Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][CH:15]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:31][O:30]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[O:30]1[CH2:31][CH:29]1[CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][CH:15]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: O=C(c1ccc(Cn2nccc2-c2ccc(O)cc2)cc1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(Cn2nccc2-c2ccc(OCC3CO3)cc2)cc1)N1CCCC1
Yield: 99.6 %

Procedure:
(4-((5-(4-hydroxyphenyl)-1H-pyrazol-1-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone (173 mg, 0.5 mmol), 2-(bromomethyl)oxirane (544 mg, 3 mmol) and K2CO3 (552 mg, 4 mmol) were charged to a 100-mL flask containing 2-butanone (20 mL) and heated at reflux temperature for 17 h. The mixture was cooled, filtered and evaporated in vacuuo to give crude product as an oil (201 mg, 98%). This crude material was used without further purification. LCMS (m/z): 404.2 [M+H]
Reaction SMILES: Cl[CH:2](Cl)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([Cl:17])[CH:6]=1)Cl.C[Li]>CCOCC>[Cl:17][C:7]1[CH:6]=[C:5]([C:3]#[CH:2])[CH:10]=[CH:9][C:8]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1cc(C(Cl)C(Cl)Cl)ccc1C1CCCCC1
Agent: [Li]C
Solvent: CCOCC
Product: C#Cc1ccc(C2CCCCC2)c(Cl)c1

Procedure:
β,β,α,3-tetrachloro-4-cyclohexylphenylethane (55.8 g.; 0.17 moles) is dissolved in anhydrous ether (100 ml). The solution is cooled in an ice-bath with stirring under nitrogen. Methyl lithium (2.3 M in ether; 300 cc) is added dropwise and the mixture stirred in the icebath for 2.5 hours before destroying the excess methyl lithium with ice. The ethereal fraction is washed thoroughly with saline until the washings are neutral. Removal of solvent gives 3-chloro-4-cyclohexyl-1-ethynylbenzene (b.p. 82°-88° /0.15 m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][CH2:49][CH:50]([OH:62])[CH2:51][N:52]1[CH2:61][CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:53]1[C:54]2[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:60][CH2:61][N:52]1[CH2:51][CH:50]([OH:62])[CH2:49][NH:48][C:18]([C:17]1[CH:16]=[C:15]([CH:23]=[CH:22][CH:21]=1)[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:19]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)O)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CC1
Temperature: 28 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
The solution of 3-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)benzoic acid (100 mg, 0.31 mmol) and HATU (119 mg, 0.31 mmol) in DCM (10 mL) was stirred at 28° C. for 30 min. Then 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (64.4 mg, 0.31 mmol) and DIPEA (48.4 mg, 0.38 mmol) was added and the resulting solution was stirred at 28° C. for 16 h. The solution was concentrated and the residue was purified by column chromatography to give the crude title product (150 mg, Yield 94%). LCMS (m/z): 509.2 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([NH2:14])[N:4]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([NH2:14])[N:4]=1)=[O:23]
Reactant: CNc1nc(SC)nc(N)c1[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CNc1nc(S(C)=O)nc(N)c1[N+](=O)[O-]

Procedure:
Prepared from 2-methylsulphenyl-4-methylamino-5-nitro-6-amino-pyrimidine by reacting with m-chloro-perbenzoic acid, melting point: 229–234° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]=1[F:17].C(O[C:25]1[CH:30]=[CH:29][C:28](Br)=[C:27](F)[CH:26]=1)CCCCC>>[CH2:9]([O:8][C:4]1[CH:5]=[CH:6][C:7]([C:2]2[CH:7]=[CH:6][C:5]([C:25]3[CH:26]=[CH:27][C:28]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:29][CH:30]=3)=[CH:4][CH:3]=2)=[C:2]([F:1])[C:3]=1[F:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1cccc(F)c1F
Reactant: CCCCCCOc1ccc(Br)c(F)c1
Product: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(CCCCC)cc3)cc2)c(F)c1F

