23]([O:22][C:20]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[C:32](=[O:33])[NH:18][C:16]1[CH:17]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[C:13]([Cl:19])=[CH:14][CH:15]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)[C@H]3CCCN3C(=O)OC(C)(C)C)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (800 mg), (R) —N-Boc-2-pyrrolidinecarboxylic acid (608 mg) and HBTU (1.46 g) in dry DMF (30 ml) containing N-methylmorpholine (1.26 ml) was stirred at room temp for 18 h. Silica gel (5 g) was then added and the mixture evaporated. The residue was purified by chromatography. Elution with 12:1 petrol:ethyl acetate gave a viscous brown gum (987 mg)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[N:15]2[CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Cc2ccc(OCc3ccccc3)cc2N1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1C(=O)Cc2ccc(OCc3ccccc3)cc21
Yield: 31 %

Procedure:
A mixture of 6-benzyloxy-1,3-dihydro-2H-indol-2-one (Example 9) (0.12 g; 0.5 mmol), K2CO3 (0.07 g; 0.5 mmol) and CH3I (0.031 ml) in acetone (5 ml) was refluxed under argon atmosphere for 6 hours. After evaporation to dryness, the residue was purified by flash chromatography eluting with petroleum ether/AcOEt 60/40 to give 6-benzyloxy-N-methyl-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cncnc3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-pyrimidin-5-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A, and benzenesulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.90 (s, 2H), 7.88 (m, 2H), 7.62 (m, 1H), 7.55 (m, 2H), 7.42 (d, 2H), 7.21 (d, 2H), 7.12 (m, 1H), 7.03 (d, 1H), 6.87 (d, 1H), 6.78 (s, 1H), 4.36 (s, 2H), 4.33 (s, 2H), 3.65 (s, 3H), 2.78 (t, 2H), 2.47 (t, 2H).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[H-].[Na+].[C:16](Cl)([Cl:18])=[O:17]>ClCCl.C1(C)C=CC=CC=1>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][C:4]([O:7][C:16]([Cl:18])=[O:17])=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cl)Oc1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
2.00 g (11.75 mmol) of [1,1′-biphenyl]-4-ol in suspension in 50 ml of dichloromethane are introduced into a 50-ml three-necked flask, 0.47 g (11.75 mmol) of 60% sodium hydride in mineral oil is added portionwise, and the solvent is evaporated off under reduced pressure. A white solid is obtained which is added over 1 h to 6.84 ml (12.92 mmol) of a 20% solution of phosgene in toluene at 30° C. and left in contact for 3 h.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].[NH2:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:35])=[N:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:23][C:24]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:35])=[N:29]3)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22]
Reactant: Cc1ncc2c(N)cc(F)cc2n1
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(C)c1OC
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cc(F)cc2nc(C)ncc12)C(F)(F)F)c1ccc(F)c(C)c1OC

Procedure:
In the same way as in Example 130, 300 mg (0.93 mmol) of (2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 183 mg (1.03 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 0.58 ml (1.86 mmol) of titanium tert-butoxide is reacted to give 5-{[(2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-1-[(7-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol. 460 mg of crude imine are cyclized in the same way as in Example 130 at −30° C. with 7.6 ml (7.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-65%) yields 135 mg of desired product.
