Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[S:14][CH:13]=[C:12]([CH3:15])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].BrN1C(=[O:22])CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[S:14][CH:13]=[C:12]([CH:15]=[O:22])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cnc2c(C)csc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(C=O)csc2c1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
To a solution of 3-methyl-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (1.2 g) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (2.4 g) followed by AIBN (50 mg) and the resulting mixture was heated at reflux for 4 hours. The reaction mixture was cooled; the solids were removed by filtrations and copiously washed with carbon tetrachloride. The filtrate was evaporated under reduced pressure, the residue was dissolved in dimethyl sulfoxide (20 mL) and the resulting mixture was heated at 80° C. for 1 hour. The reaction mixture was cooled, diluted with water, basified by addition of a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (acetone/DCM, 5/95) to give 0.8 g of 3-formyl-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:10]1[C:28]([CH3:29])=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[CH:25]=[N:24][N:23]([CH3:26])[C:20]4=[N:21][CH:22]=3)[S:16][C:12]=2[C:11]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO>[C:38]([O:37][C@@H:9]([C:10]1[C:28]([CH3:29])=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[CH:25]=[N:24][N:23]([CH3:26])[C:20]4=[N:21][CH:22]=3)[S:16][C:12]=2[C:11]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH2:8][OH:7])([CH3:41])([CH3:39])[CH3:40]
Reactant: Cc1cc2nc(-c3cnc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3cnc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 50 °C

Procedure:
To a solution of compound (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzo[d]thiazol-6-yl)ethyl pivalate (14 mg, 0.024 mmol) in THF (0.50 mL) and MeOH (0.50 mL) was added aqueous NaOH (0.10 mL of a 2 N solution). The reaction mixture was heated at 50° C. for 17 h, cooled, diluted with satd. aqueous NH4Cl and extracted with ethyl acetate. The organic layer was dried and concentrated to give the desired product which was used without any further purification. LCMS-ESI+: calc'd for C27H28ClN4O2S: 507.2 (M+H+); 507.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][CH:14]1[CH2:16][CH2:15]1)=[O:5].[H-].[Na+]>N1C=CC=CC=1>[CH:14]1([N:13]2[C:2]3[N:20]=[CH:19][CH:18]=[CH:17][C:3]=3[C:4](=[O:5])[NH:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH2:16][CH2:15]1
Reactant: O=C(Nc1ccccc1NC1CC1)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C1Nc2ccccc2N(C2CC2)c2ncccc21
Temperature: 80 °C
Yield: 67.5 %

Procedure:
To a solution of title compound 80a (1.9 g, 6.6 mmol) in pyridine (60 mL) was added washed sodium hydride (0.8 g, 19.8 mmol, 60% in oil). Bubbling occurred and the clear solution turn yellow. The mixture was heated to 80° C. for 1 h and overnight at room temperature. It was then heated to 120° C. for 1 h (the mixture turned black). The mixture was cooled down to room temperature and 1N HCl (20 mL) was added slowly. This mixture was extracted with DCM (2×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude was purified by flash chromatography (SiO2, 0% to 50% ethyl acetate in hexanes over 20 min then 50% for 10 min) to afford the title compound 81a (1.12 g, 68%) as a beige solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([CH3:19])=[C:10]([CH2:17]Br)[C:11](=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([CH3:19])=[C:10]([CH2:17][N:24]3[C:23](=[O:25])[C:22]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]4[C:20]3=[O:30])[C:11](=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(C)c(CBr)c(=O)oc2c1C
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2c(C)c(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1C
Temperature: 0 °C

