Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]3[O:37][C:38]4[CH:44]=[CH:43][C:42]([CH2:45][CH3:46])=[CH:41][C:39]=4[N:40]=3)=[CH:31][CH:30]=2)[O:23]1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[C:18]([OH:19])(=[O:23])[CH3:17].[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH3:20])[CH2:13]3)[N:3]=[C:2]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]4[O:37][C:38]5[CH:44]=[CH:43][C:42]([CH2:45][CH3:46])=[CH:41][C:39]=5[N:40]=4)=[CH:31][CH:30]=3)[C:10]=12
Reactant: CCc1ccc2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: COCCN1CCC(n2nc(I)c3c(N)ncnc32)C1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: CC(=O)O
Product: CCc1ccc2oc(Nc3ccc(-c4nn(C5CCN(CCOC)C5)c5ncnc(N)c45)cc3)nc2c1

Procedure:
rac-N2-(4-{4-Amino-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-1,3-benzoxazol-2-amine monoacetate was prepared from rac-3-iodo-1-[1-(2-methoxyethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.319 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-ethyl-1,3-benzoxazol-2-amine (0.145 g, 0.399 mmol) in a manner similar to that used for the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as a white solid (0.082 g, 52%). 1H NMR (DMSO-d6, 400 MHz) 1.23 (t, 3H), 1.90 (s, 3H), 2.33-3.47 (m, 10H), 2.66 (q, 2H), 3.25 (s, 3H), 5.40 (m, 1H), 6.99 (d, 1H), 7.33 (s, 1H), 7.40 (d, 1H), 7.66 (d, 2H), 7.93 (d, 2H), 8.25 (s, 1H), 10.81 (s, 1H); RP-HPLC Rt 11.781 min, 93% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 499 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH3:31]>C(O)C.O.Cl>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]2[N:19]=[C:2]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: CC(C)N1CC(F)(F)C(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Yield: 55.8 %

Procedure:
A mixture of 0.5 g (0.0017 mole) of 2-chloro-7,7-difluoro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292b) and 0.35 g (0.002 mole) of 4-amino-3-methoxy-benzoic acid in 20 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with 0.5M hydrochloric acid and water and dried to give 0.40 g of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-292).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][N:5]([S:7]([CH3:10])(=[O:9])=[O:8])[CH2:4][C@H:3]1[NH:11][C:12]1[C:13]2[N:14]([CH:21]=[C:22]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)[CH:23]=2)[N:15]=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19].C1CCN2C(=NCCC2)CC1.[CH3:40][C:41]1([CH3:44])[CH2:43][O:42]1>C(#N)C.CO>[OH:42][C:41]([CH3:44])([CH3:43])[CH2:40][N:26]1[CH:25]=[C:24]([C:22]2[CH:23]=[C:13]3[C:12]([NH:11][C@H:3]4[C@@H:2]([CH3:1])[CH2:6][N:5]([S:7]([CH3:10])(=[O:8])=[O:9])[CH2:4]4)=[C:17]([C:18]([NH2:20])=[O:19])[CH:16]=[N:15][N:14]3[CH:21]=2)[CH:28]=[N:27]1
Reactant: C[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cn[nH]c3)cc12
Reactant: CC1(C)CO1
Solvent: CC#N
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CC(C)(C)O)c3)cc12
Temperature: 60 °C
Yield: 31.9 %

