Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH:19]=2)[CH:17]=[O:18])[CH2:8][CH2:7]1)(C)(C)C.[C:21](=[O:24])([O-:23])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>CN1C(=O)CCC1.C(OCC)(=O)C>[C:16]([O:23][C:21]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:13]=[CH:14][C:15]([O:20][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:16]([CH:17]=[O:18])[CH:19]=2)[CH2:10][CH2:11]1)=[O:24])([CH3:19])([CH3:17])[CH3:15]
Reactant: CC(C)(C)ON1CCN(c2ccc(O)c(C=O)c2)CC1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CBr
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1C=O

Procedure:
0.5 g of 5-(4-tert-butoxypiperazin-1-yl)-2-hydroxybenzaldehyde are dissolved in 5 ml of NMP at 20° under nitrogen with stirring, and 0.25 g of potassium carbonate and 0.2 ml of ethyl bromoacetate are added. The mixture is stirred at 110° for 30 minutes and cooled to 25°. 30 ml of water and 30 ml of ethyl acetate are added to the mixture, the phases are separated, and the aqueous phase is extracted with 30 ml of ethyl acetate. The combined organic phases are washed with 30 ml of water and freed from solvent under reduced pressure. 30 ml of toluene, 30 ml of water and 5 ml of 1N HCl are added to the crystal slurry which remains, the toluene phase is removed under reduced pressure, and the crystalline precipitate is separated off and dried at 40° under reduced pressure (0.48 g; 75%), m.p. 93-94° C.; MS 392 (M+), 336 (100%), 250/249, 57.
Reaction SMILES: [NH2:1][C:2]1[O:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](Cl)=[N:6][C:5]=2[CH:4]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=2)[C:3]=1[C:28]#[N:29].[CH2:30]([N:32](CC)CC)C.CN>CN1C(=O)CCC1.O>[NH2:1][C:2]1[O:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([NH:32][CH3:30])=[N:6][C:5]=2[CH:4]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([Br:27])[CH:18]=2)[C:3]=1[C:28]#[N:29]
Reactant: CCN(CC)CC
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2nc(Cl)c2ccccc32)cc(Br)c1OC
Agent: CN
Solvent: CN1CCCC1=O
Solvent: O
Product: CNc1nc2c(c3ccccc13)OC(N)=C(C#N)C2c1cc(Br)c(OC)c(OC)c1
Temperature: 80 °C

Procedure:
3-Amino-1-(3-bromo-4,5-dimethoxy-phenyl)-9-chloro-1H-4-oxa-10-aza-phenanthrene-2-carbonitrile (34) (47 mg, 0.1 mmol) and triethylamine (14 μl, 0.1 mmol) and methylamine (2M in MeOH, 75 μl, 0.15 mmol) were taken in dry NMP (2 ml) and stirred at 80° C. till the reaction was complete. The reaction mixture was diluted with water to about 7 ml, stirred at room temperature for 2 h, precipitates were collected by filtration, washed with water. The residue was then purified on HPLC (high pressure liquid chromatography) (21 mm×250 mm, RP18, 5 mm) with a methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to pure title compound (36 mg, 77%).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[OH:55].I([O-])(=O)(=O)=O.[Na+]>CN(C=O)C.CO.O>[CH3:52][C@H:18]1[O:19][C@@H:20]([O:24][C@@H:25]2[CH2:30][C@H:29]3[CH2:31][CH2:32][C@H:33]4[C@@:38]5([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]6[CH2:47][O:46][C:44](=[O:45])[CH:43]=6)[C@@:37]5([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]4[C@@:28]3([CH3:51])[CH2:27][CH2:26]2)[CH2:21][C@H:22]([OH:23])[C@@H:17]1[O:16][C@@H:12]1[O:11][C@H:10]([CH3:53])[C@@H:9]([O:8][CH:6]([O:7][CH:2]([CH:3]=[O:55])[CH3:1])[CH2:5][CH:4]=[O:54])[C@@H:14]([OH:15])[CH2:13]1
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C=O)OC(CC=O)O[C@H]1[C@@H](O)C[C@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3CC[C@@]4(C)[C@H](CC[C@@H]5[C@@H]4C[C@@H](O)[C@]4(C)[C@@H](C6=CC(=O)OC6)CC[C@]54O)C3)O[C@@H]2C)O[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
Digoxin (2 g) was dissolved in a mixture of DMF (20 ml), methanol (14 ml) and water (14 ml) and treated dropwise with a solution of sodium periodate (1.434 g) in a mixture of water (10 ml) and methanol (10 ml). The solution was stirred for 3 hours at room temperature, then for 2 days at 4° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried, and evaporated to yield the digoxin dialdehyde as an oily white solid (2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=O.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=C.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC>C(OCC)(=O)C(OCC)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH:5]=[CH:13][C:12]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C=CC(=O)OCC
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C=Cc1ccc(Cl)c(Cl)c1
Yield: 11.4 %

