Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[C:14]([Br:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CO)nc3N21
Yield: 93.4 %

Procedure:
To a solution of 5.00 g (4R,9aR)-6-Hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 50 ml tetrahydrofuran was added at 0°° C. 2.75 g N-bromosuccinimide at once and the mixture was stirred at 0° C. for 1 h. The reaction mixture was partitioned between 10% sodium thiosulfate and ethyl acetate. The phases were separated and the organic phase was washed with 10% sodium bicarbonate and brine dried over magnesium sulfate and evaporated. The residue was triturated in ca 20 ml heptane:ethyl acetate 1:3 to yield 5.75 g of the title compound as white crystals melting at 110-112° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.Cl.[Cl:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH:17]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:10].[Cl:25][C:20]1[CH:19]=[C:18]([C:16]2[CH:15]=[N:14][CH:13]=[C:12]([CH2:11][N:5]3[CH:6]=[CH:7][N:8]=[C:4]3[CH3:3])[CH:17]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: ClCc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Reactant: Cc1ncc[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nccn1Cc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a suspension of sodium hydride (17 mg of a 55% dispersion in mineral oil, 0.39 mmol) in DMF (5 ml) was added 2-methylimidazole (32 mg, 0.39 mmol). This mixture was stirred for 1.5 h at 20° C. Following this, 3-chloromethyl-5-(3,4-dichloro-phenyl)-pyridine hydrochloride (1:1) (100 mg, 0.32 mmol) and triethylamine (78 mg, 0.78 mmol) were added and the mixture heated to 100° C. for 4 h. After cooling, the DMF was evaporated and the residue was directly chromatographed [silica, elution with CH2Cl2/(2M NH3 in MeOH)=85:15] to afford the free base of the title compound as a yellow oil. This material was dissolved in MeOH, cooled to 4° C. with stirring and treated with HCl/EtOH (1.46 M 1.1 eq) for 15 min. Evaporation of the solvent and drying under high vacuum at 50° C. for 2 h afforded the title compound (71 mg, 62%) as a light yellow solid. MS: m/e=317.1 (M+)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:17](=[O:23])[N:18]([CH2:21]C)CC)=[C:9]([CH:16]=1)CNC(=O)OC)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Li+].Cl>CO>[C:1]([C:5]1[CH:16]=[C:9]2[C:8](=[CH:7][CH:6]=1)[C:17](=[O:23])[NH:18][CH2:21]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)C(=O)c1ccc(C(C)(C)C)cc1CNC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CNC2=O
Temperature: 110 °C
Yield: 56.2 %

Procedure:
A 25-mL microwave vial equipped with a magnetic stirrer was charged with 102b (858 mg, 2.68 mmol), tetrahydrofuran (5 mL), methanol (5 mL) and 2 M aqueous lithium hydroxide (5 mL). The vial was loaded in a Biotage microwave and heated at 110° C. for 2.5 h. After this time, the solution was neutralized with 2 M hydrochloric acid to pH 7 and concentrated in vacuo. The resulting residue was partitioned between ethyl acetate (150 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 50% ethyl acetate to 100% ethyl acetate/hexanes) to afford a 56% yield (285 mg) of 102c as an off-white solid: mp=132-134° C.; 1H NMR (300 MHz, CDCl3) δ 7.80 (d, 1H, J=7.8 Hz), 7.52 (m, 2H), 6.71 (br s, 1H), 4.44 (s, 2H), 1.37 (s, 9H), MS (ESI+) m/z 190.1 (M+H).
Reaction SMILES: C(N(CC)CC)C.Br.[CH3:9][N:10]1[C:14]2[CH2:15][NH:16][CH2:17][CH2:18][C:13]=2[CH:12]=[N:11]1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[N:27]=[C:28]([CH3:40])[N:29]2[C:34]=1[C:33](N1C=NC=N1)=[N:32][CH:31]=[N:30]2>ClCCl>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[N:27]=[C:28]([CH3:40])[N:29]2[C:34]=1[C:33]([N:16]1[CH2:17][CH2:18][C:13]3[CH:12]=[N:11][N:10]([CH3:9])[C:14]=3[CH2:15]1)=[N:32][CH:31]=[N:30]2
Reactant: Cc1nc(-c2ccccc2F)c2c(-n3cncn3)ncnn12
Reactant: Cn1ncc2c1CNCC2
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2F)c2c(N3CCc4cnn(C)c4C3)ncnn12
Temperature: 40 °C