Procedure:
To slurry of 4-((3S,4S)-4-methyl-1-(methylsulfonyl)pyrrolidin-3-ylamino)-6-(1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 211, 40 mg, 0.099 mmol) in acetonitrile (0.3 mL) was added DBU (0.060 mL, 0.397 mmol) and 2,2-dimethyloxirane (25.02 mg, 0.347 mmol) and the resulting mixture was heated at 60° C. for ˜16 h. The mixture was cooled, diluted with MeOH, and was purified via preparative reverse-phase HPLC (method B). Fractions which contained the major product were combined and concentrated to give an aqueous solution which was lyophilized to afford a near white solid. This solid was triturated with 1 mL of aq sat. NaHCO3, sonicated, and the resulting solid was collected, rinsed with water and dried on the filter to afford 15 mg (30%) of the title compound as an off-white solid. HPLC (method B) retention time=2.57 min. LCMS (M+1)=476.2. 1HNMR (400 MHz, METHANOL-d4) δ 8.18 (s, 1H), 7.99 (s, 1H), 7.88 (d, J=1.5 Hz, 1H), 7.85 (s, 1H), 7.10 (d, J=1.5 Hz, 1H), 4.98-4.93 (m, 1H), 4.15 (s, 2H), 3.85 (dd, J=10.8, 4.4 Hz, 1H), 3.75 (dd, J=9.8, 7.8 Hz, 1H), 3.58 (dd, J=10.9, 1.7 Hz, 1H), 3.25 (t, J=10.1 Hz, 1H), 2.88 (s, 3H), 2.86-2.77 (m, 1H), 1.27-1.22 (m, 9H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([O:19][CH3:20])=[O:18])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C

Procedure:
(S)-methyl 6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoate (8.60 g) was hydrogenated in 150 mL MeOH over 5% palladium on activated carbon (1.08 g) under 1 atm hydrogen at ambient temperature for 3 hours. The spent catalyst was removed by vacuum filtration through a celite pad which was washed with MeOH. The combined filtrate and wash were concentrated under reduced pressure, affording (S)-methyl 6-amino-2-(tert-butoxycarbonylamino)hexanoate (TU3000-128) as clear viscous oil. MS (ESI+): calcd. 261.17. found 261.20 (MH+). H-NMR (600 MHz, CDCl3):1.328 (2H, m), 1.375 (9H, s), 1.390 (2H, m), 1.55 (1H, m), 1.74(1H, m), 2.623(2H, d, J=6.9 Hz), 3.671 (3H, s), 4.237 (1H, m), 5.007 (1H, m).
Reaction SMILES: C(O[C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)C.[OH-].[NH4+:17].[ClH:18].CCOCC>C(O)C>[NH2:17][C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1.[ClH:18].[NH2:17][C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1
Reactant: [NH4+]
Reactant: CCOC1=NCc2c[nH]c3cccc1c23
Agent: Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: NC1=NCc2c[nH]c3cccc1c23

Procedure:
To a suspension of 5-ethoxy-1,3-dihydropyrrolo[4,3,2-de]isoquinoline (200 mg, 1 mmole), described in Example 5, in ethanol (2 ml), aqueous ammonium hydroxide (25%, 0.5 ml, 1.4 mmole) is added followed by 2.3 N HCl in ethanol (0.5 ml). The mixture is heated at reflux for 0.5 hour, then ether is added and the light green crystalline precipitate collected to give the hydrochloride salt of the title compound, 5-amino-1,3-dihydropyrrol[4,3,2-de]isoquinoline hydrochloride, mp 227° - 228°C.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[S:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1.C1(C)C=CC=CC=1>O>[Br:2][CH2:6][C:7]1[S:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1ccc(CO)s1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(CBr)s1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 261.6 %