Reaction SMILES: S[CH2:2][CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH:7]1[C:16]([OH:18])=[O:17])=[O:5].[OH-:19].[Na+].II.[S:23]([O-])([O-])(=O)=[S:24].[Na+].[Na+].Cl>O.C(O)C>[O:5]=[C:4]([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH:7]1[C:16]([OH:18])=[O:17])[CH2:3][CH2:2][S:23][S:24][CH2:2][CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH:7]1[C:16]([OH:18])=[O:17])=[O:19]
Reactant: [OH-]
Reactant: O=C(O)C1CCc2ccccc2N1C(=O)CCS
Reactant: O=S([O-])([O-])=S
Agent: Cl
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCc2ccccc2N1C(=O)CCSSCCC(=O)N1c2ccccc2CCC1C(=O)O

Procedure:
(±)-1,2,3,4-Tetrahydro-1-(3-mercapto-1-oxopropyl)-2-quinolinecarboxylic acid (13.27 g) was suspended in water (125 ml) and the pH was adjusted to 6-7 by the addition of 2 N sodium hydroxide. To the resulting clear solution was added 0.5 M iodine in 95% ethanol dropwise while maintaining the pH at 6.5 by the slow addition of 2 N sodium hydroxide. When a yellow color remained for at least five minutes, addition of the iodine solution was termined and the color was discharged with saturated aqueous sodium thiosulfate. The mixture was then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with 10% hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure to yield 11 g of (±) 1,1'-[dithiobis(1-oxo-3,1-propanediyl]-bis-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, m.p. 92°-103° (dec).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[CH:5]=[C:6]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O.S1C=CC=C1.[O-2].[Ca+2]>CO.[Pd]>[NH2:10][C:9]1[CH:8]=[CH:7][C:6]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:5][C:4]=1[CH:3]([O:2][CH3:1])[O:21][CH3:22]
Reactant: COC(OC)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: c1ccsc1
Solvent: CO
Product: COC(OC)c1cc(C(=O)c2ccccc2)ccc1N
Yield: 96.8 %

Procedure:
A mixture of 68 parts of intermediate 10, namely [3-(dimethoxymethyl)-4-nitrophenyl] phenylmethanone, 4 parts of a solution of thiophene in methanol 4%, 20 parts of calcium oxide and 474 parts of methanol was hydrogenated for 24 hours at normal pressure and room temperature with 6 parts of palladium-on-charcoal catalyst 10%. The catalyst was filtered off and the filtrate was evaporated. The residue was co-evaporated with methylbenzene, yielding 59.1 parts (96.8%) of [4-amino-3-(dimethoxymethyl)phenyl] phenylmethanone (interm. 64).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1)=[O:17])[CH3:14].C(Br)C=C.C1C[O:32][CH2:31][CH2:30]1>CCCCCC>[CH2:13]([O:15][C:16]([C:18]1([CH2:7][CH:5]=[CH2:6])[CH2:23][CH2:22][CH2:21][C:20]2([O:32][CH2:31][CH2:30][O:24]2)[CH2:19]1)=[O:17])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1CCCC(=O)C1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: CCCCCC
Product: C=CCC1(C(=O)OCC)CCCC2(C1)OCCO2
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
Then, to a round bottom flask was added N,N-diisopropylamine (3.97 mL, 28.4 mmol) and THF (22.1 mL). The mixture was cooled at −20° C. 1.6 M of n-butyllithium in hexane (15.8 mL) was added. The crude mixture was stirred at 0° C. for 30 min and then cooled down at −20° C., and 1,4-dioxa-spiro[4.5]dicane-7-carboxylic acid ethyl ester (4.50 g, 21.0 mmol) from step 1 was added dropwise. The mixture was stirred at 0° C. for 30 min, and then cooled at −20° C., and allyl bromide (2.00 mL, 23.1 mmol) was added. The mixture was warmed up to rt slowly and stirred at rt for 30 min. The reaction mixture was quenched with ice, diluted with ethyl acetate (60 mL), and washed sequentially with 1N aqueous HCl (5 mL), water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 4.30 g (81%) of the title compound, 7-allyl-1,4-dioxa-spiro[4.5]decane-7-carboxylic acid ethyl ester, as a yellow oil. It was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ5.64-5.74 (m, 1H), 4.97-5.05 (m, 2H), 4.05-4.17 (m, 2H), 3.82-3.99 (m, 4H), 2.34-2.41 (m, 1H), 2.27 (dt, J=13.6, 2.1 Hz, 1H), 2.08-2.16 (m, 2H), 1.76-1.88 (m, 1H), 1.60-1.72 (m, 2H), 1.46-1.54 (m, 1H), 1.42 (d, J=13.6 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H), 1.08-1.16 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[C:16]([O:25]CC)(=[O:24])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].CC(C)([O-])C.[K+].Cl>C(O)(C)(C)C>[CH2:22]([O:21][C:19]([C:18](=[C:6]([C:5]1[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:17][C:16]([OH:25])=[O:24])=[O:20])[CH3:23]
