Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([CH:25]4[CH2:28][CH2:27][CH2:26]4)[CH2:24][CH2:23]2)[N:16]=3)=[C:9]([F:29])[CH:8]=1.Cl.[OH-].[Na+]>C1COCC1>[CH:25]1([C:22]2([C:17]3[N:16]=[C:15]4[S:14][C:13]([C:10]5[CH:11]=[CH:12][C:7]([CH:2]=[O:1])=[CH:8][C:9]=5[F:29])=[N:21][C:20]4=[CH:19][CH:18]=3)[CH2:24][CH2:23]2)[CH2:26][CH2:27][CH2:28]1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(C4CCC4)CC3)nc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3ccc(C4(C5CCC5)CC4)nc3s2)c(F)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-cyclobutyl-cyclopropyl)-thiazolo[5,4-b]pyridine (85.7 mg, 0.209 mmol) and hydrochloric acid (5.0N, aq.) (2.00 mL, 10.02 mmol) in THF (4.0 mL) was stirred at 65° C. for 3 h. The reaction mixture was then cooled on an ice bath, and NaOH (5.0N, aq., 2.0 mL) was added. THF was removed in vacuo, and the resulting mixture was partitioned between EtOAc and water. The organic layer was separated, sequentially washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-30% EtOAc/hexanes) furnished 4-(5-(1-cyclobutylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzaldehyde as a light yellow solid. MS (ESI) m/z: Calculated: 352.1; Observed: 353.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C@H:32]3[CH2:37][CH2:36][C@@H:35]([O:38][CH3:39])[CH2:34][CH2:33]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C@H:32]3[CH2:33][CH2:34][C@@H:35]([O:38][CH3:39])[CH2:36][CH2:37]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C[C@H]2CC[C@@H](OC)CC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: COc1cn(C(C[C@H]2CC[C@@H](OC)CC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.5 h

Procedure:
2.10 g (3.55 mmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoyl}amino)benzoate (racemate) in 129 ml of ethanol/water (2.6/1) were reacted with 5.89 g (18.1 mmol) of caesium carbonate according to General Method 4. After complete conversion, the pH was adjusted to 5-6 with hydrochloric acid (1N) and the mixture was stirred for another 30 min. The precipitate was filtered off with suction, washed with a little water and dried under high vacuum and it corresponded to the title compound. Yield: 1.24 g (60% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1)([O-:16])=[O:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.CC(O)=O>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:20]3[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=3)[CH2:26][CH2:27]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Reactant: COc1cc(CC=O)ccc1C#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-methoxy-4-(2-oxoethyl)benzonitrile (100 mg, 0.57 mmol), 1-[2-(4-Nitrophenyl)ethyl]piperazine (134 mg, 0.51 mmol) in 60 mL of dry methanol were added 2 drop of HOAc and then stirred at room temperature for 1 hr. Then NaBH(OAc)3 (362 mg, 1.71 mmol) was added an the then the mixture was stirred overnight. Concentrated and the residue was purified via prep-TLC to give 2-methoxy-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.14 (d, J=8.6 Hz, 2H), 7.35˜7.47 (m, 3H), 6.79˜6.85 (m, 2H), 3.12 (s, 3H), 2.48˜2.96 (m, 16H). MS m/z: 395 (M+1)+. (0.052 μM)
Reaction SMILES: OO.[ClH:3].[CH2:4]([N:7]1[C:11]2=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:13]=[CH:14][CH:15]=[C:10]2[C:9]([S:26][CH3:27])=[C:8]1[CH3:28])[CH:5]=[CH2:6].S([O-])([O-])(=[O:31])=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[ClH:3].[CH2:4]([N:7]1[C:11]2=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:13]=[CH:14][CH:15]=[C:10]2[C:9]([S:26]([CH3:27])=[O:31])=[C:8]1[CH3:28])[CH:5]=[CH2:6]
Reactant: O=S([O-])([O-])=S
Reactant: C=CCn1c(C)c(SC)c2ccnc(N3CCc4ccccc4C3)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: OO
Solvent: CC(=O)O
Product: C=CCn1c(C)c(S(C)=O)c2ccnc(N3CCc4ccccc4C3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydrogen peroxide (50 wt. %, 100 μl) was added to a solution of 2-(1-allyl-2-methyl-3-methylsulfanyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (45 mg, 0.12 mmol) prepared in Example 631 in acetic acid (3 ml). The reaction mixture was stirred for 30 minutes at room temperature and sodium thiosulfate was added thereto. The reaction mixture was basified with a potassium carbonate solution and then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in ethyl ether, saturated with hydrochloric acid gas, and then filtered to give 5.5 mg of the titled compound as a white solid.
Reaction SMILES: C[O:2][CH:3]=[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])[CH3:5].Cl>C1COCC1.C(OCC)(=O)C>[CH3:21][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:10][C:6]=1[CH:4]([CH3:5])[CH:3]=[O:2]
Reactant: COC=C(C)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)C=O
Yield: 52.4 %

