Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.Cl[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][O:17][C:15]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
tert-Butyl(3S)-3-aminopyrrolidine-1-carboxylate (0.09 mL, 0.5 mmol) was combined with methyl chloroformate (0.049 mL, 0.64 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The residue was purified on silica gel (eluting with 0 to 10% methanol in dichloromethane) to give tert-butyl (3S)-3-[(methoxycarbonyl)amino]pyrrolidine-1-carboxylate, LCMS [M+Na] 267.1. The latter was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give the crude product (35 mg, 40%), which was used directly in the next step. LCMS calculated for C6H13N2O2 (M+H)+: m/z=145.1; Found: 145.1.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Br:64][C:65]1[CH:66]=[C:67]([CH2:73][NH2:74])[CH:68]=[CH:69][C:70]=1[O:71][CH3:72]>ClCCl>[Br:64][C:65]1[CH:66]=[C:67]([CH2:73][NH:74][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:68]=[CH:69][C:70]=1[O:71][CH3:72]
Reactant: COc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(Br)c2)n1
Reaction time: 1.5 h
Yield: 121.5 %

Procedure:
To a suspension of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (30 g, 66.3 mmol) in a 1 L round-bottom flask in dichloromethane (DCM) (300 mL) was added triethylamine (46.2 mL, 331 mmol) giving a solution to which was added TBTU (31.9 g, 99 mmol). The mixture became cloudy and was then stirred at room temperature under nitrogen for 5 min when 1-[3-bromo-4-(methyloxy)phenyl]methanamine hydrochloride (18.42 g, 72.9 mmol) was added. After 1.5 h the reaction was worked up. The mixture was partitioned between dichloromethane and water and the aqueous layer extracted well with dichloromethane. The combined organics were washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated to give 52.41 g (121%) of a golden foam. The crude product was purified on a 750 g Companion XL silica cartridge, eluting with 20-100% of {1% MeOH in EtOAc) in dichloromethane over 12 column volumes. The fractions were checked by HPLC and product fractions were combined and solvent evaporated to give 30.15 g (˜65%) of a cream foam that lab HPLC showed to be 97.2% pure (ret time 2.11 min) LC-MS m/z 650, 652 (M+H)+, 1.03 min (ret time).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:19]([C:21]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:20]#[C:19][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:3]=1)=[O:17]
Reactant: C#CC1(O)CCCC1
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: O=C(NCCC(O)c1cccc(C#CC2(O)CCCC2)c1)C(F)(F)F

Procedure:
Sonogashira reaction of bromide 25 with 1-ethynylcyclopentanol yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1-hydroxycyclopentyl)ethynyl)phenyl)propyl)-acetamide as brown oil. Yield (0.55 g, 55%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.28-7.35 (m, 3H), 4.85-4.87 (m, 1H), 3.66-3.70 (m, 1H), 3.38-3.44 (m, 1H), 2.41 (bs, 1H), 1.76-2.08 (m, 10H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])(=O)=O)=CC=1.[F:20][C:21]([F:33])([F:32])[CH2:22][CH2:23][S:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])(=[O:26])=[O:25].[H-].[Na+].Cl>CS(C)=O>[F:15][C:14]([F:17])([F:16])[CH:13]([CH3:18])[CH2:12][CH2:11][CH:27]([S:24]([CH2:23][CH2:22][C:21]([F:20])([F:32])[F:33])(=[O:25])=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)C(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CCC(C)C(F)(F)F)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 20 h
Yield: 34.3 %