Procedure:
Triethylamine (0.510 mL, 3.66 mmol) and C9 (0.333 g, 1.58 mmol) were added to a solution of C6 (0.360 g, 1.22 mmol) in dichloromethane (10 mL), and the reaction mixture was heated at 40° C. for 18 hours. The mixture was then washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification was effected first via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane), then by reversed phase HPLC (Column: Phenomenex Gemini C18, 5 μm; Mobile phase A: 0.1% ammonium hydroxide in water; Mobile phase B: 0.1% ammonium hydroxide in methanol; Gradient: 5% to 100% B). The product was obtained as a solid. Yield: 202 mg, 0.556 mmol, 46%. LCMS m/z 364.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 7.63 (ddd, J=7.6, 7.5, 1.8 Hz, 1H), 7.52 (dddd, J=8.3, 7.5, 5.2, 1.8 Hz, 1H), 7.35 (ddd, J=7.6, 7.5, 1.1 Hz, 1H), 7.22 (br ddd, J=10.0, 8.3, 1.0 Hz, 1H), 7.16 (br s, 1H), 4.45 (br s, 2H), 3.76-3.84 (m, 2H), 3.43 (s, 3H), 2.67 (s, 3H), 2.35-2.41 (m, 2H).
Reaction SMILES: CO.[OH-].[Na+].[CH3:5][C:6]1([CH3:17])[CH:8]([CH2:9][C:10](Cl)([Cl:12])[Cl:11])[CH:7]1[C:14]([OH:16])=[O:15]>O>[CH3:5][C:6]1([CH3:17])[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[CH:7]1[C:14]([OH:16])=[O:15]
Reactant: CC1(C)C(CC(Cl)(Cl)Cl)C1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Yield: 86.2 %

Procedure:
To 120 ml of methanol solution containing 4.8 g of sodium hydroxide were added 11.1 g of 2,2-dimethyl-3-(2',2',2'-trichloroethyl)-cyclopropanecarboxylic acid (purity: 91.8%, cis/trans ratio: 82.8/17.2) to heat the resulting mixture for 37 hours under reflux. The mixture was diluted with water and neutral part was removed by extraction with ether. The water layer was acidified with conc. hydrochloric acid and extracted with ether. The ether layer was concentrated to obtain 8.15 g of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylic acid, cis/trans ratio 79.8/20.2, purity 92.4%, yield 86.8%.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[NH4+]>O1CCCC1.CO.[Zn]>[NH2:10][C:9]1[C:2]([CH3:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: Cc1c(C#N)cccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(N)cccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a mixture of 2-methyl-3-nitrobenzonitrile (5.50 g, 33.9 mmol) and ammonium chloride (25.4 g, 475 mmol) in tetrahydrofuran (100 mL) and methanol (100 mL) at 0° C. was added zinc dust (31.1 g, 475 mmol) in portions. The mixture was stirred at room temperature for 2 hr. The insoluble material was removed by suction filtration through CELITE®, and the filtrate was concentrated under vacuum. The residue was diluted with water (50 mL) and extracted with CH2Cl2 (4×100 mL). The combined extract was dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (4.19 g, 31.7 mmol, 93% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:35]([NH:37][CH2:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:36])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([N:17]([S:24]([NH:27][C:28]([O:30]C(C)(C)C)=O)(=[O:26])=[O:25])[CH2:18]C(OCC)=O)[CH2:13]1)[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([N:12]3[CH2:16][CH2:15][C@H:14]([N:17]4[CH2:18][C:28](=[O:30])[NH:27][S:24]4(=[O:26])=[O:25])[CH2:13]3)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:35]([NH:37][CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:36]
Reactant: CCOC(=O)CN([C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN([C@H]2CCN(c3ccc4c(C(=O)NCC5CCCCC5)c(Cl)ccc4n3)C2)S(=O)(=O)N1
Reaction time: 3 h
Yield: 3.8 %