Procedure:
This compound is prepared by an analogous route using 1,2-difluoro-3-octoxybenzene instead of 8B. This is prepared using the method as for 3A.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>C1COCC1.CCCCCC>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([OH:16])[CH3:15]
Reactant: Brc1ccccc1Br
Reactant: CC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)(c1ccccc1)c1ccccc1Br
Reaction time: 0 h
Yield: 81 %

Procedure:
A microsystem composed of three T-shaped micromixers (M1, M2 and M3) and two microtube reactors (R1 and R2) was used. The whole microsystem was dipped in a cooling bath (−78° C.). A solution of o-dibromobenzene (0.27 M) in THF (flow rate: 6 mL/min, 1.62 mmol/min) and a solution of n-BuLi (1.5 M) in n-hexane (flow rate: 1.2 mL/min, 1.8 mmol/min) were introduced to the first T-shaped mixer M1 (inner diameter: 250 μm) by using syringe pumps. The resulting solution was passed through the tube reactor R1 and was mixed with acetophenone (0.65 M) in THF (flow rate: 3 mL/min, 1.95 mmol/min) in the second T-shaped mixer M2 (inner diameter: 500 μm). The solution was introduced to the third T-shaped mixer M3 (inner diameter: 500 μm), where the solution was quenched with methanol (neat, flow rate=3.0 mmol/min). The residence time of the tube reactor R1 (inner diameter: 500 μm, length=50 cm) was 0.82 second. The residence time of the tube reactor R2 (inner diameter: 1,000 μm, length=75 cm) was 3.46 second. After finishing the reaction, an aliquot of the product solution was taken (15 sec) and was analyzed by GC (column, CBP1; 0.25 mm×25 m; initial oven temperature, 50° C.; rate of temperature increase, 10° C./min). As a result, 1-(2-bromophenyl)-1-phenylethanol (GC retention time: 23.5 min) was obtained in 81% yield. 1H NMR (400 MHz, CDCl3) δ: 1.95 (s, 3H), 3.49 (s, 1H), 7.16 (dt, J=7.6, 1.6 Hz, 1H), 7.20-7.30 (m, 5H), 7.38 (dt, J=7.6, 1.2 Hz, 1H), 7.52 (dd, J=8.0, 1.2 Hz, 1H), 7.80 (dd, J=7.6, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 30.4, 77.4, 122.2, 125.4, 126.7, 127.2, 128.0, 128.3, 129.0, 134.7, 144.7, 147.4. HRMS (EI) m/z: calcd. for C14H13BrO 276.0150, found 276.0155.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH4+:20].[OH-]>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:20])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cccc([N+](=O)[O-])c1Cl

