Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[Na+].[Na+].Br[CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20].Cl>O>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20])([OH:10])=[O:9]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C1OCCC1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1NC1CCOC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 68.6 g of anthranilic acid, 132.2 g of sodium carbonate and 400 ml of water was stirred at room temperature for 1 hour and, under ice-cooling, 103.2 g of α-bromo-γ-butyrolactone was added dropwise. The mixture was stirred under ice-cooling for 5 hours and, then, at room temperature for 24 hours. The mixture was made acidic with hydrochloric acid, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The ethyl acetate was distilled off and ethyl ether was added to the residue. The resulting crystals were recovered by filtration. By the above procedure was obtained α-[(2-carboxyphenyl)amino]-γ-butyrolactone, melting point: 197°-198° C.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12]C(=O)C)[C@H:10]([O:16]C(=O)C)[C@@H:9]([O:20]C(=O)C)[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44]OS(C)(=O)=O)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=O)C.[CH2:50]1[C:55]2([CH2:60][CH2:59][N:58]([C:61](=[O:71])[CH2:62][NH:63][C:64]([NH:66][CH2:67][CH:68]([CH3:70])[CH3:69])=[O:65])[CH2:57][CH2:56]2)[CH2:54][NH:53][CH2:52][CH2:51]1.C(N(C(C)C)CC)(C)C.C[O-].[Na+]>CO.C(#N)C>[CH2:67]([NH:66][C:64]([NH:63][CH2:62][C:61]([N:58]1[CH2:59][CH2:60][C:55]2([CH2:50][CH2:51][CH2:52][N:53]([CH2:44][CH2:43][CH2:42][O:41][C:38]3[CH:39]=[CH:40][C:35]([CH2:34][C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])[N:24]([C@H:8]5[C@H:9]([OH:20])[C@@H:10]([OH:16])[C@H:11]([OH:12])[C@@H:6]([CH2:5][OH:4])[O:7]5)[CH:25]=4)=[CH:36][CH:37]=3)[CH2:54]2)[CH2:56][CH2:57]1)=[O:71])=[O:65])[CH:68]([CH3:69])[CH3:70]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCCOS(C)(=O)=O)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)CNC(=O)NCC(=O)N1CCC2(CCCNC2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC#N
Product: Cc1cccc2c1c(Cc1ccc(OCCCN3CCCC4(CCN(C(=O)CNC(=O)NCC(C)C)CC4)C3)cc1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 80 °C

Procedure:
To a 0.25 L round bottom flask add [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[4-methyl-3-[[4-(3-methylsulfonyloxypropoxy)phenyl]methyl]indol-1-yl]tetrahydropyran-2-yl]methyl acetate (7.2 g, crude), 1-[2-(4,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]-3-isobutyl-urea (12.28 mmol), acetonitrile (100 mL), and diisopropylethylamine (40.92 mmol). Heat at 80° C. for 16 hours then concentrate under reduced pressure. Add methanol (50 mL) and sodium methoxide (20.46 mmol, 30% solution in MeOH) and stir at room temperature for 1 hour. Quench by adding a small piece of dry ice. Concentrate under reduced pressure. Purify by reverse phase flash chromatography (400 g C18 cartridge) eluting with 5-80% water (0.1% formic acid) in acetonitrile (0.1 % formic acid) in three portions. Concentrate under reduced pressure to yield the title compound as a formic acid salt containing small impurities. Dissolve the salt in 7N ammonia in methanol (20 mL) then concentrate to form the free base. Purify the free base by flash chromatography (330 g silica gel cartridge) eluting with 5% 7N ammonia in methanol/dichloromethane. Concentrate the product fractions under reduced pressure to yield the title compound (1.75 g, 22.81%): MS (m/z): 746.6 (M+H). H1 NMR (400.31 MHz, CD3OD): δ 7.28 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 2H), 7.02 (s, 1H), 6.97 (t, J=8.8 Hz, 1H), 6.69 (d, J=7.2 Hz, 1H), 5.37 (d, J=9.2 Hz, 1H), 4.15 (s, 2H), 3.95 (t, J=6.0 Hz, 2H), 3.91 (d, J=1.6 Hz, 2H), 3.87-3.80 (m, 2H), 3.65 (dd, J=11.6, 5.6 Hz, 1H), 3.57-3.38 (m, 5H), 3.31 (bm, 2H), 2.90 (d, J=6.8 Hz, 2H), 2.46-2.13 (m, 8H), 1.88 (pentet, J=6.8 Hz, 2H), 1.68 (septet, J=6.8 Hz, 1H), 1.61-1.28 (m, 8H), 0.86 (d, J=6.8, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[O:12]CN=C[C:4]=2[N:3]=1>B(Br)(Br)Br>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1
Reactant: Clc1nc2c(c3ccccc13)OCN=C2
Agent: BrB(Br)Br
Product: Oc1cnc(Cl)c2ccccc12