Procedure:
N-[(3S)-1-[6-Chloro-5-[[(cyclohexylmethyl)amino]carbonyl]-2-quinolinyl]-3-pyrrolidinyl]-N-[[[(1,1-dimethylethoxy)carbonyl]amino]sulfonyl]-glycine, ethyl ester (Example 112 (b)) (670 mg) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added and the mixture stirred for 3 hours before being concentrated. Sodium methoxide (25% in methanol, 3 mL) was added and the mixture was stirred under nitrogen for 2 hours. The products were concentrated onto silica gel and purified by chromatography (SiO2, dichloromethane:methanol 92:8 as eluant). Further purification by HPLC (Symmetry—0.1% aqueous trifluoroacetic acid/acetonitrile) gave the title compound as a solid (20 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[O:32]1[C:36]2C=CC(C3(C(NC4C=CC(C(OCCCO)C5C=CC=CC=5OC)=CN=4)=O)CC3)=C[C:35]=2OC1>C(O)CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:35][CH2:36][OH:32])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Solvent: OCCO
Product: COc1ccccc1C(OCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-hydroxyethoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and ethane-1,2-diol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((3-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.S([O-])(O)=O.[Na+].CN(C=O)C>O>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=Cc1ccccc1F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2ccccc2F)nc2cc(C(F)(F)F)cnc21
Temperature: 153 °C
Yield: 30.2 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (1.91 g), 2-fluorobenzaldehyde (1.86 g), sodium hydrogen sulfite (1.56 g), and DMF (10 ml) was stirred with heating under reflux at 153° C. for 3 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.89 g of 2-(2-fluorophenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound (1E)-F1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH2:9][CH2:10][CH3:11])[CH:7]=1.C1(C)C(C)=CC=CC=1.[NH2:22][NH2:23]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:23][N:22]=[C:8]2[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(=O)c1cc(Br)ccc1F
Reactant: NN
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: CCCc1n[nH]c2ccc(Br)cc12
Temperature: 65 °C
Yield: 52.3 %

Procedure:
To 1-(5-bromo-2-fluorophenyl)butan-1-one (2.0 g, 8.1 mmol) in THF, anhydrous hydrazine (11 mL) in THF was added and heated at reflux (60-70° C.) for 5-6 hours. Xylene was added to the reaction mixture and heated at reflux for 20-24 hours. The reaction mixture was concentrated to give a crude product, which was purified by column chromatography using 15% ethyl acetate/pet-ether as eluents to afford 5-bromo-3-propyl-1H-indazole (1.02 g, 52.3%) as a solid. 1H NMR (CDCl3): δ 7.9 (s, 1H), 7.4 (d, 1H), 7.3 (d, 1H), 2.9 (t, 2H), 1.8 (q, 2H), 1.0 (t, 3H).
Reaction SMILES: N(CN[C:5](N)=[O:6])=O.[OH-].[K+].[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]([CH3:20])=[C:14]2[CH2:21][C:22](O)=[O:23].N#N>ClCCl.C(OCC)C>[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15]([CH3:20])=[C:14]2[CH2:21][C:22]([O:6][CH3:5])=[O:23]
Reactant: NC(=O)NCN=O
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CC1=C(C)Cc2ccc(F)cc21
Yield: 93 %