Procedure:
5-(2-Methoxy-1-methyl-vinyl)-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (7.0 g, 22.3 mmol) in THF (200 mL) is treated with concentrated HCl aqueous solution (7 mL) at 50° C. for 2 hours. The reaction mixture is diluted with ethyl acetate, washed with sodium bicarbonate aqueous solution, dried over sodium sulfate. Concentration and column chromatography on silica gel provided the title compound (3.5 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:11]=2[CH2:12]O)=[O:6])[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:26][CH2:12][C:11]1[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:9]=[N:8][C:7]=1[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:6]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 149.5 %

Procedure:
To a suspension of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxamide (500 mg) obtained in Example 112 and carbon tetrabromide (630 mg) in dichloromethane (5 ml) was added in small portions triphenylphosphine (598 mg) at 0° C., and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column (ethyl acetate/hexane=4/1 to ethyl acetate) to give the title compound as a white solid (890 mg).
Reaction SMILES: [F:1][C:2]1([F:14])[CH:7]=[CH:6][CH2:5][O:4][C:3]1([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>CCOC(C)=O.[Pd]>[F:14][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][O:4][C:3]1([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1(C)OCC=CC1(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C)OCCCC1(F)F
Reaction time: 1 h
Yield: 96 %

Procedure:
A stirred suspension of 10% Pd—C (37.5 mg, 0.035 mmol) in a solution of ethyl 3,3-difluoro-2-methyl-3,6-dihydro-2H-pyran-2-carboxylate in EtOAc (10 mL) was hydrogenated under balloon pressure for 1 h. The suspension filtered and evaporated to dryness to yield ethyl 3,3-difluoro-2-methyltetrahydro-2H-pyran-2-carboxylate as a clear oil (136 mg, 96%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.35-4.24 (m, 2H), 3.89-3.80 (m, 1H), 3.78-3.69 (m, 1H), 2.34-2.09 (m, 2H), 2.03-1.90 (m, 1H), 1.85-1.75 (m, 1H), 1.57-1.51 (m, J=1.5, 0.5 Hz, 3H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>COCCOC>[CH:22]([N:12]([C:10](=[O:11])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([O:32][CH3:31])[CH:38]=1)[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])[CH3:23]
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 59.1 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-methoxy-phenylboronic acid (29 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (32 mg, 60%). LC-MS m/e 417.35 (M+H+)
Reaction SMILES: C(OC([C:6]1[O:7][C:8]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:9]=2[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)C.[Cl-].[Na+].O>CS(C)=O>[CH2:14]([O:13][C:11]([C:10]1[C:9]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:8]=2[O:7][CH:6]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1oc2cc(F)ccc2c1C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1coc2cc(F)ccc12
Temperature: 160 °C
Reaction time: 4 h
Yield: 49.8 %

Procedure:
109 (40 g, 142.7 mmol) is dissolved in 300 ml of a DMSO and after addition of sodium chloride (16.7 g, 285.4 mmol) and water (5.1 ml) the mixture is stirred for 4 h at 160° C. (temperature of reaction mixture). Then the mixture is allowed to cool down and evaporated at high vacuum. The residue is dissolved in ethyl acetate, washed with water and brine and dried over sodium sulfate. Evaporation gave 14.8 g of an red oil, which is further purified by filtration over silica gel (ethyl acetate/hexanes 2:8).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[SH:22]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[S:22][C:2]1[S:3][C:4]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])c(Br)s1
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Yield: 25 %

Procedure:
Prepared by a similar procedure to that described as in Step D for example 22 from the 2-bromo-5-methylsulfonyl-3-nitro-thiophene (148 mg, 0.52 mmol) and 2,4-dichlorobenzenethiol (100 mg, 0.56 mmol) to afford the title product as a solid (50 mg, 25% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.35 (1H, s), 8.10 (1H, m), 8.20 (1H, m), 7.74 (1H, m), 3.42 (3H, s). MS m/z: 381.81 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH2:10])=[N:2]1.[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][C:18]1[N:2]2[N:1]=[C:5]3[N:6]=[CH:7][CH:8]=[CH:9][C:4]3=[C:3]2[N:10]=[C:14]([C:13]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=2[Cl:11])[C:15]=1[C:16]#[N:17]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: Nc1n[nH]c2ncccc12
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)nc2c3cccnc3nn2c1N