Procedure:
6-Chloro-1,3-Oxazino[5,6-c]isoquinoline was prepared by the procedure of Miyoko Toyama and Hirotaka Otomasu starting from 1-chloro-4-hydroxy isoquinoline. The starting material: 1-chloro-4-hydroxy isoquinoline (Example 226c) was prepared by the synthetic sequence shown above. MCPBA oxidation of 4-methoxy isoquinoline (Example 222a) was carried as usual to give 79.1% of the corresponding N-oxide (Example 226a). The material was converted into the 1-chloro derivative immediately afterward in POCl3 to give the chloride (Example 226b) in essentially quantitative yield. The crude 1-chloro-4-methoxy isoquinoline was de-methylated in BBr3 at room temperature to give the corresponding 1-chloro-4-hydroxy isoquinoline (Example 226c) after treating the crude BBr3 mixture with anhydrous methanol at room temperature, followed by evaporation to get rid of excess of borate residues. The reaction of Miyoko Toyama and Hirotaka Otomasu gave 266 mg of 6-chloro-1,3-oxazino[5,6-c]isoquinoline (Example 226d, 62.3%) overall yield from 300 mg of 4-methoxy isoquinoline in 4 steps. LC/MS Rt-min ([M-HCHO]H+) [method D]: 2.45 (192). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 5.02 (s, 2 H) 5.41 (s, 2 H) 7.68 (m, 1 H) 7.77 (ddd, J=8.25, 6.91, 1.22 Hz, 1 H) 8.10 (d, J=8.31 Hz, 1 H) 8.26 (d, J=8.56 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1>CO>[CH3:1][CH:2]1[CH2:3][CH2:4][CH:5]([O:6][CH2:7][CH2:8][OH:9])[CH2:10][CH2:11]1
Reactant: Cc1ccc(OCCO)cc1
Solvent: CO
Product: CC1CCC(OCCO)CC1
Yield: 80.9 %

Procedure:
20 Grams (0.13 moles) of 2-(4-methylphenoxy)ethanol (prepared above) and 100 ml of dry methanol are charged to a Parr shaker bottle. N2 is bubbled through for 15 minutes. 2 Grams of 5% rhodium on carbon are then added and the shaker bottle set in a Parr apparatus. The system is purged three times with H2 and then pressurized to 30 psi. Hydrogen is periodically added over a period of about 20 hours up to a maximum pressure of 30 psi. The catalyst is then filtered off over dicalite and methanol is removed by evaporation. The product is distilled utilizing a 4" glass column packed with glass beads to obtain 80.9% 2-(4-methylcyclohexoxy)ethanol product.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCOc1ccc2ncc(C(=O)OCC)c(O)c2c1
Product: CCCOc1ccc2ncc(C(=O)OCC)c(Cl)c2c1

Procedure:
Prepared as in Example 1b from ethyl 4-hydroxy-6-propoxyquinoline-3-carboxylate (Example 14c) and POCl3 as a pale yellow solid. MS 294, 296 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@:6]2([CH2:10][S:11](Cl)(=[O:13])=[O:12])[C:7]([CH2:9][C@H:3]1[CH2:4][CH2:5]2)=[O:8].[NH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][N:22]1[C:30]2[C:29]([CH3:31])=[C:28]([CH3:32])[N:27]=[C:26]([NH2:33])[C:25]=2[N:24]=[C:23]1[CH3:34]>>[NH2:33][C:26]1[C:25]2[N:24]=[C:23]([CH3:34])[N:22]([CH2:21][CH2:20][O:19][CH2:18][CH2:17][NH:16][S:11]([CH2:10][C:6]34[C:2]([CH3:15])([CH3:1])[CH:3]([CH2:4][CH2:5]3)[CH2:9][C:7]4=[O:8])(=[O:13])=[O:12])[C:30]=2[C:29]([CH3:31])=[C:28]([CH3:32])[N:27]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)Cl)C(=O)C2
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCOCCNS(=O)(=O)CC34CCC(CC3=O)C4(C)C)c2c1C