Procedure:
To a solution of 2.0 g of 4,4,4-trifluoro-3-methylbutyl p-toluenesulfonate and 1.6 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide was added 0.3 g of sodium hydride (60% in oil) at room temperature. The reaction mixture was heated to 60° C., stirred at the same temperature for 20 hours, and then allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.83 g of methyl 6,6,6-trifluoro-5-methyl-2-(3,3,3-trifluoropropylsulfonyl)hexanoate (hereinafter referred to as the present compound (1)).
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[CH:17]=2)[NH:12][N:11]=1
Reactant: Cc1ccncc1-c1cnc2c(c1)c(-c1nc3ccncc3[nH]1)nn2C1CCCCO1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccncc1-c1cnc2[nH]nc(-c3nc4ccncc4[nH]3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
To a solution of 3-(3H-imidazo[4,5-c]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (LIX) (0.110 g, 0.26 mmol) in dry DCM (5 mL) was added triethylsilane (0.104 mL, 0.65 mmol) followed by TFA (2.5 mL) and stirred at room temperature for 3 h under nitrogen. The solvent was evaporated under reduced pressure, the residue was taken up water (10 mL), and basified with concentrated NH4OH. The precipitates were filtered, washed by cold water and dried under vacuum at room temperature. The crude product was suspended in DCM (10 mL), sonicated briefly and then heated to boiling for 5 min. The solution was cooled to room temperature and the solids were filtered, washed with DCM and dried under vacuum at room temperature to produce 3-(3H-imidazo[4,5-c]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (29) as a white solid (37 mg, 0.11 mmol, 43% yield). 1H NMR (DMSO-d6) δ ppm 2.33 (s, 3H), 7.45 (d, J=4.78 Hz, 1H), 7.75 (bd, 1H), 8.43 (d, J=5.29 Hz, 1H), 8.54 (bs, 2H), 8.69-8.82 (m, 3H), 14.64 (s, 1H); ESIMS found for C18H13N7 m/z 328.4 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[CH:10]3)[C:6]=2[CH:22]=1.[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])[CH3:24].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=5)=[CH:10]4)[C:6]=3[CH:22]=2)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: CC(C)N1CCC(S)CC1
Reactant: Cc1ccnc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccnc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)ccc2OCC3)c1
Temperature: 120 °C
Yield: 77.3 %

Procedure:
A mixture of 9-bromo-2-(4-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (147 mg, 0.411 mmol), 1-isopropylpiperidine-4-thiol (98 mg, 0.617 mmol), Pd2(dba)3 (19 mg, 5 mol %), XantPhos (24 mg, 10 mol %) and DIPEA (288 l, 1.64 mmol) in dioxane (5 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The reaction mixture was then diluted with DCM (100 mL) and purified by column chromatography (Si-PCC, gradient 0-8% 2M NH3/MeOH in DCM followed by C18, gradient 10-50% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording the title compound as a colorless foam (138 mg, 77%). LCMS: RT1.79 min [M+H]+ 435.2
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[C:7]1([N:6]2[C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:3][N:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CNCCN1
Reactant: Clc1nnnn1-c1ccccc1
Product: c1ccc(-n2nnnc2N2CCNCC2)cc1
Yield: 99.7 %

Procedure:
Using 5-chloro-1-phenyl-1H-tetrazol (2.10 g) and piperazine (10.0 g), and reaction at 100° C. in the same manner as in Example 196 (1), 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (2.67 g) was obtained as a pale-yellow powder.
Reaction SMILES: B(Br)(Br)Br.[C:5]([CH2:8][CH:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:24][C:23]=2[O:38]C)[CH2:12][CH2:11][CH2:10]1)([OH:7])=[O:6].O>ClCCl>[C:5]([CH2:8][CH:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:24][C:23]=2[OH:38])[CH2:12][CH2:11][CH2:10]1)([OH:7])=[O:6]
Reactant: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(CC(=O)O)c2cc(Cl)ccc21
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)CC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)cc2O)c2ccc(Cl)cc21
Reaction time: 8 h
Yield: 93.3 %