Procedure:
Commercial 1H-pyrazolo[3,4-b]pyridin-3-amine and (2,4-dichlorobenzylidene)malononitrile (Intermediate 1) were reacted according to the procedure of Example 1, Step A, and the crude product was purified by preparative HPLC (C18 reverse phase column, gradient elution with 10-80% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the title compound as a yellow solid. LC-MS 355 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(Cl)cn1N
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1ccc(Cl)cc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and 4-chloro benzaldehyde in refluxing methanol for 12 h. 1H NMR (CDCl3, δ in ppm): 8.35 (s, 1H), 7.78 (d, 2H, J=7.6 Hz), 7.42 (d, 2H, J=7.6 Hz), 7.19 (d, 1H, J=2.2 Hz), 6.89 (d, 1H, J=2.2 Hz), 3.83 (s, 3H).
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N+:18]=[N-:19].CO.C[O-].[Na+].[OH-].[Na+]>CO>[C:20]1([N:17]2[C:2]([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:3]([C:4]([OH:6])=[O:5])[N:19]=[N:18]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Reactant: [N-]=[N+]=Nc1ccccc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nnn(-c2ccccc2)c1CCc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 32.8 %

Procedure:
A solution of ethyl 3-oxo-5-phenylpentanoate (1.1 g) in methanol (50 ml) was cooled to 0° C.-5° C., azidobenzene (600 mg) and 28% sodium methoxide methanol solution (965 mg) were added and the mixture was stirred at 60° C. for 3 hr. Then, 1N sodium hydroxide (10 ml) was added and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated under reduced pressure and water (20 ml) was added. 1N Hydrochloric acid was added for neutralization and the mixture was extracted with ethyl acetate (30 ml×2). The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (480 mg) as a powder.
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16](=[O:18])[NH2:17])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:19][C:20](OCC)=[O:21])=[CH:8][C:9]=1[NH:10]2.[BH4-].[Li+].[NH4+].[Cl-]>C1COCC1.O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([CH2:19][CH2:20][OH:21])=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:16]([NH2:17])=[O:18])=[CH:13][C:14]=1[F:15]
Reactant: CCOC(=O)Cc1ccc2c(c1)[nH]c1c(C(N)=O)cc(F)c(Br)c12
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cc(F)c(Br)c2c1[nH]c1cc(CCO)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A solution of ethyl 2-(5-bromo-8-carbamoyl-6-fluoro-9H-carbazol-2-yl)acetate (500 mg, 1.27 mmol) in THF (10 mL) was treated with lithium borohydride (139 mg, 6.36 mmol) and stirred at room temperature overnight. The mixture was treated with saturated aqueous NH4Cl and stirred for 15 min. The mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were dried and concentrated, and the residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 30-100%), to provide 4-bromo-3-fluoro-7-(2-hydroxyethyl)-9H-carbazole-1-carboxamide as a white solid (310 mg, 69% yield). Mass spectrum m/z 351, 353 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.24 (br. s., 1H), 7.98 (d, J=10.3 Hz, 1H), 7.72-7.63 (m, 2H), 7.15 (dd, J=8.4, 1.3 Hz, 1H), 4.68 (t, J=5.3 Hz, 1H), 3.73-3.64 (m, 2H), 2.90 (t, J=7.0 Hz, 2H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11]=[C:10]([CH:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])[C:9]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=O)(=[O:3])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClC(Cl)C.O>[F:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH3:20])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[C:8]2[C:6]1[O:3][C:1]([CH3:2])=[N:4][N:5]=1
Reactant: CC(=O)NNC(=O)c1c(-c2ccccn2)c(C(C)NC(=O)OC(C)(C)C)nc2ccc(F)cc12
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: O
Solvent: CC(Cl)Cl
Product: Cc1nnc(-c2c(-c3ccccn3)c(C(C)NC(=O)OC(C)(C)C)nc3ccc(F)cc23)o1