Procedure:
Using the method of Examples 34–50, D-(+)-10-camphorsulfonyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 478.2455.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)[CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60].CCOC(C)=O>C(Cl)Cl>[CH3:58][S:59]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)[N:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1)(=[O:61])=[O:60]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(CO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(COS(C)(=O)=O)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
{1-(cis-4-{[6-(Hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (110.0 mg, 0.1609 mmol) was dissolved in methylene chloride (2.22 mL) and was cooled to 0° C. To that was added N,N-diisopropylethylamine (45.8 μL, 0.263 mmol), followed by methanesulfonyl chloride (18 μL, 0.23 mmol). The reaction was stirred at 0° C. for 1 hour. The reaction was worked up using EtOAc and used in the next reaction. MS (ES): 762 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>ClCCl>[C:14]([NH:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1)(=[O:16])[CH3:15]
Reactant: NC1=NN(c2ccc(Cl)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NC1=NN(c2ccc(Cl)cc2)CC1

Procedure:
3-Amino-1-(p-chlorophenyl)-2-pyrazoline (5 g) was added to acetic anhydride (4.0 ml) at room temperature. On stirring with a glass rod the mixture became warm and afforded a dark red liquid. The mixture was taken up in dichloromethane (100 ml) washed (water, 100 ml; saturated sodium bicarbonate, 100 ml; water, 100 ml), dried over sodium sulphate and the solvent removed in vacuo to afford the title compound (m.p. 171°-173°).
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([N:11]=[N+:12]=[N-:13])[N:3]=1.[H+].[B-](F)(F)(F)[F:16].C(ON=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.O>[N:11]([C:4]1[N:3]=[C:2]([F:16])[N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2)=[N+:12]=[N-:13]
Reactant: F[B-](F)(F)F
Reactant: [N-]=[N+]=Nc1nc(N)nc2nc[nH]c12
Agent: CC(C)(C)ON=O
Agent: O=C([O-])[O-]
Agent: [H+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1nc(F)nc2nc[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-amino-6-azidopurine (13.0 gm, 73.6 mmol) in tetrahydrofuran (THF, 163 mL), and 48% aqueous HBF4 (42.24 mL) was cooled in a bath at -20° C. A solution of t-butylnitrite (12.65 mL) in THF (10 mL) was added over a 5 minute period. The bath was replaced with an ice-water bath for 30 minutes and then with a bath at 50° C. for 15 minutes. The mixture was then poured over ice (600 g), and water (200 mL) was added. The suspension was neutralized (pH 6-7) with saturated potassium carbonate (K2CO3), and ethyl acetate was added. The resulting solid potassium fluoborate (KBF4) was collected by filtration and washed thoroughly with ethyl acetate. The aqueous layer was washed repeatedly with ethyl acetate and the combined ethyl acetate extracts were washed sequentially with water (500 mL) and saturated sodium chloride (NaCl) (250 mL) and dried over magnesium sulfate (MgSO4) along with decolorizing carbon. The ethyl acetate was then filtered through celite and concentrated in vacuo to afford 9.36 g of the title compound. mp 190°-195° C. (d) (from ethyl acetate/pet. ether; The decomposition or melting point of this material varies from sample to sample); IR (KBr) 2240, 2200, 1620, 1595, 1565 cm-1 ; MS (EI+, m/z) 179(M+, 55%), 151 ((M-N2)+, 100%); 1H NMR (DMSO-d6, 360 MHz) δ8.53 (s, 1H), 13.8 (bs, 1H); 13C NMR (DMSO-d6, 90 MHz) 120 (very broad), 145.4 (broad), 152.2 (broad), 156 (very broad), 157.0 (d, JCF =210 Hz) ppm; UV (MeOH) λmax, 250, 286 nm.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:32][C:25]=3[S:24]4)=[CH:17][CH:16]=2)=[O:13])[CH:7]=1)([CH3:5])[CH3:4].[NH4+].F[C@H:44]1[O:52][C@H:51]([C:53]([O-:55])=[O:54])[C@@H:49]([OH:50])[C@H:47]([OH:48])[C@H:45]1[OH:46]>CS(C)=O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[OH:50][CH:49]1[CH:47]([OH:48])[CH:45]([OH:46])[CH:44]([O:1][CH2:2][C:3]([CH3:4])([C:6]2[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[N:22]=[C:23]5[N:27]([CH:28]=4)[C:26]4[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)=[CH:32][C:25]=4[S:24]5)=[CH:17][CH:16]=3)=[O:13])[CH:7]=2)[CH3:5])[O:52][CH:51]1[C:53]([OH:55])=[O:54]
