Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.O.Cl>C(O)(C)C>[CH2:1]1[CH2:2][CH2:3][CH:4]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])[CH2:5][CH2:6]1
Reactant: N[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: N[C@@H](C(=O)O)C1CCCCC1
Temperature: 55 °C
Reaction time: 7 h

Procedure:
100 g (661.5 mmol) D-phenylglycine are dissolved or suspended in 890 ml deionised water, 290 ml isopropanol and 66.7 ml (802 mmol) 37% hydrochloric acid. After addition of 10 g of the Pt/Rh catalyst, 4% Pt+1% Rh on activated carbon (water content approx. 50%, corresponding to approx. 5 wt. % catalyst relative to D-phenylglycine used), the reaction mixture is introduced into a 2 l hydrogenation autoclave. After being rendered inert with nitrogen three times, it is rinsed with hydrogen twice, then a hydrogen overpressure of 8-10 bar is established and the reaction solution heated to 50-60° C. After approximately 6 to 8 hours, hydrogen uptake is completed (theoretical amount of H2 44.4 l). The hydrogenator is depressurised and once again rendered inert with nitrogen three times. The still hot reaction solution is extracted with a nutsch filter and the catalyst is washed with 200 ml deionised water. The filtrate is first adjusted at 40-60° C. to a pH of 2-2.5 with 50% sodium hydroxide solution, during which process the first crystals form. It is then stirred for a further 15-30 minutes at this pH and then adjusted to a pH of 5-6 with 50% sodium hydroxide solution. The reaction mixture is cooled in an ice bath to a temperature of 0-10° C., the product is extracted with a nutsch filter, washed with 300 ml deionised water and dried in a drying oven in vacuo at 50-70° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3].[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](F)[CH:22]=1>>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([Br:20])[CH:22]=1)[CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: Fc1cccc(Br)c1
Reactant: C=CCN(C)CCCCCc1ccc2[nH]ccc2c1
Product: C=CCN(C)CCCCCc1ccc2c(ccn2-c2cccc(Br)c2)c1

Procedure:
In analogy to example 4.6, Allyl-[5-(1H-indol-5-yl)-pentyl]-methyl-amine and 1-bromo-3-fluoro-benzene were converted to yield Allyl-{5-[1-(3-bromo-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amine as light brown oil, MS: 411 (MH+, 1Br).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:27])[N:16]([C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:15]([CH2:25][OH:26])[CH2:14][O:13]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:27][C:12]1([CH3:11])[N:16]([C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:15]([CH:25]=[O:26])[CH2:14][O:13]1
Reactant: CCCCCCC(=O)N1[C@H](CO)COC1(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCC(=O)N1[C@H](C=O)COC1(C)C
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
A solution of oxalyl chloride (105 μl, 1.23 mmol) in CH2Cl2 (2.75 mL) is cooled to -60° C. A solution of DMSO (192 μL) in CH2Cl2 (0.55 mL) is ,added over a period of 5 min. and the resulting milky mixture is stirred for 15 min at -60° C. The alcohol from Example 39 (133 mg., 0.55 mmol) in CH2Cl2 (0.55 ml) is added to the mixture over 5 min. The bath is allowed to warm up to -20° C. (20 min.) and the clear solution is stirred for 20 min. at -20° C. Triethylamine (0.77 mL) and H2O (3.4 mL) are added and the mixture is stirred for 5 minutes at ambient temperature. Workup with CH2Cl2 gives a crude oil which is purified by chromatography (1.5×20 cm, 3:1 together) to give 9a: NMR δ0.85 (m, 3H), 1.30 (m, 6H), 1.60 (s, 3H), 1.60-1.70 (m, 2H), 1.70 (s, 3H), 2.00-2.40 (m, 2H), 4.00-4.30 (m, 3H), 9.65 (d, J=1, 1H).
Reaction SMILES: [CH:1]1([N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:6]3[N:7]([C:23]([C:26]#[N:27])=[CH:24][N:25]=3)[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=3)[CH:10]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[CH:1]1([NH:4][C:5]2[C:6]3[N:7]([C:23]([C:26]#[N:27])=[CH:24][N:25]=3)[N:8]=[C:9]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:16][CH:17]=3)[CH:10]=2)[CH2:3][CH2:2]1
Reactant: CCN(CC)c1ccc(Nc2cc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)c1ccc(Nc2cc(NC3CC3)c3ncc(C#N)n3n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.12 %