Procedure:
DMF (3 drops) was added to a mixture of 2-chloro-3-nitrobezoic acid (0.99 g, 4.9 mmol), oxalyl chloride (0.47 mL, 5.4 mmol) in CH2Cl2 (20 mL) at 25° C. stirring under N2. After gas formation ceased, all the solid went into solution. After 3 hours the solvent was removed under reduced pressure to leave a light yellow solid which was treated with cold NH4OH (20 mL). 2-Chloro-3-nitrobenzamide was collected as an off-white solid (1.02 g, 100%).
Reaction SMILES: Cl/[C:2](=[N:8]\[OH:9])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[CH:11].C(N(CC)CC)C>CCOCC>[C:12]1([C:10]2[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)/C(Cl)=N/O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a mixture of (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (3.03 g, 20 mmol) and ethynylbenzene (4.39 mL, 40 mmol) in ether (80 mL) at room temperature was added a solution of triethylamine (5.58 mL, 40.0 mmol) in ether (20 mL) dropwise over 60 minutes. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was filtered, and the filtrate was concentrated to a yellow oil which was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (0-12%) to afford ethyl 5-phenylisoxazole-3-carboxylate (3.06 g, 14.09 mmol, 70% yield) as a white solid. The compound had an HPLC retention time=2.99 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS:(M+H)=218.12. 1H-NMR (400 MHz, CDCl3) δ ppm 1.45 (t, J=7.3Hz, 3H), 4.48 (q, J=7.3, 2H), 6.93 (s, 1H), 7.45-7.53 (m, 3H), and 7.77-7.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]#[C:13][CH2:14][O:15][CH3:16])[C:10]=1[CH3:11])[C:5]([OH:7])=O.C([N:20](CC)[CH:21]([CH3:23])[CH3:22])(C)C.C1(N)CC1.[NH4+].[Cl-].C(OC(C)C)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]#[C:13][CH2:14][O:15][CH3:16])[C:10]=1[CH3:11])[C:5]([NH:20][CH:21]1[CH2:23][CH2:22]1)=[O:7]
Reactant: CCN(C(C)C)C(C)C
Reactant: COCC#Cc1cc(C(=O)O)cc(Br)c1C
Agent: NC1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)C
Product: COCC#Cc1cc(C(=O)NC2CC2)cc(Br)c1C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To 3-bromo-5-(3-methoxy-prop-1-ynyl)-4-methyl-benzoic acid (0.38 M solution in THF) was added N,N-diisopropylethylamine (1.8 equiv.) and cyclopropylamine (1.35 equiv.) maintaining the internal temperature below 25° C. The mixture was cooled to 5° C. and 2-propanephosphoric acid anhydride (50 wt % in EtOAc, 1.5 equiv.) was added whilst maintaining the internal temperature below 25° C. The reaction mixture was aged for 1 h at ˜20° C. then cooled to 2° C. and 10 wt % aq. NH4Cl solution added, maintaining the internal temperature <30° C. Isopropyl acetate was added and the layers were allowed to settle. The lower aqueous layer removed. The organics were then washed with 1M HCl, followed by 10% NaHCO3 solution and finally 10% NaCl solution. The organic layer was concentrated to ˜1 M followed by the addition of toluene. The batch was then reconcentrated to ˜2 M and the resultant slurry aged for 18 h. Heptane was then added and the solids were filtered, washed with a mixture of 1:1 toluene/heptane and dried to give the title compound as an off-white solid. 1H NMR (500 MHz, Acetone-d6): δ 8.01 (s, 1 H), 7.92 (s, 1 H), 7.86 (s, 1 H), 4.37 (s, 2 H), 3.39 (s, 3 H), 2.95-2.89 (m, 1 H), 2.53 (s, 3 H), 0.76-0.67 (m, 2 H), 0.68-0.60 (m, 2 H). HRMS (ES, M+H) Calcd 322.0443. Found 322.0457.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12](O)[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH:12]([Br:16])[CH3:13])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(Br)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanol (390 mg, 1.45 mmol) and carbon tetrabromide (577 mg, 1.74 mmol) in tetrahydrofuran (2 mL) at 0° C. was added triphenylphosphine (456 mg, 1.74 mmol). The resulting solution was stirred at room temperature for 2 h. The reaction was treated with an additional portion of carbon tetrabromide (289 mg, 0.87 mmol)) and triphenylphosphine (228 mg, 0.87 mmol). The reaction was stirred at room temperature for 1 h, diluted with several volumes of pentane, and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (1→3% ethyl acetate/hexanes) to give 439 mg (91%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.76 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 5.12 (q, J=7.0 Hz, 1H), 2.03 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 146.4, 133.5, 132.9 (q, J=32.6 Hz), 128.4 (q, J=3.8 Hz), 123.0, 123.0 (q, J=273 Hz), 122.6 (q, J=3.8 Hz), 46.1, 26.6.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([CH2:21]O)=[CH:19][N:18]=[C:17]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(=O)[NH:38]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>O1CCCC1>[NH2:38][CH2:21][C:20]1[CH:19]=[N:18][C:17]2[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[CH:24]=[CH:25][C:16]=2[C:15]=1[NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(CO)cnc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(CN)cnc21
Yield: 24.2 %