Procedure:
Phosphorus tribromide (PBr3) (10.45 g) was added dropwise to a mixture of 2-hydroxymethyl-5-nitrothiophene (17.7 g) and toluene (150 ml) and this mixture was stirred at 70° C. for 1.5 hours. The reaction mixture was poured into water and extracted with ether. The ether layer was washed with water and dried (MgSO4), after which the solvent was evaporated off. The residual oil was subjected to solica gel column chromatography and eluted with chloroform to yield 2-bromomethyl-5-nitrothiophene (22.43 g, 92%) as an oil.
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:52]2[CH:57]=[C:56]([O:58][CH3:59])[C:55]([O:60][CH3:61])=[C:54]([O:62][CH3:63])[CH:53]=2)=[C:10]([CH:51]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:50])[C:29]3[CH:34]=[C:33]([N+:35]([O-])=O)[CH:32]=[CH:31][C:30]=3[C:38]3[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=3)[CH2:24][CH2:23]2)[CH2:15][CH2:14]1)=[O:12])([O-])=O>[Pd].C(O)(=O)C.CO>[NH2:35][C:33]1[CH:32]=[CH:31][C:30]([C:38]2[CH:39]=[C:40]([O:48][CH3:49])[C:41]([O:46][CH3:47])=[C:42]([O:44][CH3:45])[CH:43]=2)=[C:29]([CH:34]=1)[C:28]([N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]3[CH:51]=[C:6]([NH2:3])[CH:7]=[CH:8][C:9]=3[C:52]3[CH:53]=[C:54]([O:62][CH3:63])[C:55]([O:60][CH3:61])=[C:56]([O:58][CH3:59])[CH:57]=3)[CH2:14][CH2:15]2)[CH2:23][CH2:24]1)=[O:50]
Reactant: COc1cc(-c2ccc([N+](=O)[O-])cc2C(=O)N2CCN(CCCN3CCN(C(=O)c4cc([N+](=O)[O-])ccc4-c4cc(OC)c(OC)c(OC)c4)CC3)CC2)cc(OC)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(-c2ccc(N)cc2C(=O)N2CCN(CCCN3CCN(C(=O)c4cc(N)ccc4-c4cc(OC)c(OC)c(OC)c4)CC3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
10% Palladium on carbon (50 mg) was added to a solution in acetic acid-methanol (1 ml—1 ml) of 1,3-bis[4-[5-nitro-2-(3,4,5-trimethoxyphenyl)benzoyl]1-piperazinyl]propane dihydrochloride (91 mg; 0.10 mmol) synthesized by the process described in Example 8. After the mixture was stirred at room temperature for 3 hours under hydrogen, the catalyst was removed from the reaction mixture by filtration. The filtrate was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resultant concentrated residue to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 29 mg (yield: 37%) of 1,3-bis[4-[5-amino-2-(3,4,5-trimethoxyphenyl)benzoyl]-1-piperazinyl]propane as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10](=[O:11])/[C:9](=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])/[CH:8]([CH3:18])[CH2:7][C:5]=2[N:6]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1>C1COCC1>[Br:1][C:2]1[S:3][C:4]2[C:10]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)([OH:11])/[C:9](=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])/[CH:8]([CH3:18])[CH2:7][C:5]=2[N:6]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)/C=C1/C(=O)c2sc(Br)nc2CC1C
Solvent: C1CCOC1
Product: CCOC(=O)/C=C1\C(C)Cc2nc(Br)sc2C1(O)c1ccc(Cl)cc1
Temperature: -65 °C

Procedure:
A 3-liter flask equipped with a mechanical stirrer, addition funnel, and nitrogen inlet was charged with (E)-ethyl 2-(2-bromo-5-methyl-7-oxo-4,5-dihydrobenzo[d]thiazol-6(7H)-ylidene)acetate (24.1 g, 73 mmol, 1.0 equiv) and then diluted with THF (800 mL). To the resulting solution was added 0.6M LaCl3.2LiCl (243 mL, 146 mmol, 2.0 equiv) and then the reaction mixture was cooled to −65° C. by the aid of a dry-ice acetone bath. The addition funnel was then charged with 1.0M 4-chlorophenylmagnesium bromide (146 mL, 146 mmol, 2.0 equiv) and then slowly added to the reaction mixture over a 25 minute period. Upon completion of the addition, TLC analysis showed full consumption of the starting material (TLC of the starting material in 20% EtOAc/Hex has Rf=0.50; TLC of the product in 20% EtOAc/Hex has Rf=0.38), and the reaction was quenched with saturated NH4Cl (100 mL) and then diluted with EtOAc (1 L) and H2O (1.5 L). The cooling bath was removed and the mixture was allowed to warm to room temperature with stirring. The layers were separated and the aqueous extract was washed with EtOAc (1 L). The combined organics were dried over Na2SO4, filtered through a small plug of silica gel eluting with EtOAc, and then concentrated in vacuo. The resulting crude residue was chromatographed using a 330 g RediSep normal phase silica gel cartridge (EtOAc/Hex, 5%→15%) on a CombiFlash system to afford desired product. TLC (20% EtOAc/Hex) Rf=0.38; 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=8.6 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 5.62 (s, 1H), 4.57-4.40 (m, 1H), 4.22-4.04 (m, 2H), 3.03 (qd, J=16.6, 3.8 Hz, 2H), 2.61 (br s, 1H), 1.38 (d, J=7.2 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].[C:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:32]3[CH:33]=[CH:34][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][CH:31]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(-c3ccc(C(C)(C)C)cc3)c1)C(C)(C)C2
Yield: 80 %