Procedure:
Nitrosomethylurea (99.5 mmol) is added in portions to a cold (0° C.) mixture of aqueous 50% KOH (50 ml) and diethylether (150 ml) at 0° C. The yellow ether solution of diazomethane (Note: explosive) is separated, is washed with water, and is added in portions to a solution of 5-fluoro-2-methylindene-3-acetic acid (90 mmol) in dichloromethane (200 ml). When the evolution of N2 ceases, the reaction is complete. After evaporation of the solvents, the residue is recrystallized from hexane to give methyl 5-fluoro-2-methyl-3-indenylacetate (yield 93%; m.p. 53° C.).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.ClCCCl.[Cl-].[Al+3].[Cl-].[Cl-].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]12[CH2:37][CH2:36][CH2:35][C:33]3[C:34]1=[C:29]([CH:30]=[CH:31][CH:32]=3)[NH:28][C:27]2=[O:38]>CO>[CH3:7][O:6][C:5]([C:32]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:38])[C:26]3([CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[CH2:37][CH2:36][CH2:35][C:33]=1[C:34]=23)=[O:11]
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCCl
Product: COC(=O)c1ccc2c3c1CCCC3(CCCCBr)C(=O)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A 1.44 g (4.87 mmol) portion of triphosgene was added to 1,2-dichloroethane suspension (30 ml) of aluminum chloride (1.95 g, 14.61 mmol) and the mixture was cooled to 0° C. Thereto was added 30 ml of 1,2-dichloroethane solution containing 1.50 g (1.64 mmol) of 2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one, subsequently carrying out 2 hours of stirring at 0° C. The reaction solution was mixed with 50 ml of methanol, stirred at a room temperature for 1 hour, extracted with chloroform and then washed with 1 N hydrochloric acid. After drying (Na2SO4), the solvent was evaporated under a reduced pressure, and the thus obtained oily substance was purified by a silica gel column chromatography (300 cc; elution with ethyl acetate-hexane=1:1) and then recrystallized from ethyl acetate-hexane to obtain 0.63 g of the title compound (35% in yield).
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH:9]1[CH2:12][CH:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3([CH2:27][N:28]([CH3:30])[CH3:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10]1>CC(C)=O>[CH:1]1([N:9]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4([CH2:27][N:28]([CH3:30])[CH3:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CC1(c2ccc(OCC3CNC3)cc2)CCOCC1
Reactant: BrC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(C)CC1(c2ccc(OCC3CN(C4CCCC4)C3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.5 %