Procedure:
A mixture of 7-acetoxy-3-bromomethyl-4,8-dimethylcoumarin (200 mg, 0.617 mmol) and potassium phthalimide (126 mg, 0.680 mmol) was stirred overnight at room temperature in DMF (3 mL). The slurry was poured into ice water, filtered and washed with a copious amount of water to remove traces of DMF to give 7-acetoxy-4,8-dimethyl-3-phthalimidomethylcoumarin, a creamy white solid after drying (221 mg, 91.7%). 1H NMR (CDCl3): δ7.84-7.67 (m, 4H), 7.55 (d, J=8.8 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 4.92 (s, 2H), 2.62 (s, 3H), 2.36 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])[C:11](=[O:32])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.I[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[N:41]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C1CCCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:30][CH3:31])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])[C:11](=[O:32])[C@H:10]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[N:41]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: COc1cccc(CI)n1
Agent: O=C([O-])O
Agent: [Li]C(C)CC
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC[C@@H](CN1CCCS1(=O)=O)N1C(=O)[C@H](Cc2cccc(OC)n2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
To a solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)piperidin-2-one (Example 420, Step A, 0.7 g, 1.413 mmol) in THF (5.65 ml) at −78° C. was added dropwise sec-butyllithium, (1.4 M in cyclohexane, 1.06 ml, 1.483 mmol). The reaction was warmed to −10° C. After about 5 minutes, the reaction was returned to a −78° C. bath. A solution of 2-(iodomethyl)-6-methoxypyridine (Example 420, Step B, 0.387 g, 1.554 mmol) in THF (1 mL) was added dropwise to the cooled reaction mixture. The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction contents were poured into saturated sodium bicarbonate and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (step gradient elution 5 to 50% diethyl ether in dichloromethane) afforded the title compound as the more polar diastereomer.
Reaction SMILES: [Cl:1][C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:25](#N)C.[H-].[Na+]>IC>[Cl:1][C:2]1[N:24]=[C:5]2[C:6]([N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:25])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(Cc1ccccc1N(C)S(C)(=O)=O)c1cccn2nc(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
185 a) To a solution of N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (250.0 mg, 0.6834 mmol) in acetonitrile (1 mL, 20 mmol) at room temperature was added sodium hydride, 60% disp. in mineral oil (33.0 mg, 0.825 mmol) followed by iodomethane (46.80 uL, 0.7517 mmol). The mixture was stirred at room temperature for 2 hours then additional iodomethane (10 uL) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to a tan resin. The recovered material was purified via chromatography using an ISCO automated purification apparatus (silica gel column 24 g 20%→80% ethyl acetate:hexane solvent gradient). N-(2-{[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-methyl-amino}-methyl]-phenyl)-N-methyl-methanesulfonamide was isolated as tan foam (0.207 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.6 Hz, 1H), 7.35-7.27 (m, 4H), 6.89-6.84 (m, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.54-5.40 (br m, 1H), 5.06-4.90 (br m, 1H), 3.32 (s, 3H), 3.24 (s, 3H), 3.01 (s, 3H). MS=380, 382 (MH)+. 185 b) N-Methyl-N-{2-[(methyl-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-amino)-methyl]-phenyl}-methanesulfonamide was prepared from N-(2-{[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-methyl-amino]-methyl}-phenyl)-N-methyl-methanesulfonamide (75.0 mg, 0.197 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (42.0 mg, 0.220 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (18.0 mg, 0.0329 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.023 g, 21%). 7.94 (d, J=6.6 Hz, 1H), 7.56-7.51 (m, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.35-7.28 (m, 3H), 6.88 (d, J=8.1 Hz, 2H), 6.70 (t, J=7.3 Hz, 1H), 6.57-6.50 (m, 2H), 5.35-5.23 (m, 1H), 5.12-5.00 (m, 1H), 3.23 (s, 3H), 3.15-3.10 (m, 4H), 3.07 (s, 3H), 2.99 (s, 3H), 2.63-2.58 (m, 4H), 2.36 (s, 3H). MS=535 (MH)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[N:17][CH:18]=1)[NH:15][CH2:14][CH2:13][CH2:12]2.FC(F)(F)[C:23]([OH:25])=[O:24]>C(Cl)Cl>[C:3]([O:25][C:23]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:3]=3[C:2]([F:19])([F:1])[F:20])=[CH:18][N:17]=2)[CH2:12][CH2:13][CH2:14]1)=[O:24])([CH3:8])([CH3:4])[CH3:2]
Reactant: FC(F)(F)c1ccncc1-c1cnc2c(c1)CCCN2
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cnccc3C(F)(F)F)cnc21

Procedure:
6-(4-Trifluoromethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester is synthesized according to the procedure of Suzuki Coupling Method V, as illustrated above. It is then used in the synthesis of 6-(4-trifluoromethyl-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine according to the procedure for Step 2 of Example 27 using 20% trifluoroacetic acid in DCM as the reagent.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:23]1[N:27]([CH2:28][CH2:29][C:30]#[N:31])[N:26]=[N:25][N:24]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:8][C@H:9]([C:23]1[N:27]([CH2:28][CH2:29][C:30]#[N:31])[N:26]=[N:25][N:24]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)c1nnnn1CCC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCCn1nnnc1[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.83 h