Procedure:
{4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl}methanol (212 mg, 0.454 mmol), phthalimide (134 mg, 0.909 mmol) and triphenylphosphine (238 mg, 0.909 mmol) in tetrahydrofuran was stirred at room temperature for 30 minutes and with diisopropyl azodicarboxylate (184 mg, 0.909 mmol) for one day. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with ethyl acetate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1/(v/v)) to remove triphenylphosphine oxide. The residue was dissolved in ethanol (10 mL) and stirred with hydrazine monohydrate (1.00 mL, 11.6 mmol) at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound (51.1 mg, yield 24%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:13]1([C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C@H:16]2[CH2:17][CH2:18][C@H:13]([C:20]3[CH:29]=[CH:28][C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[CH2:14][CH2:15]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NCCCc1cc(F)cc(F)c1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4cc(F)cc(F)c4)CC3)cc2o1

Procedure:
Condensation of 3-(3,5-difluorophenyl)-1-propylamine (1.5 g, 6.5 mmol) and ketone 5 (1.5 g, 6.5 mmol), following the procedure described in Example 1, gave 6-(trans-4-[3-(3,5-difluorophenyl)propylamino]cyclohexyl}-3H-benzoxazol-2-one (640 mg, 26%), as a white solid: 1H NMR (500 MHz, DMSO-d6): δ 7.13 (s, 1H), 7.01-6.92 (m, 5H), 2.66 (t, J=8 Hz, 2H), 2.57 (t, J=8 Hz, 2H), 2.49-2.40 (m, 2H), 1.95 (br d, J=10 Hz, 2H), 1.78 (br d, J=10 Hz, 2H), 1.74-1.68 (m, 2H), 1.45 (dddd, J=13, 13, 13, 3 Hz, 2H), 1.14 (dddd, J=13, 13, 13, 3 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9](OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:14]([NH:17][NH2:18])([NH2:16])=[NH:15].Cl>CO>[NH2:16][C:14]1[N:15]=[C:9]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:18][N:17]=1
Reactant: N=C(N)NN
Reactant: COC(=O)C#Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Nc1n[nH]c(C#Cc2ccccc2)n1
Yield: 75 %

Procedure:
The synthesis method of Example 7-(2) was applied. The compound (5.63 g) obtained in (1) above, methanol (85 ml), metallic sodium (3.29 g) and aminoguanidine hydrochloride (15.8 g) were used as reagents to give 4.87 g of a pale-brown solid (yield 75%).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].Cl>C1COCC1>[CH:18]([O:17][C:15]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:16])([CH3:20])[CH3:19]
Reactant: NC(C(=O)O)c1ccccc1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)OC(=O)NC(C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Amino-phenyl-acetic acid (0.505 g, 2.44 mmol) was dissolved in THF (7 mL) and cooled to 0° C. in an external ice/brine bath. Aqueous sodium hydroxide (12.5M, 0.47 mL, 5.856 mmol) and isopropyl chloroformate (0.23 mL, 2.948 mmol) were added at 0° C. Upon completion of the addition, the solution was removed from the ice bath and allowed to warm to room temperature, and stirred. After 18 hours, the crude reaction mixture was adjusted to pH 1 with 1N HCl and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated to give Isopropoxycarbonylamino-phenyl-acetic acid as an off-white solid. LCMS-ESI+: calc'd for C12H15NO4: 237.10 (M+); Found: 238.05 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[CH:12]=2)[CH:7]=1)=O)C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[F:22][C:20]([F:21])([F:23])[S:17]([O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH2:4][OH:3])[CH:15]=[CH:14]2)(=[O:18])=[O:19]
Reactant: CCOC(=O)c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=S(=O)(Oc1ccc2cc(CO)ccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a slurry of 6-trifluoromethanesulfonyloxy-naphthalene-2-carboxylic acid ethyl ester (136.50 g, 0.392 mol) in toluene (1.0 L) at −70° C. was added a solution of DIBAL (1.5 M, 5.75 mL, 0.862 mol) dropwise while maintaining an internal temperature below −55° C. The resulting mixture was allowed to stir for 1 hour and subsequently quenched with acid to pH 5–6 while warming to room temperature. The mixture was extracted with ether (2×). The organics were combined, washed with water (3×), brine and dried (MgSO4). After filtering, the solvents were evaporated and the crude material was purified on silica (eluent: hexane:CH2Cl2, 1:1 to 100% CH2Cl2) to afford 86.0 g (72%) of 6-trifluoromethanesulfonyloxy-naphthalen-2-yl-methanol as an off-white solid. 1H NMR (300 MHz; CDCl3) 2.31 (brs, 1 H), 4.83 (s, 2 H), 7.34 (dd, J1=9.0 Hz, J2=2.0 Hz, 1 H), 7.51 (dd, J1=8.4 Hz, J2=2.0 Hz, 1 H), 7.71 (d, J=2.0 Hz, 1 H), 7.75–7.90 (m, 3 H).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([NH:29][CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(NC5CCNCC5)n4)n[nH]c3cn2)cn1
Yield: 5.4 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl 4-aminopiperidine-1-carboxylate were reacted and the product was deprotected to give 200 as a white solid (5.4% over two steps). 1H NMR (400 MHz, MeOD) δ 8.97 (s, 1H), 8.61 (s, 1H), 8.47 (s, 2H), 8.12 (s, 1H), 8.01 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.44 (d, J=7.3 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 4.69 (m, 1H), 4.41-4.32 (m, 1H), 3.99 (s, 3H), 3.52-3.43 (m, 2H), 3.12 (dd, J=16.9, 6.7 Hz, 2H), 2.44-2.33 (m, 2H), 1.97-1.85 (m, 2H). LC/MS: m/z 375.1 [M+1]
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl.CN.[BH3-][C:22]#[N:23].[Na+]>CO>[CH3:22][NH:23][CH:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=2)[CH2:12][CH2:13]1
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCN(c2ccncc2)CC1
Reaction time: 0.33 h
Yield: 82 %