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(CC(=O)O)=C(c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution of commercially available 4-fluorobenzophenone (42 g., 0.21 mole), diethyl succinate (43.6 g., 0.25 mole) and potassium t-butoxide (23.7 g., 0.21 mole) in t-butanol (250 ml.) was stirred at reflux for 6 hours and then stirred at room temperature for an additional 16 hours. The reaction mixture was then acidified with 6N hydrochloric acid (200 ml.), evaporated under vacuum to remove the t-butanol and extracted with ether (2×250 ml.). The combined ether extract was extracted with 10% aqueous ammonium hydroxide (2×350 ml.). The combined aqueous extract was washed with ether (2×200 ml.), re-acidified with 6N hydrochloric acid and extracted again with ether (2×400 ml.). The combined ether extract was dried (MgSO4), filtered and evaporated under vacuum to an oil, which was crystallized by dissolution in hexane (100 ml.) followed by scratching the flask to initiate crystallization (48 g., 70% yield, m.p. 98°-99° C., elemental analysis calculated: 69.50% C; 5.22% H; 5.78% F; found: 69.34% C; 5.36% H; 6.09% F).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([NH:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)=[O:5].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.C(N(CC)CC)C>CC(O)C>[CH3:1][N:2]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1)[CH2:3][C:4]([NH:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)=[O:5]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CNCC(=O)NC1CN(C(=O)OC(C)(C)C)C1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN(CC(=O)NC1CN(C(=O)OC(C)(C)C)C1)c1ncnc2ccc(C(F)(F)F)cc12

Procedure:
A mixture of tert-butyl 3-(2-(methylamino)acetamido)azetidine-1-carboxylate (348 mg, 1.43 mmol) as prepared in the previous step and commercially available 4-chloro-6-(trifluoromethyl)quinazoline (327 mg, 1.41 mmol) were stirred in anhydrous iPrOH and triethylamine at 90° C. under argon for 1 hour. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0%-5% MeOH/EtOAc) to give a yellow solid after drying under high vac.
Reaction SMILES: C(NC(=O)O[CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[S:20]([NH:23][C:24](=[O:39])[C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)(=[O:22])=[O:21])[CH2:14][CH2:13]1)C1C=CC=CC=1.[CH2:48]([N:56]=[C:57]=[O:58])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(N=C=[O:68])C1C=CC=CC=1>>[C:50]1([CH2:49][CH2:48][NH:56][C:57](=[O:68])[O:58][CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[S:20]([NH:23][C:24](=[O:39])[C:25]3[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:26]=3)(=[O:21])=[O:22])[CH2:14][CH2:13]2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C(NCc1ccccc1)OCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: O=C=NCCc1ccccc1
Product: O=C(NCCc1ccccc1)OCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
Following procedure to make (9), phenethyl isocyanate was substituted for benzyl isocyanate to give the title compound after purification. 1H NMR (500 MHz, DMSO-d6): δ 12.43 (s, 1H), 8.45 (s, 2H), 8.10 (s, 1H), 7.37 (d, 2H), 7.27 (t, 3H), 7.16 (m, 3H), 7.07 (t, 2H), 4.34 (s, 2H), 3.61 (d, 2H), 3.14 (m, 2H), 3.30 (water), 2.88 (d, 2H), 2.66 (t, 2H), 2.48 (DMSO), 1.62 (m, 2H), 1.52 (m, 2H), 1.32 (m, 1H), 1.26 (m, 1H), 0.63 (m, 4H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]#[N:14])(=[O:3])[CH3:2].C(N(CC)CC)C.[SH2:22]>N1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13](=[S:22])[NH2:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2CC1C#N
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccccc2CC1C(N)=S