Procedure:
0.152 g (0.5 millimol) of bis-(acetylacetonato)palladium(II), 10.53 g (50 millimols) of 3,4-dichlorobenzoyl chloride, 7.5 g (75 millimols) of ethyl acrylate and 17.65 g (50 millimols) of tri-n-octylamine in 100 ml of diethyl oxalate are stirred for 2.5 hours at 120° C. The crude product is distilled in vacuo and then recrystallised from methanol. 1.4 g (11% of theory) of ethyl 3,4-dichlorocinnamate are obtained; melting point 56.0° C.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[CH2:7][NH:6][CH2:5][C@H:4]1[OH:8].Cl[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.C(=O)(O)[O-].[Na+]>O>[S:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[N:6]1[CH2:7][C:3]([CH3:9])([CH3:2])[C@H:4]([OH:8])[CH2:5]1
Reactant: Clc1nc2ccccc2s1
Reactant: CC1(C)CNC[C@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C)CN(c2nc3ccccc3s2)C[C@H]1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a slurry of 600 mg (4 mmol) of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride and 670 mg (4 mmol) of 2-chlorobenzthiazole was added a solution of 1.0 g (12 mmol) of sodium bicarbonate in water. The reaction mixture was stirred at 80° C. overnight, diluted with water, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure to afford 950 mg (96%) of (3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethyl-3-pyrrolidinol. 1H NMR (300 MHz, DMSO-d6) δ 7.72 (d, J=8 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 7.23 (t, J=7 Hz, 1H), 7.00 (t, J=7 Hz, 1H), 5.23 (d, J=5 Hz, 1H), 3.84 (m, 1H), 3.77 (m, 1H), 3.38-3.21 (m, 3H) 1.02 (s 3H), 1.00 (s, 3H). Cl-LCMS m/z 249 (M+H).
Reaction SMILES: [H-].[Na+].[CH:3]([S:6]([NH2:9])(=[O:8])=[O:7])([CH3:5])[CH3:4].F[C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].Cl>CS(C)=O>[CH:3]([S:6]([NH:9][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])(=[O:8])=[O:7])([CH3:5])[CH3:4]
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)S(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)S(=O)(=O)Nc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Yield: 95 %

Procedure:
To 50 ml. of dimethylsulfoxide (DMSO) was added 1.01 g. (0.021 m.) of 50% sodium hydride in oil. After the initial gas evolution ceased, 2.53 g. (0.0206 m.) of isopropylsulfonamide [prepared according to Duguet, Rec. Trav. Chim., 25, 215 (1906)] was added. The mixture was stirred under a calcium chloride drying tube for ten minutes after which time 4.90 g. (0.020 m.) of 3-fluoro-4-nitrobenzophenone was added, followed by 20 ml. of DMSO. After stirring for five hours at room temperature, the reaction solution was poured into a mixture of ice and 1N hydrochloric acid which was then extracted several times with ethyl acetate. The extracts were combined, washed with water, and dried over magnesium sulfate. The oil remaining after evaporation was triturated with isopropanol to give 6.65 g. (95% yield) of 3-(isopropylsulfonyl)amino-4-nitrobenzophenone as a yellow powder. Crystallization from isopropanol gave pale yellow needles, m.p. about 115°-116° C.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.Br[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:24])[CH:16]=1.[C:25](=O)([O-])[O-].[K+].[K+]>CO.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>[OH:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:21][CH3:25])=[O:20])=[C:17]([CH3:24])[CH:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: COCOc1cccc(B(O)O)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(-c2cccc(O)c2)cc1C

