Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>COCCOC.C(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>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: Cc1ccc(B(O)O)cc1
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: CCO
Product: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reaction time: 0.08 h

Procedure:
A room temperature solution of ethyl 4-bromobenzoate (0.70 mL, 4.3 mmol) in DME (20 mL) was treated with Pd(PPh3)4 (246 mg, 0.2 mmol), stirred for 5 minutes, treated with a solution of 4-methylphenylboronic acid (870 mg, 6.4 mmol) in ethanol (10 mL), stirred for 5 minutes, treated with 2M Na2CO3 (18.0 mL, 36.0 mmol), heated to reflux, stirred for 16 hours, and concentrated. The concentrate was dissolved in water (75 mL) and diethyl ether (50 mL), filtered through celite, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 33% acetone/hexanes. The resulting product was dissolved in methanol (10 mL) and THY (5 mL), treated with 1M NaOH (4.3 mL, 4.3 mmol), stirred for 48 hours, concentrated, dissolved in water (10 mL), adjusted to pH 1 with 12M HCl, and filtered. Recrystallization from ethyl acetate provided the desired product. MS (APCI(+)) m/e 213 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]=O)=[CH:16][CH:15]=3)=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:30])[CH3:2].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][OH:31])[CH2:35][CH2:36]2)=[CH:16][CH:15]=3)=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:30])[CH3:2]
Reactant: OCCN1CCNCC1
Reactant: CCc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCc1ccc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 90.6 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-ethyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (87.6 mg, 0.217 mmol) was dissolved in acetonitrile (7 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (113 mg, 0.868 mmol), acetic acid (0.248 mL, 4.34 mmol) and sodium triacetoxyborohydride (184 mg, 0.868 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-ethyl-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (102 mg, yield 91%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([CH:28]([OH:41])[CH:29]5[CH2:34][CH2:33][N:32](C(=O)C(F)(F)F)[CH2:31][CH2:30]5)=[CH:24][CH:23]=4)[CH3:21])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([CH:28]([OH:41])[CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:24][CH:23]=4)[CH3:21])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](Nc1ncc(C#N)c(-c2cnc3c(Cl)cccn23)n1)c1ccc(C(O)C2CCN(C(=O)C(F)(F)F)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](Nc1ncc(C#N)c(-c2cnc3c(Cl)cccn23)n1)c1ccc(C(O)C2CCNCC2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 78.8 %