Procedure:
A solution of 244A (5 mg, 10.38 μmol) in DCM (1 mL) was treated with TFA (1 mL, 12.9 mmol) and stirred at room temperature for three hours. The reaction mixture was concentrated and dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min., 20 min. gradient, monitored at 220 nm) to give Example 244, (1.2 mg, 22.12% yield). HPLC: Rt=3.178 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=362.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.09-11.33 (1H, m), 9.70 (1H, s), 8.15 (1H, s), 7.82-8.05 (2H, m), 7.51-7.67 (2H, m), 6.24 (1H, s), 1.01 (6H, t, J=6.80 Hz), 0.72-0.86 (2H, m, J=5.54 Hz), 0.53-0.72 (2H, m, J=2.77 Hz).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[F:6][C:7]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:8]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:28][CH3:29])[N:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].Cl>C(Cl)Cl.C(O)(=O)C>[N:2]1([CH:24]2[CH2:25][CH2:26][N:21]([S:18]([NH:17][C:15]3[CH:14]=[C:13]([O:28][CH3:29])[N:12]=[C:11]([S:10][CH2:9][C:8]4[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:7]=4[F:6])[N:16]=3)(=[O:19])=[O:20])[CH2:22][CH2:23]2)[CH2:5][CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: COc1cc(NS(=O)(=O)N2CCC(=O)CC2)nc(SCc2cccc(F)c2F)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(NS(=O)(=O)N2CCC(N3CCC3)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Azetidine hydrochloride (0.11 g) was added to a solution of acetic acid (0.025 mL) and N-{2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-4-oxopiperidine-1-sulfonamide (the product of example 148, step iii) (0.10 g) in DCM (4 mL). The solution was stirred at room temperature for 1 h then sodium triacetoxyborohydride (0.24 g) was added in portions. The mixture was stirred at room temperature overnight then 3M aqueous sodium hydroxide (6 mL) added to the residue. The mixture was shaken vigorously then acidified to pH 8 with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were concentrated then methanol (1 mL) was added and the resulting suspension filtered. The solid was washed with water, methanol and ethyl acetate to afford the title compound as a white powder. Yield: 47 mg
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:31])[CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C@@H:11]([OH:14])[C@H:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[S:9][C:8]2[C:23]3[C:28]([CH:29]=[CH:30][C:7]1=2)=[CH:27][CH:26]=[CH:25][CH:24]=3.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([O:14][C@H:11]1[C@H:10]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[S:9][C:8]2[C:23]3[C:28]([CH:29]=[CH:30][C:7]=2[N:6]([CH2:5][CH2:4][N:3]([CH3:2])[CH3:31])[C:12]1=[O:13])=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:34])[CH3:33]
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Yield: 91 %

Procedure:
A mixture of 1.1 g of (±)-trans-5-[2-(dimethylamino)ethyl]-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one hydrochloride and 20 mL acetic anhydride was heated at 100° for 17 hours. The excess reagent was removed under reduced pressure and the residue was partitioned between ethyl acetate and dilute sodium hydroxide. The ethyl acetate solution was washed with brine and dried (magnesium sulfate). Removal of the solvent gave 1.0 g (91%) of (±)-trans-3-(acetyloxy)-2,3-dihydro-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one. A sample was crystallized from ether--pet. ether, mp 122°-123°.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].C(N(CC)C(C)C)(C)C.Cl>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=1)[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][Cl:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCCl
Reactant: CCOC(=O)c1ccc(NCc2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(N(Cc2ccccc2)C(=O)CCCCl)cc1
Reaction time: 12 h