Procedure:
(S)-3-[5-(1-t-butoxycarbonylamino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile (9.22 g, 22 mmol) is dissolved in methylene chloride (135 mL) under nitrogen. To the stirred solution is added trifluoroacetic acid (50 mL). After 50 minutes, the solution is concentrated under reduced pressure and the residue is treated with ether (200 mL). The amorphous solid is filtered off, washed with ether and dried under vacuum at 45° for 2 hours, then at room temperature for 18 hours to yield (S)-3-[5-(1-amino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile trifluoroacetate salt, m.p. 211°-212°, [α]D =+23.35° (c 1.05, DMSO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:18]([NH:21]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:19][CH:20]=1)[C:5]([OH:17])([C:10]#[C:11][C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:6]([F:9])([F:8])[F:7].Cl.C(=O)(O)[O-].CCOCC>CO>[NH2:21][C:18]1[C:4]([C:5]([OH:17])([C:10]#[C:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:6]([F:7])([F:8])[F:9])=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=1
Reactant: OC(C#Cc1ccco1)(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOCC
Product: Nc1ccc(Cl)cc1C(O)(C#Cc1ccco1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 20 g of 3-Chloro-6-(triphenylmethy)amino-α-(2-furanyl)ethynyl-α-(trifluoromethyl)benzyl alcohol (Example 9, Part B) in 20 mL of methanol was added 0.125 mL of 12 N aqueous hydrochloric acid, and the resulting solution was stirred at ambient temperature for 30 min. The reaction mixture was poured onto aqueous bicarbonate and extractec with ether. The ether layer was washed with brine, dried and evaporated. The residue was dissolved in methanol after cooling in ice for 1 h, the precipitated methyl trityl ether was filtered off. After evaporation of the filtrate, the residue was chromatographed over silica gel (elution with hexanes/ethyl acetate 3:1) affording after crystalization from hexane/ethyl acetate 280 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:10]([OH:12])=O.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:35])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]1>ClCCl.CO>[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:10](=[O:12])[C:9]#[C:8][C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][C:2]=2[Br:1])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH2:33]1
Reactant: CC1CCN(CCc2ccc(N)cc2Cl)CC1
Reactant: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Br
Solvent: CO
Solvent: ClCCl
Product: CC1CCN(CCc2ccc(NC(=O)C#Cc3ccc(-c4ccccc4)cc3Br)cc2Cl)CC1

Procedure:
Prepared analogously to Example 2.3.f. from (3-bromobiphenyl-4-yl)propynoic acid and 3-chloro-4-[2-(4-methylpiperidin-1-yl)ethyl]phenylamine. Yield: 0.24 g (50% of theory); C29H28BrClN2O (M=535.90); calc.: molecular ion peak (M+H)+: 535/37/39; found: molecular ion peak (M+H)+: 535/37/39; Rf value: 0.48 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([NH2:32])=[CH:30][C:29]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:28][N:27]=2)[CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[N:23]1([C:26]2[C:31]([NH:32][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[CH:3]=3)=[CH:30][C:29]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:28][N:27]=2)[CH2:22][CH2:21][O:20][CH2:25][CH2:24]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Fc1cc(F)c2c(Cl)cc(-c3ccccn3)nc2c1
Solvent: Cc1ccccc1
Product: Fc1cc(F)c2c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)cc(-c3ccccn3)nc2c1

Procedure:
Prepared according to Procedure H using 4-chloro-5,7-difluoro-2-(pyridin-2-yl)-quinoline (40.0 mg, 0.145 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 8.65 (1H, d, J=7.2 Hz), 8.62 (1H, dt, J=4.8, 0.8 Hz), 8.54 (1H, s), 8.46 (1H, d, J=17.8 Hz), 7.87 (1H, td, J=7.7, 2.0 Hz), 7.83 (1H, d, J=2.7 Hz), 7.69 (1H, d, J=2.7 Hz), 7.66 (1H, br. s.), 7.36 (1H, ddd, J=7.5, 4.7, 1.1 Hz), 7.02 (1H, ddd, J=14.1, 8.4, 2.5 Hz), 3.89 (4H, dd, J=5.7, 3.9 Hz), 3.80-3.87 (4H, m), 3.24 (4H, dd, J=5.7, 3.9 Hz), 3.03-3.17 (4H, m). Mass Spectrum (ESI) m/e=505.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][CH3:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]=1
Reactant: CCc1ccc(OCC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1ccc(OCCNc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(4-ethylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 445 (M++1)
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([O:12][CH2:13][CH3:14])=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][S:4](=[O:16])(=[O:15])[N:3]=1.[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:17]1([NH:23][C:24]([NH:1][C:2]2[C:7]3[C:8]([O:12][CH2:13][CH3:14])=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][S:4](=[O:16])(=[O:15])[N:3]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C=NC1CCCCC1
Reactant: CCOc1cccc2c1C(N)=NS(=O)(=O)O2
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOc1cccc2c1C(NC(=O)NC1CCCCC1)=NS(=O)(=O)O2
Reaction time: 18 h