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 1-acetyl-2,3-dihydro-1H-indole-2-carbonitrile (0.00988 mol) and Triethylamine (0.0197 mol) in pyridine (50 ml) was treated with hydrogen sulfide (gas) at room temperature via a bubbler for 2 hours and the resultant saturated reaction mixture was closed and allowed to set for 16 hours. The reaction mixture was poured into 200 ml of an ice water slurry. A voluminous precipitate formed. The mixture was recooled in an ice bath and the precipitate was collected by suction filtration, washed with cold water, and air dried, yielding 1.62 g of 1-acetyl-2,3-dihydro-1H-indole-2-carbothioamide (intermediate 13, mp. 194-195° C.).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(=O)(=O)(O)O>>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: c1ccccc1
Reactant: CC1=CCCCC1
Agent: O=S(=O)(O)O
Product: CC1(c2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 36.5 %

Procedure:
A mixed solution of 75.0 mL (632 mmol) of 1-methyl-1-cyclohexene and 56.4 mL (632 mmol) of benzene was added dropwise to 225.6 mL (2.53 mol) of a benzene solution of 231 g (2.36 mol) of sulfuric acid at 0° C. over 1.5 hours. The resulting mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was quenched with 300 mL of water to separate the aqueous layer. The resulting organic layer thus obtained was washed with 100 mL of a saturated aqueous solution of sodium bicarbonate, 100 mL of water, and 100 mL of saturated saline and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated to obtain crude 1-methylcyclohexylbenzene. The resulting crude 1-methylcyclohexylbenzene was purified by distillation under reduced pressure (110 to 113° C./10 mmHg) to obtain 40.2 g of the intended product. Yield: 36.5%.
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.Cl[CH2:12][C@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C(#N)C.O>[CH3:18][C:15]1([CH3:19])[O:14][C@@H:13]([CH2:12][N:9]2[CH:8]=[C:4]3[N:5]=[CH:6][CH:7]=[C:2]([I:1])[C:3]3=[N:10]2)[CH2:17][O:16]1
Reactant: Ic1ccnc2c[nH]nc12
Reactant: CC1(C)OC[C@H](CCl)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CC1(C)OC[C@H](Cn2cc3nccc(I)c3n2)O1
Temperature: 120 °C
Yield: 34.8 %

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (100 mg, 0.408 mmol), (R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (0.056 ml, 0.408 mmol) and cesium carbonate (266 mg, 0.816 mmol) were combined in DMF (5 mL) at room temperature. The mixture was heated at 120° C. for 1 hour, then cooled and purified by preparative HPLC using a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column eluting with a gradient of 20-70% 10 mmol NH4HCO3 in 20/80 (v/v) water/acetonitrile in 10 mmol NH4HCO3 in water to give (S)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-7-iodo-2H-pyrazolo[4,3-b]pyridine (51 mg, 34.8% yield). MP 85-87° C. MS [M+H] found 360.1.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:3]=1[C:4]#[N:5].[Cl:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[O:28][CH2:29][CH2:30][NH2:31].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[Cl:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[O:28][CH2:29][CH2:30][NH:31][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(-c2cc(Nc3cc(C)[nH]n3)nc(Cl)c2C#N)cc1
Reactant: NCCOc1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2cc(Nc3cc(C)[nH]n3)nc(NCCOc3ccccc3Cl)c2C#N)cc1
Product: Cl
Temperature: 100 °C
Reaction time: 27 h

Procedure:
Compound C (200 mg, 589 mmol), 2-(2-chlorophenoxy)ethylamine (202 μl) and sodium hydrogencarbonate (495 mg) were added to DMSO (6 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(2-chlorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-(4-methoxyphenyl)nicotinonitrile hydrochloride (12 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:31]C)C=C4)N(CC2)C1.[O-]S([O-])=O.[Na+].[Na+].[OH2:74]>CC(O)(C)C>[CH3:1][C:2]1[CH:3]=[C:4]([C@H:5]([OH:31])[CH2:6][OH:74])[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=Cc1cccc(C)c1
Reactant: O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: Cc1cccc([C@H](O)CO)c1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3-methylstyrene (1.69 ml, 12.7 mmol), and AD-mix-α (17.78 g, 12.7 mmol) in water (65 ml) and t-BuOH (65 ml) was stirred at 0° C. for 3.5 h. To this reaction mixture was added Na2SO3 (20 g) and the mixture was stirred at rt for 1 h. The reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), and concentrated to give 2.07 g of light brown oil, which was purified by column chromatography (silica gel: 110 g, ethyl acetate/hexane: 3/2) to afford 1.89 g (98%) of desired product as light brown oil.