Procedure:
To a solution of ethyl 4-benzylaminobenzoate (6.0 g) in methylene chloride (60 mL) is added dropwise chlorobutyryl chloride (3.95 mL) and N,N-diisopropylethylamine (6.14 mL) under ice-cooling, and the mixture is stirred for 12 hours. The reaction mixture is diluted with chloroform and thereto is added 10% HCl. The organic layer is separated, washed successively with water, a saturated sodium hydrogencarbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=4:1) to give ethyl 4-[N-benzyl-N-(4-chlorobutyryl)amino]benzoate (8.27 g, yield; quantitative) as an oil. MS (APCI) m/z; 360/362 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:9]=[CH:10][C:3]=12.CCN(CC)CC.[C]=O.[CH3:27][CH2:28][O:29][C:30](C)=[O:31]>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:28]([O:29][C:30]([C:2]1[C:3]2[CH:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:5]=[N:6][CH:7]=1)=[O:31])[CH3:27]
Reactant: CCOC(C)=O
Reactant: Fc1ccc(-n2ncc3c(Br)cncc32)cc1
Agent: [Fe+2]
Agent: [C]=O
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine (3.5 g, 12 mmol), Et3N (3.5 mL, 25 mmol), Pd[PhCN]2Cl2 (105 mg, 0.273 mmol), and dppf (418 mg, 0.754 mmol) in absolute ethanol (90 mL) was placed in a sealed bomb with stifling and placed under 15 bars of carbon monoxide and warmed to 140° C. for 4 hours. The mixture was then cooled to room temperature, returned to atmospheric pressure and opened. The reaction was monitored by TLC (EtOAc-hexanes 4:6 and EtOAc) indicating the starting material was consumed. The reaction was diluted with water (300 mL) and the solid was collected by filtration washing with water. The filtrate was diluted with water (200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (2×100 mL). The still moist filter cake was dissolved in EtOAc and combined with the extracted organic layers, dried over magnesium sulfate, treated with activated carbon) and filtered through a pad of diatomaceous earth and a layer of silica gel. The material from the pad was dissolved in dichloromethane and passed through a pad of silica gel eluting with dichloromethane to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid ethyl ester.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1ccccc1
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccccc1
Yield: 81 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and phenylhydrazine according to the method described for Example 1 in 81% yield. MS: M=315.1 (M+H)+
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13]2([C:18]([F:21])([F:20])[F:19])[CH2:17][CH2:16][NH:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Br)[N:26]=1.C(N(CC)C(C)C)(C)C.CC(N(C)C)=O>C(OCC)(=O)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2([C:18]([F:21])([F:19])[F:20])[CH2:17][CH2:16][N:15]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Br:24])[N:26]=3)[CH2:14]2)[CH:4]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:8]=1
Reactant: Brc1cccc(Br)n1
Reactant: FC(F)(F)c1cc(C(F)(F)F)cc(C2(C(F)(F)F)CCNC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(C(F)(F)F)cc(C2(C(F)(F)F)CCN(c3cccc(Br)n3)C2)c1
Yield: 92.3 %

Procedure:
A mixture of 3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidine (3.0 g), 2,6-dibromopyridine (2.22 g), N,N-diisopropylethylamine (2.2 g) and dimethylacetamide (15 ml) was reacted at 160° C. in a sealed tube for 1 hour. Upon the completion of the reaction, the mixture was added with ethyl acetate, washed with water and then saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain 2-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-6-bromopyridine (4.0 g).
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([CH3:10])=[C:6]([CH3:9])[C:7]=1[CH3:8].C(#N)C.[Br-:14].[C:15]1([PH+:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[Br-:14].[CH3:8][C:7]1[C:6]([CH3:9])=[C:5]([CH3:10])[S:4][C:3]=1[CH2:2][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: Cc1sc(CO)c(C)c1C
Agent: [Br-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1sc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Temperature: 50 °C

Procedure:
2.2 G. of 2-hydroxymethyl-3,4,5-trimethyl-thiophene were dissolved in 25 ml. of acetonitrile and 4.6 g. of triphenylphosphonium bromide were added. The resulting reaction mixture was heated to 50° C. for 3 hours. After evaporation of the solvent, the residue which formed was diluted with ethyl acetate, heated briefly and filtered. The crystalline (3,4,5-trimethyl-2-thenyl)-triphenyl phosphonium bromide obtained was dried at 50° C. under high vacuum and had m.p. 208°-215° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]([N:8]=[N:9][C:10]1(Cl)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:7])[CH3:6].O>CO>[CH:5]([N:8]=[N:9][C:10]1([N:1]=[N+:2]=[N-:3])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:7])[CH3:6]
Reactant: CC(C)N=NC1(Cl)CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)N=NC1(N=[N+]=[N-])CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 9.75 grams (0.15 moles) of sodium azide in 100 mls of 70% aqueous methanol in a 250 ml erlenmeyer flask cooled in an ice bath, was added 18.85 grams (0.1 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) over 15 minutes while holding the reaction temperature below 10° C. After the addition was complete the mixture was stirred an additional 20 minutes at room temperature, poured into 200 ml water and extracted into 100 ml of pentane. The pentane solution was washed successively with 50 ml portions of water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 18.4 grams (94.4 % crude yield). It was not shock sensitive and its infrared spectrum was in agreement with the structure of 1-isopropylazo-1-azidocylohexane (strong azide band at 2100 cm-1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](B(O)O)=[CH:3][N:2]=1.Br[C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[NH:20][N:19]=[CH:18]2.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[Cl:24][C:22]1[CH:23]=[C:15]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=[N:2][CH:3]=2)[CH:16]=[C:17]2[C:21]=1[NH:20][N:19]=[CH:18]2
Reactant: OB(O)c1cncc2ccccc12
Reactant: Clc1cc(Br)cc2cn[nH]c12
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
Product: Clc1cc(-c2cncc3ccccc23)cc2cn[nH]c12
Temperature: 85 °C
Yield: 72.1 %