Procedure:
237 mg of the compound [37-3] was dissolved in a mixed solvent of 3 mL of tetrahydrofuran and 1 mL of methanol, then 163 μL of 5N aqueous solution of sodium hydroxide was added thereto, and the mixture was stirred for 5 hours at 50° C. After standing to cool, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5-93/7), to obtain 156 mg of 4-(8-chloroimidazo[1,2-a]pyridin-3-yl)-2-[((1S)-1-{4-[hydroxy(piperidin-4-yl)methyl]phenyl}ethyl)amino]pyrimidine-5-carbonitrile [374] (hereinafter, referred to as the compound [374]).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>C(O)CCC>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: C1CNCCN1
Reactant: Brc1nccs1
Solvent: CCCCO
Product: c1csc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
The procedure described in J. Med. Chem 1996, 39(7), 1431 was followed to provide the title compound. A mixture of 2-bromothiazole (3 g, 18.3 mmol) and piperazine (3.15 g, 36.6 mmol) was refluxed in n-butanol for 18 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was treated with an aqueous solution of 10% K2CO3 and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure to provide 2.7 g (87%) of the title compound as brown oil used directly in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 2.99 (m, 4H), 3.47 (m, 4H), 6.57 (d, 1H, J=4.5 Hz), 7.20 (d, 1H, J=4.5 Hz); MS (DCI/NH3) m/e 170 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([CH3:21])([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:23][C:24]([F:37])([F:36])[C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([CH3:21])([CH3:20])[C:16]([F:18])([F:17])[F:19])=[C:9]([C:10]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:29][C:25]([C:24]([F:37])([F:23])[F:36])=[CH:26][N:27]=3)[CH2:31][CH2:32]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CC(C)(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1)C(F)(F)F
Yield: 52 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-benzoic acid (Example A14) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (ethyl acetate/heptane) to yield the title compound as a white solid (yield 52%). MS (m/e): 546.3 (M+H+, 100%). B.p.=182–183° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[CH:24]=[N:25][N:26](C3CCCCO3)[CH:27]=2)=[C:12]([F:34])[C:11]=1[F:35])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:35][C:11]1[C:12]([F:34])=[C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3cnn(C4CCCCO4)c3)c(F)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1ccc(O[C@H]2CCCC[C@@H]2c2cn[nH]c2)c(F)c1F
Yield: 34.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2,3-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)benzenesulfonamide (70 mg, 0.10 mmol) prepared in Example 83a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL), dichloromethane (1.0 mL) and methanol (1.0 mL), to yield the title compound (15 mg, 33%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[NH:31][CH2:30][C:29]([F:33])([F:32])[F:28])=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: NCC(F)(F)F
Solvent: CO
Product: N=C(NCC(F)(F)F)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 2,2,2-trifluoroethanamine (18 μl, 0.23 mmol) via procedure W to afford 56 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2,2,2-trifluoroethyl)carbamimidoyl)benzamide. MS (Q1) 433 (M)+.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4].[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>>[CH2:3]([O:5][C:6](=[O:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:39]([CH:36]3[CH2:38][CH2:37]3)=[O:40])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CNCc2ccccc2)c1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CN(Cc2ccccc2)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: {3-[2-(benzylamino-methyl)-quinolin-3-yl]-4-methoxy-phenyl}-acetic acid ethyl ester, dihydrochloride and cyclopropanecarbonyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>O1CCCC1.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cccc(S(=O)(=O)CCO)c1
Yield: 100 %

Procedure:
2-(3-Nitrophenylsulfonyl)ethanol (10 g; 43 mmol) was dissolved in 200 ml tetrahydrofuran and 200 mL ethanol, 3 g Pd/C (10%) was added and the mixture treated with hydrogen gas. The solvents were removed to obtain 8.8 g (43 mmol, 100% yield) of the desired compound as colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:17][C:6]1[CH:7]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:9]=[C:2]([Br:1])[C:3]=1[CH:4]=[O:5])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Br)cc(OC2CCCCO2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 166.1 %

Procedure:
To a mixture of 2-bromo-6-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (1.8 g, 6.0 mmol) and anhydrous K2CO3 (1.66 g, 12.0 mmol) in DMF (10 mL) was slowly added 1-(bromomethyl)benzene (1.22 g, 7.2 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h before quenched by water (15 mL). The resulting mixture was further stirred for 20 min and white precipitate was collected by filtration. The solid was washed with ether and dried under high vacuum to give the title compound as a white powder (3.9 g, yield: 83%).
Reaction SMILES: [C:1]1([CH2:7][Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[CH3:11][N+:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19]>CCOCC>[CH2:7]([CH:17]1[CH:16]=[C:15]([CH3:18])[CH:14]=[C:13]([CH3:19])[N:12]1[CH3:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc[n+](C)c(C)c1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [I-]
Solvent: CCOCC
Product: CC1=CC(Cc2ccccc2)N(C)C(C)=C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
PhCH2MgCl (1 M in Et2O, 180 mL) is added dropwise to a solution of 1,2,4-trimethyl-pyridinium iodide (24.3 g) in Et2O(90 mL) chilled in an ice bath. After stirring in the ice bath for 2 h, the solution is poured into a mixture of 72% aqueous HClO4 (40 mL) and crushed ice (ca. 900 mL). The resulting mixture is stirred for 1 h and the precipitate formed is separated by filtration. The precipitate is washed with methanol and dried to afford the HClO4 salt of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][CH3:21])[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:9])=[C:6]([O:11][C:12]2[N:13]=[C:14]([O:20][CH3:21])[N:15]=[C:16]([O:18][CH3:19])[N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step G, using equimolar amounts of 6-chloro-2-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)benzoic acid, 4-nitrophenol, and dicyclohexylcarbodiimide in methylene chloride to yield 4-nitrophenyl 6-chloro-2-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:12]=O.[C:14](/[CH:16]=[C:17](\[O-:19])/[CH3:18])#[N:15].[Na+]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:12]=[C:16](/[C:17](=[O:19])[CH3:18])\[C:14]#[N:15]
Reactant: Cc1n[nH]c2cc(F)c(C=O)cc12
Reactant: C/C([O-])=C/C#N
Agent: [Na+]
Product: CC(=O)/C(C#N)=C/c1cc2c(C)n[nH]c2cc1F