Reactant: CC(C)(CO)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Reactant: O=C([O-])[C@H]1O[C@H](F)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COC1OC(C(=O)O)C(O)C(O)C1O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Alternatively, 3,4,5-trihydroxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid (I-6) is prepared by following an alternative general procedure given in Org. Lett. 2008, 10, 1585. To a stirred mixture of 1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1) (1 equivalent) in a mixture of dimethyl sulfoxide (final volume 12.5-25% v/v) and 50 mM sodium phosphate buffer (pH=7.5) at rt, is added a solution of 1-deoxy-1-fluoro-α-D-glucopyranuronic acid ammonium salt (prepared as described in Org. Lett. 2008, 10, 1585) (1.2 equivalents) in 50 mM sodium phosphate buffer (pH=7.5). To this mixture is added E. coli. E504G β-glucuronylsynthase (final concentration 0.1-0.2 mg/mL) or E. coli. E504A β-glucuronylsynthase (final concentration 0.1-0.2 mg/mL) and the mixture is stirred at rt for 4 days. Lyophilization of the mixture and purification of the residue by preparative reverse-phase HPLC or silica gel flash chromatography affords 3,4,5-trihydroxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid (I-6).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:31][CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)[C:11]1[CH:12]=[C:13]([C:17]#[C:18][CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)[CH:14]=[CH:15][CH:16]=1.O.NN>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:31][CH:32]1[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]1)[C:11]1[CH:12]=[C:13]([C:17]#[C:18][CH2:19][NH2:20])[CH:14]=[CH:15][CH:16]=1
Reactant: CN1CCC(OC(c2cccc(C#CCN3C(=O)c4ccccc4C3=O)c2)c2nc3ccccc3[nH]2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1CCC(OC(c2cccc(C#CCN)c2)c2nc3ccccc3[nH]2)CC1
Reaction time: 0.08 h

Procedure:
A solution of 2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynyl)isoindole-1,3-dione (70 mg) and hydrazine hydrate (70 μL) in ethanol (0.7 mL) is stirred a room temperature for 3 hours. Ethanol is removed under reduced pressure and 1N hydrochloric acid in water is added to the organic residue and stirred for 5 minutes. The mixture is filtered, cake washed with ethyl acetate. The filtrate is extracted by dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure The residue purified by chromatography (dichloromethane/methanol/ammonia from 90/10/1) to afford 3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine melting at 101° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH2:23]=O>C(O)=O>[CH3:23][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: CCCn1nc(C(=O)NC2CCNCC2)c2ccccc21
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CCCn1nc(C(=O)NC2CCN(C)CC2)c2ccccc21
Yield: 18 %

Procedure:
To N-(4-piperidyl)-1-n-propylindazole-3-carboxamide hydrochloride (0.32 g) obtained in Example 20 were added formic acid (0.7 ml) and a 36% aqueous solution of formaldehyde (0.3 ml), and the mixture was stirred at room temperature for 5 hours. Then formic acid (4 ml) and a 36% aqueous solution of formaldehyde (1.6 ml) were further added, and the mixture was heated under reflux for 2.5 hours. The reaction solution was distilled off under reduced pressure, and to the residue were added chloroform and aqueous ammonia. After extraction with chloroform, the chloroform layer was washed with saturated aqueous sodium chloride, dried over anhydrous potassium carbonate, and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform methanol:aqueous ammonia 90:10:2) to give the title compound (0.06 g). Yield 18%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:25](O)=[O:26]>>[CH:25]([C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1])=[O:26]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: COC(=O)Cc1ccc(O)c(C=O)c1