Procedure:
A solution of tert-butyl 1-(4-(2-acetylhydrazinecarbonyl)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate (0.553 g, 1.183 mmol) and Burgess reagent (1.128 g, 4.73 mmol) in dichloroethane (11.83 mL) was heated in the microwave at 120° C. for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2×50 mL). The organic extracts were washed with brine (1×50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by silica gel column chromatography eluting with a gradient of 0% to 100% EtOAc in hexane, to provide tert-butyl 1-(6-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate as a pink solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (1H, d, J=4.3 Hz), 8.22-8.32 (1H, m), 7.80-7.92 (3H, m), 7.36-7.49 (2H, m), 7.17 (1H, d, J=7.0 Hz), 4.88 (1H, t, J=7.1 Hz), 2.34 (3H, s), 1.22-1.38 (12H, m); LC-MS (ESI) m/z 450.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:32]([O:34][CH3:35])=[O:33].[CH3:36][N:37](C)C=O>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>[C:36]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:32]([O:34][CH3:35])=[O:33])#[N:37]
Reactant: COC(=O)c1c(Br)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1c(C#N)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 126C (100 mg), dicyanozine (222 mg) and Pd(PPh3)4 (21.87 mg, 0.019 mmol) in N,N-dimethylformamide (4 ml) was heated at 180° C. for 400 seconds in a microwave reactor (CEM Discover) and then concentrated. The residue was dissolved in dichloromethane and purified by flash chromatography, eluting with 50%-100% dichloromethane in hexane to provide the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[N+:12]([C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([O:10][CH3:11])=[C:2]([CH3:1])[C:7]=1[CH3:8])([O-:14])=[O:13]
Reactant: COc1c(C)ccc(C)c1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1c(C)cc([N+](=O)[O-])c(C)c1C
Yield: 72 %

Procedure:
To a stirred, heated (70°-80° C.) solution of 20.3 g (0.135 mol) of 2,3,6-trimethylanisole in 200 ml of acetic acid was added dropwise 9.65 ml of conc. aqueous HNO3 in 20 ml of acetic acid. After the addition the mixture was poured onto ice, and the resulting mixture was extracted 3 times with methylene chloride. The organic phase was evaporated to remove acetic acid and methylene chloride, and the residue was dissolved in ether and washed twice with NaOH-solution and twice with NaHCO3 -solution. Drying (MgSO4) and evaporation gave 19.0 g (72%) of the product, which was used without further purification in the next step.
Reaction SMILES: Cl.[Sn](Cl)Cl.[N+:5]([C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)([O-])=O.C(=O)(O)[O-].[Na+]>CO>[NH2:5][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1Cc2ccccc2C1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 38.9 %

Procedure:
Concentrated hydrochloric acid (1.13 ml, 13.5 mmol) and anhydrous tin dichloride (1.38 g, 7.28 mmol) were sequentially added at 0° C. to a methanol (7 ml) solution of 2-[2-nitro-4-(trifluoromethyl)phenyl]isoindoline (641 mg, 2.08 mmol), obtained as described in Referential Example 20-1. The resulting mixture was warmed to room temperature and stirred for 8.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture. The resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=15/1). Thus, 2-[2-amino-4-(trifluoromethyl)phenyl]isoindoline (225 mg, 38.9%) was yielded as a red-orange colored oily material.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:15])=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][CH:9]=[CH:8]2)=O.[NH3:16]>>[OH:15][C:6]1[C:5]([C:3]([NH2:16])=[O:2])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2
Reactant: COC(=O)c1ccc2cnccc2c1O
Reactant: N
Product: NC(=O)c1ccc2cnccc2c1O

Procedure:
5-Hydroxy-6-isoquinolinecarboxylic acid methyl ester as reported by Dyke, S. F. et al., in Tetrahedron 1973, 29(6), 857-62, is reacted with excess ammonia in a steel bomb for 12-18 hr. The excess ammonia is allowed to evaporate and the residue is crystallized from a suitable solvent mix such as ethyl acetate-toluene to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N:14]=[C:15]=[S:16])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[C:31]([NH2:39])(=[NH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]2[S:16][N:39]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:38]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Reactant: N=C(N)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(-c2ccccc2)ns1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.1 %

Procedure:
A mixture of 2-(2-tert-butylphenoxy)-3-isothiocyanatopyridine (Example 1a) (100 mg, 0.35 mmol), diisopropylethylamine (186 μL, 1.05 mmol) and benzamidine hydrochloride (55 mg, 0.35 mmol) in DMF (2 mL) was stirred at rt for 18 h. Diethylazodicarboxylate (110 μL, 0.7 mmol) was added and mixture was stirred for 4 h. The reaction mixture was purified by preparative HPLC to give the title compound (110 mg, TFA salt) as a white solid. (M+H)+=403. 1H NMR (400 MHz, DMSO d6) δ ppm 1.31 (s, 9 H), 6.94 (dd, J=7.83, 1.26 Hz, 1 H), 7.16 (dd, J=7.58, 1.26 Hz, 1 H), 7.20-7.27 (m, 2 H), 7.44 (dd, J=8.09, 1.77, 1H), 7.48-7.56 (m, 3 H), 7.79 (dd, J=4.80, 1.51 Hz, 1H), 8.20 (dd, J=7.83, 1.52 Hz, 2 H), 9.04 (dd, J=7.83, 1.52 Hz, 1 H), 10.93 (s, 1 H).