Procedure:
9.1 ml of 98% boron tribromide was dropwise added, at -10° C. with stirring, to a solution of 10 g of 5-carboxymethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 400 ml of dichloromethane. The mixture was slowly returned to room temperature and stirred overnight at the same temperature. The reaction mixture was mixed with water, followed by extraction with dichloromethane. The extract was water-washed, then dried over anhydrous magnesium sulfate, and subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography to obtain 9.08 g of 5-carboxymethyl-7-chloro-1-[2-hydroxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11](=[O:12])[N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](=[O:23])[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[C:15]2[CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: Nc1ccccn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)Nc3ccccn3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 59.1 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), 2-aminopyridine (51 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 10 mL of dichloromethane under stirring. After stirring for 20 minutes, bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.14 g, 0.54 mmol) was added to the solution. The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-3-[1-(pyridin-2-ylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 31a (0.1 g, yield 59%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=O)C(F)(F)F)[CH:5]=[CH:6][CH:7]=1.C=O.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:11]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=2)[CH2:8][CH2:9][NH:10]1
Reactant: O=C(NCCc1cccc(Br)c1)C(F)(F)F
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCNC2

Procedure:
Preferably the 1,2,3,4-tetrahydroisoquinoline intermediate (VIIa) is synthesised by Route A shown in Scheme 2. This route is a Friedel-Craft-type reaction of N-[2-(3-bromophenyl)ethyl]-2,2,2-trifluoroacetamide with formaldehyde and sulfuric acid in acetic acid (Tetrahedron Lett. 1996, 37(31), 5453-5456) giving a mixture of the 6-bromo- and 8-bromoisomer in a ratio of 3 to 1. Replacement of the trifluoroacetamide group with a BOC-group gives (VIIa). The regioisomers are not conveniently separated at this stage.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:11][CH:10]1[CH2:9][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7]2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:12]([N:8]1[CH2:9][CH:10]2[C:6]([CH2:4][OH:3])([CH2:11]2)[CH2:7]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C12CC1CN(Cc1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC12CC1CN(Cc1ccccc1)C2
Reaction time: 1 h

Procedure:
A solution of 3-benzyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester (2.5 gm, 0.0108 mole) in tetrahydrofuran (20 ml) was added to a suspension of lithium aluminium hydride (0.966 gm, 0.026 mole) in tetrahydrofuran (50 ml). The resulting mixture was heated to reflux for 2 hours. The reaction mixture was carefully quenched with saturated aqueous NH4Cl (1 ml), treated with ethyl acetate (50 ml) and stirred for 1 hour. The solution was filtered and the removal of solution from the filtrate provided the crude title product which was purified by column chromatography (100-200 mesh, silicagel), eluting the compound with 15% ethyl acetate in hexane to give pure product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][C:25]4[CH:30]=[CH:29]C([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[S:44]1C=C(CO)[N:46]=[N:45]1>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:34])[O:24][CH2:25][C:30]4[N:46]=[N:45][S:44][CH:29]=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCc1csnn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)OCc1csnn1

Procedure:
A solution of 0.50 g (0.50 mmol) of 4-nitrophenyl 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-ethylcarbamate, prepared in step 1.5., 0.128 g (0.99 mmol) of N,N-diisopropylethylamine, 0.030 g (0.25 mmol) of N,N-dimethylaminopyridine and 0.079 g (0.5 mmol) of [1,2,3]thiadiazol-4-ylmethanol (Acta Pharmaceutica Suecica (1973), 10(4), 285-96) in 5 mL of 1,2-dichloroethane is heated in a reactor tube at 80° C. for 12 hours.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[C:9]2[C:10]([CH3:23])=[CH:11][C:12]([O:14][CH2:15][C:16]3[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[CH:17]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.[OH-].[Na+].Cl>CCO>[CH3:21][N:20]1[C:16]([CH2:15][O:14][C:12]2[CH:11]=[C:10]([CH3:23])[C:9]3[C:5]([CH2:4][C:3]([OH:24])=[O:2])=[CH:6][S:7][C:8]=3[CH:13]=2)=[CH:17][C:18]([CH3:22])=[N:19]1
Reactant: COC(=O)Cc1csc2cc(OCc3cc(C)nn3C)cc(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(COc2cc(C)c3c(CC(=O)O)csc3c2)n(C)n1
Yield: 79.5 %