Procedure:
In a manner similar to that of Example 1(h), by reaction of 5.35 g (29 mmol) of 3-methoxymethoxyphenylboronic acid (described in Example 1(g)) and 5.7 g (26.7 mmol) of 4-bromo-2-methylbenzoic acid with 26.7 mL of 2.0M potassium carbonate and 1.54 g of tetrakis(triphenylphosphine)palladium, followed by deprotection in methanol, the desired product is obtained in the form of a colourless oil (m=3.22 g; Y=50%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:23])[CH:7]=1.[Br:29]N1C(=O)CCC1=O>C(#N)C>[Br:29][C:7]1[C:8](=[O:23])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=1[F:1]
Reactant: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (from step 2) (15.85 g, 41.130 mmol) suspended in acetonitrile (165 mL) was cooled in an ice-bath. N-bromosuccinimide (7.687 g, 43.186 mmol) was added and the ice-bath was removed. The reaction mixture was stirred for 1.5 hours at room temperature. Reaction was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) afforded an off white solid (17.63 g, 92%). 1H NMR (400 MHz, CDCl3) δ 8.17 (dt, J=1.41, 7.85 Hz, 1H), 7.90 (t, J=1.81 Hz, 1H), 7.67-7.41 (m, 3H), 7.05-6.88 (m, 2H), 6.13 (s, 1H), 5.30 (s, 2H), 3.95 (s, 1H), 2.01 (s, 3H). ES-HRMS m/z 464.0286 (M+H C21H16BrF2NO4 requires 464.0304).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]3[NH:10][C:9]2=[O:17])[CH2:4][CH2:3]1.O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C([BH3-])#N.[Na+]>CO>[O:17]=[C:9]1[N:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH2:7][CH2:6]2)[C@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[NH:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C1N[C@@H]2CCCC[C@@H]2N1C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
To a solution of cis-(+/−)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one Hydrochloride salt (263 mg, 1.01 mmol) in MeOH (5 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (241 mg, 1.21 mmol). The mixture was stirred at room temperature for 30 min before sodium cyanoborohydride (95 mg, 1.52 mmol) was added. The mixture was stirred overnight at room temperature, additional amount of tert-butyl 4-oxopiperidine-1-carboxylate and sodium cyanoborohydride (1 eq each) were added and stirred at room temperature for 3 more days. MeOH was concentrated in vacuo, the residue dissolved in dichloromethane (20 mL) and washed with water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. To provide the title compound (244 mg, 59%) MS (M+1): 407.4
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[C:21]=1[CH3:22].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][NH:28]4)[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[C:21]=1[CH3:22]
Reactant: Cc1c(F)ccc2nc([C@H](C)N)n(-c3ccccn3)c12
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)ccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccn3)c12
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a solution of (S)-1-(6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (300 mg, 0.87 mmol) in IPA (10 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (271 mg, 1.14 mmol) and DIPEA (448 μL, 2.62 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc). LCMS (Method C): RT=2.81 min, [M+H]+=473. The product was dissolved HCl in methanol (5 mL, 2.5M) and the reaction stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the resultant residue loaded onto an SCX 2 cartridge, washed with methanol then eluted with ammonia in methanol (2M). The eluent was concentrated in vacuo and the residue triturated with diethyl ether to give 288 as a white solid (174 mg, 51%) 1H NMR 400 MHz δ (DMSO-d6 80° C.): 8.55-8.49 (1H, m), 8.01 (1H, s), 7.89 (1H, td, J=7.7, 1.9 Hz), 7.65 (1H, d, J=7.6 Hz), 7.49 (1H, dd, J=8.7, 4.7 Hz), 7.46 (1H, ddd, J=7.6, 4.9, 0.9 Hz), 7.17 (1H, br s), 7.02 (1H, dd, J=10.6, 9.0 Hz), 5.57 (1H, br s), 1.66 (3H, s), 1.55 (3H, d, J=6.8 Hz). LCMS (Method K): RT=3.01 min, [M+H]+=389
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7](=O)[CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])=[O:30])[CH:24]=3)[CH2:19]2)=[O:17])[CH2:11][CH2:10]1)=O)C.C(O)C.O.[NH2:44][NH2:45]>C(OC(C)C)(C)C>[OH:3][C:4]1[CH:6]=[C:7]([CH2:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([O:15][C:16]([N:18]3[CH2:19][CH2:20][C:25]4[C:26](=[CH:21][CH:22]=[C:23]([NH:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])=[O:30])[CH:24]=4)[CH2:27]3)=[O:17])[CH2:13][CH2:14]2)[NH:44][N:45]=1
Reactant: CCOC(=O)CC(=O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1
Reactant: NN
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: O=C(Nc1ccc2c(c1)CCN(C(=O)O[C@H]1CC[C@H](Cc3cc(O)n[nH]3)CC1)C2)Nc1ccccc1F

Procedure:
To a mixture of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-(3-ethoxycarbonyl-2-oxo-propyl)-cyclohexyl ester (189 mg) obtained in Example (42a) and ethanol (5 mL), hydrazine monohydrate (0.022 mL) was added at 0° C. During the reaction, hydrazine monohydrate was further added thereto, and the mixture was stirred until the reaction substrate was consumed. The reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol) to obtain a white solid. This white solid was vigorously stirred in isopropyl ether and collected by filtration to obtain the title compound (90 mg, 51%) as a white solid.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]2[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1>C(O)C.Cl>[Cl:25][C:23]1[CH:24]=[C:19]([S:18][C:12]2[N:11]([CH2:27][C:28]3[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:33]=3)[C:10]([CH2:9][OH:8])=[N:14][C:13]=2[CH:15]([CH3:17])[CH3:16])[CH:20]=[C:21]([Cl:26])[CH:22]=1
Reactant: Cc1ncccc1Cn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Cn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
In a mixture of 15 ml of ethanol and 20 ml of 36% hydrochloric acid was dissolved 609 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(2-methylpyridin-3-ylmethyl)-1H-imidazole (118a), and the mixture was stirred at 90° C. for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. An aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crystals were washed with diethyl ether, filtered, and 500 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1-(2-methyl pyridin-3-ylmethyl)-1H-imidazole (119a) was obtained (yield 99%). mp 136° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][NH:29][CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:15])[F:14])[C:5]=12.C(N(CC)CC)C.FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O>C(Cl)Cl>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][N:29]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:14])[F:15])[C:5]=12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(CC(F)(F)F)C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 17.2 %