Procedure:
A mixture of isoquinolin-4-ylboronic acid (1.00 g, 5.78 mmol), 5-bromo-7-chloro-1H-indazole (892 mg, 3.85 mmol), 2.0 M sodium carbonate (3.85 mL, 7.71 mmol) and dimethoxyethane was degassed with argon. Tetrakis(triphenylphosphine)palladium(0) (233 mg, 0.193 mmol) was added, the mixture degassed again with argon, then heated to 85° C. for 24 hours. The reaction was cooled and partitioned between ethyl acetate and water, the organic layer washed with and dried with sodium sulfate. The solvent was removed under vacuum and the residue purified by column chromatography (9/1 to 6/4 hexanes/ethyl acetate gradient) to give 4-(7-chloro-1H-indazol-5-yl)-isoquinoline (777 mg, 72%): 1H NMR (300 MHz, CDCl3) δ 10.52 (s, 1H) 9.31 (s, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 8.09 (dd, J=7.4, 1.62 Hz, 1H), 7.28 (dd, J=7.4, 1.2 Hz, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.81 (d, J=1.2 Hz, 1H), 7.72-7.64 (m, 2H), 7.57 (d, J=1.3 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>C1COCC1>[F:22][C:3]1[C:2]([NH:1][C:32](=[O:36])[C:33]([CH3:35])=[CH2:34])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[C:9]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3F)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1F
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(3-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (6.5 mg, 0.022 mmol) and DIPEA (12 μL, 0.066 mmol) in THF (220 μL) at room temperature was added methacryloyl chloride (3.5 mg, 0.033 mmol) and the solution was stirred for 1 hour. The reaction was concentrated and the residues, dissolved in 2 mL of DMSO, were purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. Lyophilization of the desired fractions afforded a colorless solid. LRMS (ESI) calc'd for C19H18N4O3F [M+H]+: 369, found 369.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH:40]([CH3:42])[CH3:41])[C:9]=2[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH:40]([CH3:42])[CH3:41])[C:9]=2[C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(OC(C)C)c(-c4ccc(F)cc4)c(C4CC4)c3)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(OC(C)C)c(-c4ccc(F)cc4)c(C4CC4)c3)CC1)CC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (5 mL)-THF (5 mL) solution of methyl 6-(1-((2-cyclopropyl-4′-fluoro-6-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (470 mg), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (389 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15]C1C(F)=C(F)C(F)=C(F)C=1F)(=[O:14])=O)=[CH:7]2.[N:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29][CH:28]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(O)(=O)C>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:33][C:30]1[CH:31]=[CH:32][N:27]=[CH:28][N:29]=1)(=[O:14])=[O:15])=[CH:7]2
Reactant: Nc1ccncn1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)cccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(Br)cccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A round bottom flask was charged with perfluorophenyl 5-bromonaphthalene-2-sulfonate (Intermediate M) (0.677 g, 1.494 mmol) and pyrimidin-4-amine (0.185 g, 1.942 mmol). A septum was attached and the flask flushed with N2. THF (7.47 mL) was added and the solution was cooled to −78° C., lithium bis(trimethylsilyl)amide (1.195 mL, 1.195 mmol) was added and after addition was complete, the cold bath was removed and the solution was allowed to warm to rt. After 30 min at rt, acetic acid (0.257 mL, 4.48 mmol) was added to the solution to produce a precipitate. The mixture was concentrated and the resulting tan solid was suspended in DCM (20 mL) and collected by vacuum filtration to provide 5-bromo-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide (0.54 g) as a tan solid, which was of sufficient purity for further use.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27](O)=[O:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][CH:27]=[O:28])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=CO
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=CN[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (20 mg, 23%), MS (ISP) m/z=355.2 [(M+H)+], mp 155° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and formic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Br[CH2:21][CH2:22][CH3:23]>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[N:7]([CH2:21][CH2:22][CH3:23])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4]
Reactant: CCCBr
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCCn1nc(-c2ccc(OC)cc2)cc(C(=O)OC)c1=O
Yield: 78.3 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and bromopropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 78.3%.