Procedure:
Following the procedure described for Example 2A, the title compound was prepared using 2.74 g (15.5 mmol) 6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 3A) and 2.6 g (24.8 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate to yield 1.6 g (42% of th.) of the crude product which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:30])[C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:39]=1>ClCCl>[C:24]1([C:21]2[CH:20]=[CH:19][C:18]([C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][C:2]([O:1][S:44]([C:40]5[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=5)(=[O:46])=[O:45])=[CH:3][CH:4]=4)[CH2:9]3)=[O:30])=[CH:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(NCCCCN1CCc2ccc(O)cc2C1)c1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCN1CCc2ccc(OS(=O)(=O)c3cccnc3)cc2C1)c1ccc(-c2ccccc2)cc1
Reaction time: 18 h
Yield: 8.5 %

Procedure:
To a stored solution of 7-hydroxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline (05 g, 1.3 mmol) and triethylamine (0.21 ml; 1.5 mmol) in dichloromethane (20 ml) was added pyridine-3-sulfonyl chloride (0.25 g, 1.4 mmol). The mixture was stirred for 18 h, then partitioned between dichloromethane (4×30 ml) and saturated aqueous NaHCO3 (100 ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica using 0-5% methanolethyl acetate gradient elution gave the title compound (0.06 g, 12%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:16][N:17]([CH3:24])[CH2:18]/[CH:19]=[CH:20]/[C:21](O)=[O:22].CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13]([C:21](=[O:22])/[CH:20]=[CH:19]/[CH2:18][N:17]([CH3:24])[CH3:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2sc3c(c12)CCNC3
Reactant: CN(C)C/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine (1000 mg, 4.0 mmol, 90% pure) in THF (20 mL) were added (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (730 mg, 4.4 mmol), EDCI (840 mg, 4.4 mmol), DMAP (97 mmol, 0.8 mmol) and diisopropylethylamine (120 mg, 8.0 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was then concentrated to dryness under reduced pressure. The residue was purified by ISCO using a 20% ethyl acetate in methanol to obtain 1100 mg (82%) of the desired product. LCMS RT=1.51 min, [M+1]+=337.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:14]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:12][CH2:13]1
Reactant: COC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)C1CCC2(CC1)OCCO2