Procedure:
To a mixture of methyl(6-((1,3-dimethyl-1H-pyrazol-5-yl)methoxy)-4-methyl-1-benzothiophen-3-yl)acetate (143 mg) and EtOH (2 mL) was added 1N NaOH (0.42 mL) at room temperature, and the mixture was refluxed for 30 min. The mixture was neutralized with 1N HCl at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residual solid was crystallized from EtOAc-hexane to give the title compound (109 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(CCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1oc(-c2ccccc2)nc1CCc1ccc(CO)cc1

Procedure:
Methyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]benzoate was reduced with lithium aluminum hydride in the same manner as in Reference Example 12 to yield 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]benzyl alcohol, which was then recrystallized from ethyl acetate-hexane to yield colorless plates having a melting point of 103°-104° C.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:4]=1[C:5]([NH:7][C:8]1[C:9]([NH2:16])=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=O>P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]([CH3:24])[C:3]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:4]=1[C:5]1[NH:7][C:8]2[C:9]([N:16]=1)=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2N(C)C)c(N)n1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(-c3ccc([N+](=O)[O-])cc3N(C)C)nc2n1

Procedure:
A suspension of 1.4 gm of 3-[(2-dimethylamino-4-nitro-benzoyl)-amino]-2-amino-6-methoxy-pyridine in 40 ml of phosphorus oxychloride is refluxed for three hours. The phosphorus oxychloride is evaporated off by about two-thirds, and the residue is poured into water. The solution obtained is made ammoniacal, and the product precipitated is purified over a silica gel column [eluant: methylene chloride/ethanol (100:0 to 100:0.5)].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([CH:25]=1)[NH2:24]>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1ccc(Cl)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: COc1ccc(Cl)cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol) and 5-chloro-2-methoxyaniline (27 mg, 0.173 mmol) similar to Example 185 and was isolated as a solid (10 mg, 23% yield). 1H NMR (CDCl3): 9.72 (d, J=1.2 Hz, 1H), 8.82 (t, J=1.8 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.23 (brs, 1H), 7.71 (brs, 1H), 7.15 (dd, J=8.4, 2.4 Hz, 1H), 7.04 (s, 1H), 6.88 (d, J=8.4 Hz, 1H), 3.90 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C:14]#[CH:15])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[N:16](C=C)[N:17]=[CH:18][C:3]=12.Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C:14]#[CH:15])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[NH:16][N:17]=[CH:18][C:3]=12
Reactant: C#CCN1CCc2nc3c(cnn3C=C)c(N)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C#CCN1CCc2nc3[nH]ncc3c(N)c2C1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
To a mechanically stirred solution of 4-amino-7,8-dihydro-6-(prop-2-ynyl)-1-vinyl-1H-pyrazolo[3,4-b][1,6]napthyridin-5(6H)-one (1.91 g.) in dry acetonitrile (35 ml.) under a nitrogen atmosphere was added freshly prepared 6N aqueous HCl (11.65 ml.) at room temperature. The resulting suspension was heated under reflux for three hours, followed by cooling to room temperature and addition of water. The reaction mixture was made basic with aqueous saturated sodium carbonate and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered through diatomaceous earth and concentrated to give 4-amino-7,8-dihydro-6-(prop-2-ynyl)-1H-pyrazolo[3,4-b][1,6]napthyridin-5(6H)-one as a white solid (1.24 g.) (72% yield) which was used without further purification.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[CH:42][N:43]([CH2:45][CH2:46][CH3:47])[CH:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[CH:42][N:43]([CH2:45][CH2:46][CH3:47])[CH:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cn(CCC)cn4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cn(CCC)cn4)cc2)CCN3CC(C)C)cc1
Yield: 71.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-4-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (140 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (78 mg) in dichloromethane (15 ml) at −78° C. The reaction vessel was removed from a dry ice-acetone bath, and an aqueous solution of sodium thiosulfate was added to the reaction vessel with strongly stirring. The mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (methanol-ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-4-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (103 mg) (Compound 394) as yellow amorphous.