Procedure:
To a mixture solution of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (1.0 g, 2.5 mmol), 4-tert-butylphenylboronic acid (582 mg, 3.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (289 mg, 0.25 mmol) in dioxane (5.0 mL) was added 2 M sodium carbonate solution in water (2.5 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 110° C. The mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 2-(4′-tert-butyl-biphenyl-3-yl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (924 mg, 80%) as a white solid: LC/MS m/e calcd for C29H32ClNO2 (M+H)+: 463.04, observed: 463.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:9][CH:10]=[C:5]2[NH:4][C:3]1=[O:19].[CH3:20][C:21]1([CH2:24]O)[CH2:23][CH2:22]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:9][CH:10]=[C:5]2[N:4]([CH2:20][C:21]2([CH3:24])[CH2:23][CH2:22]2)[C:3]1=[O:19]
Reactant: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)nc21
Reactant: CC1(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1c(=O)n(CC2(C)CC2)c2ccc(-c3ccccc3C#N)nc21
Reaction time: 1 h

Procedure:
2-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)benzonitrile (4-1) (50 mg, 0.2 mmol), 1-methylcyclopropanemethanol (52 mg, 0.6 mmol), Diisopropyl azodicarboxylate (121 mg, 0.6 mmol), and triphenylphosphine (157 mg, 0.6 mmol) were added to a microwave vial under nitrogen and dissolved with DCM (1 mL). The reaction was stirred for one hour, and desired product was observed via LCMS. The mixture was diluted with methanol and purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile); the desired fractions were collected and concentrated to produce 2-{3-methyl-1-[(1-methylcyclopropyl)methyl]-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl}benzonitrile (4-2). HRMS (M+H)+: observed=319.1551, calculated=319.1553.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=C)[CH:5]=[C:4]([CH3:10])[CH:3]=1.[O-:11][Mn](=O)(=O)=O.[K+:16].[OH2:17]>CC(C)=O>[K+:16].[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O-:11])=[O:17])[CH:5]=[C:4]([CH3:10])[CH:3]=1
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=Cc1cc(C)cc(Cl)n1
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(Cl)nc(C(=O)[O-])c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of 6-chloro-4-methyl-2-vinyl-pyridine (1.24 g, 8.06 mmol) in water (50 mL) and acetone (50 mL), KMnO4 (6.53 g, 41.3 mmol) is added. The dark mixture becomes warm (40° C.) and is stirred at rt for 3 h before it is filtered over a sintered glass filter. The solvent of the colourless filtrate is evaporated to give crude 6-chloro-4-methyl-pyridine-2-carboxylic acid potassium salt (3.2 g) as a colourless solid; LC-MS: tR=67 min, [M+1]+=171.99. This material is suspended in ethanol (150 mL) and H2SO4 (2 mL) is added until a clear solution forms. The mixture is heated to 70° C. for 18 h. The mixture is carefully diluted with sat. aq. NaHCO3 solution until a pH of 9 is reached. The mixture is extracted three times with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 3:2 to give ethyl 6-chloro-4-methyl-pyridine-2-carboxylate (500 mg) as a pale yellow oil; LC-MS: tR=0.87 min; [M+1]+=200.04; 1H NMR (CDCl3): δ 1.45 (t, J=7.3 Hz, 3H), 2.45 (s, 3H), 4.48 (q, J=6.8 Hz, 2H), 7.35 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11](=[O:14])[C:12]=1[CH3:13])=[CH:9][C:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)=[C:7]([CH3:27])[CH:6]=2)[CH3:2].[H-].[Na+].Cl[C:31]([O:33][CH3:34])=[O:32]>CN(C)C=O>[C:31](=[O:32])([O:33][CH3:34])[O:14][C:11]1[C:10]2[C:5](=[CH:6][C:7]([CH3:27])=[C:8]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)[CH:9]=2)[N:4]=[C:3]([CH2:1][CH3:2])[C:12]=1[CH3:13]