Procedure:
Methyl (4-hydroxyphenyl)acetate (1.66 g) is dissolved in trifluoroacetic acid (20 ml), thereto is added hexamethylenetetramine (700 mg), and the mixture is heated under reflux for 2 hours. The reaction solution is concentrated under reduced pressure, thereto is poured ice-water, and then the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate =9/1, then 4/1) to give the title compound (1.08 g). ESI-MS M/Z:193[M−H]−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[CH:16][CH:15]=2)[N:13]=1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: FC(F)(F)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccccc2C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 5.5 h
Yield: 27.4 %

Procedure:
To a solution of 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol) in DMSO was added 1-iodo-2-(trifluoromethyl)benzene (0.13 g, 0.479 mmol), TBAF (0.301 g, 0.958 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.050 g, 0.071 mmol). The reaction mass was stirred at 110° C. for 5-6 h. The reaction mass was quenched in water and extracted with DCM and concentrated. The obtained product was purified with column chromatography on silica gel eluting with 2.0% EA:DCM to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO do): δ 7.50 (t, J=9.3 Hz, 1H), 7.57-7.73 (m, 6H), 7.82 (br s, 2H), 8.02 (d, J=8.7 Hz, 2H), 12.72 (br s, 1H). MS (m/z): 458.26 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[ClH:13].[N:14]([O-])=[O:15].[Na+].CCOCC>O>[ClH:13].[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N:14]=[O:15])=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCc2ccc(O)cc21
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CN1CCCc2cc(N=O)c(O)cc21
Temperature: 4 °C
Yield: 84 %

Procedure:
A mixture of 24.5 g (0.15 mol) of 1-methyl-1,2,3,4-tetrahydro-7-hydroxyquinoline, 75 ml of water and 75 ml of concentrated hydrochloric acid was stirred and cooled in an ice bath to 5°. To this mixture was added dropwise during 40 minutes a solution of 12.42 g(0.18 mol) of sodium nitrite in 50 ml of water while maintaining the temperature between 3 to 5° C. It was occasionally necessary to add a few ml of ether to control foaming. When the addition was complete, the reaction mixture was stirred for 40 min in the ice bath. The solid was collected and rinsed with 2N hydrochloric acid and with ether. It was recrystallized from 700 ml of 2.4 N hydrochloric acid to give 28.7 g (84%) of crude product as brown needles.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]([C:15]2([C:18]3[CH:28]=[CH:27][C:21]4[O:22][C:23]([F:26])([F:25])[O:24][C:20]=4[CH:19]=3)[CH2:17][CH2:16]2)=[O:14])[N:3]=1.[C:29]([O:33][C:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:23]1([F:26])[O:22][C:21]2[CH:27]=[CH:28][C:18]([C:15]3([C:13]([NH:12][C:4]4[N:3]=[C:2]([C:40]5[CH:41]=[C:36]([CH:37]=[CH:38][CH:39]=5)[C:34]([O:33][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:35])[C:11]5[C:6]([CH:5]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:14])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[O:24]1
Reactant: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 80 °C
Yield: 97.1 %

Procedure:
To N-(1-bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (508 mg, 1.14 mmol) in 1,2-dimethoxyethane (11 mL) was added 3-(tert-butoxycarbonyl)phenylboronic acid (328 mg, 1.48 mmol), tetrakis(triphenylphosphine)palladium (0) (131 mg, 0.114 mmol), and 2 M Na2CO3 (1.71 mL, 3.41 mmol). The mixture was heated at 80° C. overnight before it was diluted with ethyl acetate (10 mL) and washed with water (20 mL). The organics were dried over Na2SO4 and evaporated. The resulting crude material was purified by silica gel chromatography eluting with 0-10% ethyl acetate in hexanes to yield tert-butyl 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoate (603 mg, 97%). ESI-MS m/z calc. 544.6. found 545.3 (M+1)+. Retention time 2.76 minutes.