Procedure:
To a solution of 8 g (0.51 mole) of methyl 4-oxocyclohexane-1-carboxylate in 50 ml of dry benzene is added 4 g (0.064 mole) of ethylene glycol and 0.10 g of p-toluenesulfonic acid and this mixture is refluxed overnight with a Dean-Stark apparatus. The cooled reaction is allowed to stand and the bottom layer (ethylene glycol) separated and the remaining benzene layer washed with aqueous sodium bicarbonate, dried over MgSO4, and stripped to dryness, giving methyl 1,4-dioxaspiro[4,5]decane-8-carboxylate as a clear liquid residue. This material is used without further purification in the next step.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[CH:19]1([C:22]2[O:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=2)[CH2:21][CH2:20]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[CH:19]1([C:22]2[O:26][N:25]=[C:24]([C:27]([N:1]3[CH2:5][CH2:4][CH2:3][C@@H:2]3[CH2:6][O:7][C:8]3[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=3)=[O:28])[CH:23]=2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Reactant: O=C(O)c1cc(C2CC2)on1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)c1cc(C2CC2)on1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifuluoroacetic acid) salt (EXAMPLE 34 Step 1) and 5-cyclopropylisoxazole-3-carboxylic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[N:34]1([CH2:40][CH2:41][CH2:42][C:43]2[CH:44]=[C:45]([NH2:49])[CH:46]=[CH:47][CH:48]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:49][C:45]4[CH:46]=[CH:47][CH:48]=[C:43]([CH2:42][CH2:41][CH2:40][N:34]5[CH2:35][CH2:36][O:37][CH2:38][CH2:39]5)[CH:44]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]
Reactant: Nc1cccc(CCCN2CCOCC2)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(CCCN4CCOCC4)c3)n2)c1)c1c(F)cccc1F

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and {3-[3-(4-morpholinyl)propyl]phenyl}amine were reacted in a manner analogous to Example 27, Step D, to give the title compound. MS (ESI): M+H=646.27.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[N:16]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[C:40](O)(=[O:43])[CH2:41][OH:42].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:25]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:8]2[NH:7][C:6]3[S:5][CH:4]=[C:3]([CH2:2][NH:1][C:41](=[O:42])[CH2:40][OH:43])[C:11]=3[S:10](=[O:13])(=[O:12])[N:9]=2)[C:15]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CO)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Temperature: 23 °C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
To the solution of the product of Example 345 (0.0226 g, 0.048 mmol) in N,N-dimethylformamide (0.5 mL) was added triethylamine (0.020 mL, 0.145 mmol), 4-(dimethylamino)pyridine (0.018 g, 0.145 mmol), glycolic acid (0.011 g, 0.145 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.028 g, 0.145 mmol). The mixture was stirred at 23° C. for 15 hours and then was heated to 60° C. and stirred for 20 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was diluted with dichloromethane, cooled to 0° C., and hydrochloric acid (4 M in dioxane) was added (0.037 mL, 0.145 mmol). The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile in 0.1% trifluoroacetic acid/water to 95% acetonitrile in 0.1% trifluoracetic acid/water to give the title compound (10.8 mg, 42%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 3.91 (s, 2 H) 4.44 (d, J=5.88 Hz, 2 H) 5.61 (bs, 2 H) 7.14 (s, 1 H) 7.29 (m, 5 H) 7.41 (t, J=7.35 Hz, 1 H) 7.52 (d, J=9.19 Hz, 1 H) 7.75 (t, 1 H) 8.21 (dd, 1 H) 8.35 (t, 1 H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9]([NH2:14])=[N:8][CH:7]=[CH:6]2.[BrH:15]>>[BrH:15].[NH2:14][C:9]1[C:10]2[C:5](=[CH:4][C:3]([OH:2])=[C:12]([CH3:13])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1cc2ccnc(N)c2cc1C
Agent: Br
Product: Cc1cc2c(N)nccc2cc1O
Temperature: 125 °C

Procedure:
A mixture of 6-methoxy-7-methylisoquinolin-1-ylamine (5.11 g, 27.18 mmol) and 48% aqueous hydrobromic acid (150 ml) was heated at 125° C. for 2 days. The mixture was concentrated in vacuo and triturated with diethyl ether, dried in vacuo to give 1-amino-7-methyl-isoquinolin-6-ol hydrobromide (5 g), EIMS: m/z=175.1 [M+H]+. 1H NMR (DMSO-D6) δ7.06 (1H, d), 7.16 (1H, d) , 7.25 (1H, dd), 7.56 (1H, d), 8.44 (1H, dd), 8.66 (2H, broad s), 11.05 (1H, s), 12.45 (1H, s).