Reaction SMILES: [N:1]([O-])=O.[Na+].[ClH:5].[F:6][C:7]([F:18])([F:17])[CH2:8][O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].[OH-].[Na+]>O.Cl.C(OCC)(=O)C.CCOCC>[ClH:5].[F:6][C:7]([F:17])([F:18])[CH2:8][O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][NH2:1]
Reactant: O=N[O-]
Reactant: Nc1ccccc1OCC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: NNc1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Sodium nitrite (11.7 g, 0.17 mol) in 25 mL water was added dropwise to a cold stirred mixture of 2-(2,2,2-trifluoroethoxy)aniline hydrochloride (33.7 g, 0.15 mol), concentrated HCl (53 mL) and water (25 mL) so that the temperature remained at -5° to -3° C. After the additio was complete, a solution of stannous chloride dihydrate (71.7 g, 0.32 mol) in 122 mL 6N HCl was added over a 1 hour period. After 0.5 hour at 0° C. the reaction was allowed to warm to room temperature. Stirring was continued for 24 hours, the reaction diluted with water, ethyl acetate (400 mL) added, cooled and made alkaline using 50% NaOH. The phases were separated and the organic phase washed with water, dried (MgSO4), filtered and concentrated to give an oil. The oil was dissolved in ether and treated with ethereal HCl. The resulting precipitated solid was collected and dried to give 26.4 g (73%) of 2-(2,2,2-trifluoroethoxy)phenylhydrazine hydrochloride, m.p. 168°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]1[CH2:19][N:18]3[C:13](=[CH:14][C:15]([C:22](=[O:25])[CH2:23][CH3:24])=[C:16]([CH3:21])[C:17]3=[O:20])[C:7]1=[N:8]2.C(Cl)Cl.C1COCC1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]1[CH2:19][N:18]3[C:13](=[CH:14][C:15]([CH:22]([OH:25])[CH2:23][CH3:24])=[C:16]([CH3:21])[C:17]3=[O:20])[C:7]1=[N:8]2
Reactant: CCC(=O)c1cc2n(c(=O)c1C)Cc1cc3c(OC)cccc3nc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3c(OC)cccc3nc1-2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1-methoxy-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one (5.0 mg, 15 μmol) in a mixture of MeOH (0.2 mL), CH2Cl2 (0.6 mL) and THF (0.2 mL) was treated with a single portion of sodium borohydride (4.0 mg, 110 ,μmol). After stirring at room temperature for 1.5 h, the reaction mixture was concentrated under reduced pressure. The residue was treated with 10% aqueous NH4Cl (350 μL) and allowed to stand at 4° C. overnight. The solid which formed was collected by filtration, washed sparingly with H2O and dried to afford the title compound. 1H NMR (CDCl3 /MeOH-d4) d 8.77 (s, 1H), 7.69 (m, 2H), 7.59 (s, 1H), 6.92 (dd, J=6.8, 1.7 Hz, 1H), 5.23 (br s, 2H), 4.89 (m, 1H), 4.05 (s, 3H), 2.24 (s, 3H), 1.79 (m, 2H), 1.03 (t, J=7.4 Hz, 3H).