Procedure:
To a mixture of 5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitrile dihydrochloride (20 mg, 0.04 mmol) and triethylamine (20 μL, 0.14 mmol) in methylene chloride (0.3 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 mg, 0.049 mmol). The resulting mixture was stirred at 40° C. for 3 h. The solvents were evaporated and the crude material purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 3.4 mg (20%) of the desired product. The product was isolated as a racemic mixture. LCMS calculated for C22H23F5N7O (M+H)+: m/z=496.2; Found: 496.1.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[S:8][CH:9]=1)=O.[NH:14]1[CH2:18][CH2:17][NH:16][C:15]1=[S:19].C(O)C>C(O)(=O)C>[BrH:1].[S:8]1[CH:9]=[C:5]([C:3]2[N:16]3[CH2:17][CH2:18][N:14]=[C:15]3[S:19][CH:2]=2)[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]1=2
Reactant: O=C(CBr)c1csc2ccccc12
Reactant: S=C1NCCN1
Solvent: CCO
Solvent: CC(=O)O
Product: Br
Product: C1=C(c2csc3ccccc23)N2CCN=C2S1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture of 3-(2-bromoacetyl)benzo[b]thiophen (10.0 g), 2-imidazolidinethione (4.0 g), ethanol (120 ml) and acetic acid (80 ml) was heated under reflux for 24 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 3-(benzo[b]thiophen-3-yl)-5,6-dihydroimidazo[2,1-b]thiazole monohydrobromide 1.8 hydrate as a white solid (11.6 g), m.p. 227°-229° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:47][C@H:48]1[CH2:54][CH2:53][C:50]2([CH2:52][CH2:51]2)[O:49]1)(=O)=O>CC(N(C)C)=O>[CH2:51]1[C:50]2([CH2:53][CH2:54][C@H:48]([CH2:47][O:1][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([O:12][C:13]5[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]6[C:23](=[O:35])[N:24]([C:29]7[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=7)[N:25]([CH3:28])[C:26]=6[CH3:27])=[O:21])=[N:17][CH:18]=5)=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)[O:49]2)[CH2:52]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: CS(=O)(=O)OC[C@H]1CCC2(CC2)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC[C@H]5CCC6(CC6)O5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C

Procedure:
The title compound was prepared according to the procedure described in Example 2 by using N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (280 mg, 0.69 mmol), cesium carbonate (1.17 g, 3.45 mmol, Aladdin), and ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate (204 mg, 0.99 mmol) in DMA (5 mL). The title compound was purified by a silica gel column chromatography (1:8 (v/v) n-hexane/EtOAc) as a colorless solid (110 mg, 27.6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:5](=[NH:19])[NH:6][C:7]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:16]([CH3:18])[CH3:17].Cl[CH2:25][CH:26]=O.C(=O)(O)[O-].[Na+].CC(O)C>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]([C:7]3[C:8]([CH:16]([CH3:17])[CH3:18])=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]([CH3:15])[CH3:14])[CH:25]=[CH:26][N:19]=2)[CH:20]=[C:21]([CH3:23])[CH:22]=1
Reactant: Cc1cc(Br)cc(C(=N)Nc2c(C(C)C)cccc2C(C)C)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Br)cc(-c2nccn2-c2c(C(C)C)cccc2C(C)C)c1
Yield: 78.8 %

Procedure:
To a 250 mL round bottom flask was added 3-bromo-N-(2,6-diisopropylphenyl)-5-methylbenzimidamide (2.92 g, 7.82 mmol), 2-chloroacetaldehyde (50%, 2.456 g, 15.64 mmol), sodium bicarbonate (1.314 g, 15.64 mmol), 60 mL 2-propanol. The reaction mixture was heated to reflux overnight under nitrogen. The reaction mixture was cooled and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with 10% LiCl solution, brine, dried over magnesium sulfate, filtered, and evaporated. The material was purified by column chromatography eluting with 15 and 20% ethyl acetate/hexane to give desired product (2.45 g, 79%).