Procedure:
0.15 g (0.61 mmol) of 4-amino-5-ethoxy-1,2,3-benzoxathiazine 2,2-dioxide is stirred with 0.1 g (0.79 mmol) of cyclohexyl isocyanate in 30 ml of dry tetrahydrofuran in the presence of 10 mg of DBU, first at room temperature for 1 hour and then at 40° C. for 18 hours. The mixture is concentrated under reduced pressure, and the residue is dissolved in dichloromethane and washed with water. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. This gives 0.15 g of crude product which, after dissolution in 14 ml of acetonitrile and 6 ml of water, is purified by means of reversed phase HPLC (Kromasil 100 C18, 250×40 mm, 5 μm, 0.01% HCOOH/H2O acetonitrile gradient 34/66, isocratic). This gives 55 mg (24.2% of theory) of compound I-24 as a white solid.
Reaction SMILES: C(OC)(OC)OC.[Br:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([NH:15][NH2:16])=[N:13][CH:14]=1.[C:23](O)(C(F)(F)F)=O>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]2[N:13]([CH:23]=[N:16][N:15]=2)[CH:14]=1
Reactant: NNc1ncc(Br)cc1-c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: COC(OC)OC
Solvent: ClCCl
Product: Brc1cc(-c2ccccc2)c2nncn2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Trimethyl orthoformate (564 μL, 5.16 mmol) was added into a solution of 1-(5-bromo-3-phenylpyridin-2-yl)hydrazine (1.29 mmol, crude) in CH2Cl2 (12 mL). TFA (100 μL, 1.29 mmol) was added after 15 mins. The reaction mixture was stirred at room temperature for 30 mins and then concentrated. The residue was purified by a flash column using a gradient of ethyl acetate (50-80%) in heptane as an eluent. The product containing fractions were concentrated to give 6-bromo-8-phenyl-[1,2,4]triazolo[4,3-a]pyridine (328.7 mg, 85% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]#[N:24])=[N:9]2)=[CH:4][CH:3]=1.[Cl-].[NH4+].[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]3[NH:29][N:28]=[N:27][N:24]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc(F)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cc(-c3nnn[nH]3)nn2-c2ccc(F)cc2)cc1
Temperature: 105 °C
Reaction time: 10 h
Yield: 63.1 %

Procedure:
A mixture of 1-(4-fluoropheny)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile (1 g), ammonium chloride (0.25 g) and sodium azide (0.24 g) in N,N-dimethylformamide (10 ml) was stirred at 105° C. for 10 hours. The mixture was poured into ice-water, and the precipitates were collected, washed with water, and recrystallized from a mixture of ethanol and tetrahydrofuran to give crystals of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-(5-tetrazolyl)pyrazole (0.71 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3]1.[NH4+].[Cl-].[CH3:21]COCC>[Cu]Cl>[CH3:21][C:4]1([CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3][C:2]([CH3:1])([CH3:18])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]1
Reactant: CCOC(=O)C(C#N)=C1CC(C)(C)CC(C)(C)C1
Reactant: CCOCC
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(=O)C(C#N)C1(C)CC(C)(C)CC(C)(C)C1
Reaction time: 0.08 h
Yield: 47 %

Procedure:
Anhydrous copper (I) chloride (0.8 g, 8 mmol) was added to a cooled solution of alkylmagnesium iodide (prepared from magnesium (0.46 g, 19.2 mmol) and iodomethane (2.84 g, 20 mmol)) in ether (12 ml). The mixture was stirred in an inert atmosphere for 5 min and a solution of ethyl (3,3,5,5-tetramethylcyclohexylidene)cyanoacetate (16) (2 g, 8 mmol) in ether (10 ml), was added dropwise keeping the temperature below -1 5 C. After the addition of ketone was completed, the reaction mixture was stirred for 3 h and carefully neutralised with saturated aqueous NH4Cl solution. Traditional workup for Grignard reactions gave crude material which was separated on a silica gel column, eluting with a petroleum ether-ethyl acetate mixture (20:1) to give 1.0 g (47%) of 17 as an oil.
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[NH2:2].[BH4-].[Na+].[OH2:28]>O1CCCC1.[OH-].[Na+]>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][C:19]([OH:28])([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[NH2:2]
Reactant: O
Reactant: CCCCCC(C)=CCCC(CCCCCCC(=O)OCC)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCC(C)(O)CCCC(CCCCCCC(=O)OCC)C(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Mercuric acetate (3.8 g., 0.012 mole) is dissolved in water (12 ml.) and tetrahydrofuran (20 ml.) is added to give a suspension of a yellow solid. Then, ethyl 8-carbamoyl-12-methyl-11-heptadecenoate (4.2 g., 0.012 mole) in tetrahydrofuran (20 ml.) is added, and the mixture stirred at room temperature for 24 hours. After 6 hours, the yellow suspended solid has disappeared and a cloudy solution results. To the solution is added 3M sodium hydroxide solution (12 ml.), followed by 0.5M sodium borohydride solution in 3M sodium hydroxide (12 ml.). Liquids are decanted from the precipitated mercury. The organic layer is taken up in ether, washed with three portions of water and dried over sodium sulfate. Evaporation of the ether leaves 4.0 g. of ethyl 8-carbamoyl-12-hydroxy-12-methylheptadecanoate which is used in the next step without further purification.