Procedure:
Cyclopentyl bromide (0.17 ml, 1.54 mmol) and 5M aqueous sodium hydroxide (0.34 ml, 1.68 mmol) were added to a solution of 1-{4-[4-(azetidin-3-ylmethoxy)phenyl]tetrahydro-2H-pyran-4-yl]-N,N-dimethylmethanamine (425 mg, 1.4 mmol) in acetone (9 ml). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in 2N hydrochloric acid to reach pH 1 and extracted with tert-butylmethyl ether (2×15 ml). The aqueous layer was then basified to pH14 with 4M sodium hydroxide (ca 40 ml) and extracted with dichloromethane (3×30 ml). These organic layers were combined, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1 by volume) to provide the title compound (55 mg, 11%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.28-1.73 (m, 8H), 1.83-1.93 (m, 2H), 1.96 (s, 6H), 2.05-2.13 (m, 2H), 2.40 (s, 2H), 2.71 (m, 1H), 2.90 (m, 1H), 3.00 (t, 2H), 3.39-3.58 (m, 4H), 3.72-3.78 (m, 2H), 4.05 (d, 2H), 6.87 (d, 2H), 7.21 (d, 2H). LRMS ESI+ m/z 373 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[C:29]([CH:36]=O)=[CH:28]1.N1CCCCC1>CO>[NH:27]1[C:35]2=[N:34][CH:33]=[CH:32][CH:31]=[C:30]2[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[CH:28]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1c[nH]c3ncccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.107 g, 0.295 mmol) synthesized in Example A40, Step 1 in methanol (1.2 mL) was added with 7-aza-1H-indole-3-carboxaldehyde (0.0517 g, 0.354 mmol) and piperidine (0.00251 g, 0.0295 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain the objective tert-butyl (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0654 g, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]1[CH2:16][CH:15]([CH2:17][CH3:18])[NH:14][C:13]2[N:19]([CH3:23])[N:20]=[C:21]([CH3:22])[C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+].Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>O>[CH2:40]([O:39][C:37]([N:14]1[CH:15]([CH2:17][CH3:18])[CH2:16][CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:24])[C:12]2[C:21]([CH3:22])=[N:20][N:19]([CH3:23])[C:13]1=2)=[O:38])[CH3:41]
Reactant: CCC1CC(NC(=O)OCc2ccccc2)c2c(C)nn(C)c2N1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1c2c(c(C)nn2C)C(NC(=O)OCc2ccccc2)CC1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
(6-Ethyl-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-4-yl)-carbamic acid benzyl ester (0.35 g, 1.08 mmol) obtained in step (ii), dry THF (5 mL) and potassium carbonate (0.45 g, 3.2 mmol) were charged to a flask under a nitrogen atomsphere. This mixture was stirred at room temperature for about 0.5 h, after which time ethyl chloroformate (0.47 g, 3.2 mmol) was added drop-wise. This reaction mixture was then stirred for about 4 h, water was added to the mixture, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×20 mL), dried over sodium sulphate, and concentrated under vacuum to afford the title compound (0.375 g, 88%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[F:22].CN(C=O)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[O:18])=[CH:15][C:14]=1[F:22]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-tert-butyl-phenylamine was added 4-bromo-3-fluoro-benzoic acid, DMF (21 mL) and EDCI and were stirred at room temperature overnight. The reaction was diluted with DCM (8 mL) and was washed with HCl (1 M, 8 mL), NaOH (1 M, 8 mL), and brine (5 mL), dried over Na2SO4, and concentrated by stream of nitrogen. The resulting viscous oil was purified by flash chromatography with increasing concentration ethyl acetate in hexanes to afford the product. LCMS calcd for C17H17FNO (m/e) 349, obsd 350 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][C:3]=1[S:11]([OH:14])(=[O:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].Cl.Cl[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]Cl>O>[N:1]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][C:3]=2[S:11]([OH:14])(=[O:12])=[O:13])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: ClCCNCCCl
Reactant: CCCc1ccc(N)c(S(=O)(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCc1ccc(N2CCNCC2)c(S(=O)(=O)O)c1
Yield: 67.9 %

Procedure:
To 500 ml of water are added 50.0 g of 2-amino-5-n-propylbenzenesulfonic acid and 6.28 g of sodium carbonate and the mixture was dissolved by heating. To the solution was added 88.13 g of bis(2-chloroethyl)amine hydrochloride and the mixture was refluxed by heating for 3 hours, And then, a suspension containing 26.25 g of sodium carbonate suspended in 63 ml of water was added thereto, and the mixture was refluxed by heating for 12 hours. The reaction mixture was condensed under reduced pressure, extracted with methyl alcohol and then methyl alcohol was removed under reduced pressure. To the residue was added 200 ml of water, and after a pH of the mixture was adjusted to about 8.0 with sodium carbonate, 500 ml of chloroform was added thereto and the mixture was stirred. Precipitated crystals were collected by filtration, washed with chloroform and dried to give 44.83 g (yield: 67.9%) of the above title product.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[NH2:39][C:40]1[CH:41]=[C:42]([OH:55])[CH:43]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:39][C:40]1[CH:45]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[C:42]([OH:55])[CH:41]=1
Reactant: CC1(C)OB(c2cc(N)cc(O)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 64.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (0.53 g, 0.89 mmol) was treated with 3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.52 g, 2.22 mmol), sodium carbonate (0.24 g, 2.22 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.22 g, 0.27 mmol) and 22 ml 1,2-dimethoxyethane and 5 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 0.36 g (62% yield) of the title compound.