Reactant: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(OC(=O)OC)c1C
Temperature: 15 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Dimethylformamide (980 ml) and 98 g of 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one were charged into a 2000-ml glass flask equipped with a stirring device, a thermometer, a reflux condenser, and a calcium chloride tube under a nitrogen atmosphere, and the temperature of the contents of the flask was cooled to 15° C. A 55% sodium hydride (18.2 g) was added thereto, and a reaction was allowed to proceed at 15 to 20° C. for one hr. Methyl chloroformate (32.1 g) was added dropwise into the reaction solution, and a reaction was allowed to proceed at room temperature for one hr. The reaction mixture was poured into 5 L of ice-water contained in the a 10-L plastic container, and the mixture was stirred at room temperature for two hr. The precipitated solid was collected by filtration through a suction filter and was washed with water and n-hexane. The solid was dried under the reduced pressure to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4-yl methyl carbonate (103.3 g, yield: 91.4%). The results of 1H-NMR analysis showed that the compound thus obtained was No. 120 described in a brochure of International Publication No. 2006/013896.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][CH3:9])([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[S:10](Cl)(Cl)=[O:11].O>C(OCC)C>[CH2:1]([C:3]1([CH2:8][CH3:9])[CH2:6][O:7][S:10](=[O:11])[O:5][CH2:4]1)[CH3:2]
Reactant: CCC(CC)(CO)CO
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: CCC1(CC)COS(=O)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Step A A mixture of 2,2-diethyl-propane-1,3-diol (Aldrich) (5.5 g, 40 mmol) in anhydrous ethyl ether (100 mL) at 0° C. was added thionyl chloride (10.6 g, 90 mmol). The reaction mixture was stirred at 0° C. for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl ether. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, concentrated to give 5,5-diethyl-[1,3,2]dioxathiane 2-oxide as a colorless oil (7 g, 98%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](O)=[O:32]>N1C=CC=CC=1>[F:24][C:16]1[CH:15]=[C:14]([NH:13][C:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[O:32])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C(O)c1ccccn1
Reactant: COC(=O)c1ccc(N)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added to a pyridine (500 ml) solution of 18.9 g of methyl 4-amino-2-fluorobenzoate and 16.5 g of picolinic acid, and stirred at room temperature for 2 hours. The solvent was evaporated away under reduced pressure, 600 ml of ethyl acetate was added to the residue, the organic layer was washed with aqueous 0.25 N hydrochloric acid solution, aqueous 0.25 N sodium hydroxide solution and saturated saline water, dried, concentrated under reduced pressure, solidified from a mixed solvent of hexane/ethyl acetate, and the solid was taken out through filtration. This was dried under reduced pressure to obtain 28.3 g of the entitled compound as a white solid.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18])[CH2:14][CH3:15].C(N(CC)CC)C.O1CCCC1>CCOCC>[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH2:14][CH3:15]
Reactant: CC(C)CS(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)CC(C)C)n1

Procedure:
A mixture of 9.5 g. 3-isobutylsulphonyl-1,2,4-triazole, 8.2 g. dipropylcarbamoyl chloride, 7.5 ml. dry triethylamine and 100 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 11 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride, to give 1-dipropylcarbamoyl-3-isobutylsulphonyl-1,2,4-triazole, m.p. 62° - 63.5°C. (from petroleum ether, b.p. 62° - 68°C.).