Procedure:
Acetic acid (150 μl) was added to a solution of 1-(pyridin-4-yl)piperidin-4-one (450 mg, 2.55 mmol, 1 eq) and methylamine hydrochloride (190 mg, 2.81 mmol, 1.1 eq) in methanol (10 ml), and stirring was carried out for 20 min at RT. Then NaBH3CN (166 mg, 2.81 mmol, 1.1 eq) was added in portions and stirring was carried out for 16 h at RT. The solvent was concentrated, and the residue was taken up in chloroform (100 ml), washed with sat. K2CO3 solution (30 ml) and sat. NaCl solution (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The product (yellow solid) was used in the next stage without being purified further. Yield: 82% (400 mg, 2.09 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:4]=1)#N.[OH2:22].C(OCC)(=O)C.[OH2:29]>Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:4]=[C:3]([C:1]([OH:29])=[O:22])[CH:8]=1
Reactant: O
Reactant: COc1cc(C#N)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-cyano-4-methoxy-6-[3-(trifluoromethyl)phenoxy] pyridine (1.0 g, 0.0034 mol) was suspended in about 10 ml of concentrated hydrochloric acid. The obtained suspension was stirred at about 100° C. for about 2 hours. After being allowed to stand for cooling, the obtained reaction solution was mixed with water, and then distributed in ethyl acetate-water. The organic phase of the solution was washed with saturated brine, dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:28]=[C:27]([C:29]([O:31]CC)=[O:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:15][CH:14]=1.C(O)C.[OH-].[K+]>C(O)(=O)C>[NH2:3][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1nc(-c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)nc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NCc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Into a 500-mL round-bottom flask, was placed ethyl 2-[4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]phenyl]quinazoline-4-carboxylate (4 g, 9.14 mmol, 1.00 equiv), ethanol (40 mL) and 1N KOH (70 mL). The resulting solution was stirred for 24 h at 100° C. in an oil bath. The pH value of the solution was adjusted to 7 with acetic acid. The resulting mixture was concentrated under vacuum. This resulted in 2.6 g (crude) of 2-[4-(aminomethyl)phenyl]quinazoline-4-carboxylic acid as a white solid. MS (ESI) m/z 280 ([M+H]+).