Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=1.I[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15]/[CH:16]=[CH:17]/[C:30]2[CH:31]=[CH:32][C:27]([O:26][C:23]3[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Oc2ccccc2)cc1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccc(Oc2ccccc2)cc1

Procedure:
Prepared according to the procedure described in Example 32, Step 2, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol and 1-iodo-4-phenoxy-benzene.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>C1COCC1>[CH:19]([NH:22][C:14]([C:13]1[C:9]([C:5]2[CH:4]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:8]=[CH:7][CH:6]=2)=[N:10][S:11][CH:12]=1)=[O:15])([CH3:21])[CH3:20]
Reactant: CC(C)N
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1csnc1-c1cccc(C(F)(F)F)c1
Yield: 88 %

Procedure:
To a solution of 1.0 g (0.0034 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride and 20 cc of THF was added 0.45 g (2.1 equivalents) of isopropylamine. The reaction mixture was heated on a steam bath for 20 minutes. The isopropylamine hydrochloride was filtered off and the filtrate was concentrated to a solid. The solid was washed with H2O, dissolved in THF, dried (CaSO4), and concentrated under vacuum to give 0.94 g of solid. The solid was recrystallized from EtOAc/hexane to give 0.4 g white solid, m.p. 166°-167°. The filtrates gave another 0.3 g of white solid, m.p. 166.5°-168°. (Total yield=88%).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])=[CH:16][C:15]([C:31]([CH3:34])([CH3:33])[CH3:32])=[N:14]2)[CH:8]=1)C.[Li+].[OH-]>CO>[C:31]([C:15]1[CH:16]=[C:17]([NH:18][C:19]([C:21]2[N:22]=[CH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])[N:13]([C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:35])=[O:3])[CH:12]=[CH:11][CH:10]=2)[N:14]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2cc3ccccc3cn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)c2cc3ccccc3cn2)n(-c2cccc(CCC(=O)O)c2)n1
Yield: 88.1 %

Procedure:
A solution of Example 156 (47 mg, 0.1 mmol) and 2N LiOH (3 mL) in MeOH (3 mL) was stirred at RT overnight. The reaction mixture was neutralized to pH=4, and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine, and dried (NaSO4) and filtered. The filtrate was concentrated to afford 3-(3-{3-t-butyl-5-[(isoquinoline-3-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid, (39 mg, 88%). 1H NMR (CDCL3): 10.49 (s, 1H), 9.16 (s, 1H), 8.69 (s, 1H), 8.03 (d, J=7.6 Hz, 2H), 7.81 (t, J=7.2 Hz, 1H), 7.73 (t, J=7.2 Hz, 1H), 7.48-7.39 (m, 3H), 7.28 (br s, 1H), 6.94 (s, 1H), 3.02 (t, J=7.6 Hz, 2H), 2.79 (t, J=7.6 Hz, 2H), 1.42 (s, 9H); MS (ESI) m/z: 442 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7](=O)[CH2:8][CH:9]([CH2:12][CH3:13])[CH:10]=O)=[CH:5][CH:4]=1.[S:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)(=[O:20])(=[O:19])[NH2:18].N>C(O)(=O)C>[CH2:12]([C:9]1[CH:8]=[C:7]([C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:25]([C:24]2[CH:26]=[CH:27][C:21]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:22][CH:23]=2)[CH:10]=1)[CH3:13]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CCC(C=O)CC(=O)c1ccc(OC)cc1
Agent: N
Solvent: CC(=O)O
Product: CCc1cc(-c2ccc(OC)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
0.47 g (2.1 mmol) of 2-(4-methoxyphenacyl)butyraldehyde [prepared as described in step (ii) above] and 0.44 g (2.5 mmol) of 4-sulfamoylaniline were dissolved in 5 ml of acetic acid, and the resulting solution was heated under reflux for 2 hours. At the end of this time, the mixture was cooled to room temperature, concentrated aqueous ammonia was added to adjust its pH to a value of 8.0 and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was applied to a silica gel chromatography column, eluted with a 3:2 by volume mixture of hexane and ethyl acetate, to give 0.57 g (yield 76%) of the title compound as a pale yellow powder, melting at 154-156° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)=[CH:7][CH:6]=1.C(O)(=O)C.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:25]3[CH2:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24]3)[CH:12]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(-c2cccc(C=O)c2)cc1
Reactant: c1ccc2c(c1)CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Cc1ccc(-c2cccc(CN3Cc4ccccc4C3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
(3′-Formyl-biphenyl-4-yl)-acetic acid methyl ester (1.22 g), acetic acid (0.23 mL) and iso-indoline (0.48 g) were combined in methanol (10 mL). After 1 hour, sodium triacetoxyborohydride (1.27 g) was added and stirred for 18 hours, at room temperature, under nitrogen. The reaction was quenched with 0.880 ammonia solution and concentrated. The residue was dissolved in methanol and loaded onto a conditioned SCX cartridge (50 g Varian). The cartridge was washed with methanol (3×50 mL), then eluted with methanolic ammonia solution (2×50 mL) and the combined elution fractions evaporated. Purification on silica, eluting with triethylamine/ethyl acetate/iso-hexane [1:19:80], to give the subtitle compound as a dark brown oil (450 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:32][CH3:33])[C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:19]=2)[CH2:14][CH:13]1[C:29](O)=[O:30])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37]>>[F:34][C:35]([F:39])([F:38])[CH2:36][NH:37][C:29]([CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:32][CH3:33])=[O:30]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)O
Reactant: NCC(F)(F)F
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OCc3ccccc3)cc2CC1C(=O)NCC(F)(F)F

Procedure:
This compound was prepared from 1-(N-t-butoxycarbonyl-2(S)-aminobutyryl)-5-benzyloxyindoline-2-(R/S)-carboxylic acid and trifluoroethylamine as described in Example 15.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:7]1
Reactant: C[C@H]1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-tert-butyl 2-methyl-4-(4-phenylphthalazin-1-yl)piperazine-1-carboxylate (2.05 g, 5.07 mmol) was dissolved in dichloromethane (75 mL). Trifluoroacetic acid (15 mL) was added and the reaction stirred at rt for 1.5 hours. The reaction was added to saturated NaHCO3 (150 mL) and neutralized by the portion wise addition of solid NaHCO3. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The combined organics were dried (MgSO4) and evaporated to give a pale yellow foam. MS (M+H)+=305.2.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[N:9]=[CH:10][C:11](/[CH:13]=[CH:14]/[C:15](=[O:27])[N:16]3[CH2:19][CH:18]([O:20][CH2:21][C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[CH2:17]3)=[CH:12][C:6]=2[CH2:5][N:4](C(OCC(Cl)C)=O)[CH2:3]1>CO>[O:27]=[C:15]([N:16]1[CH2:19][CH:18]([O:20][CH2:21][C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:17]1)/[CH:14]=[CH:13]/[C:11]1[CH:10]=[N:9][C:7]2[NH:8][C:2](=[O:1])[CH2:3][NH:4][CH2:5][C:6]=2[CH:12]=1
Reactant: CC(Cl)COC(=O)N1CC(=O)Nc2ncc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cc2C1
Solvent: CO
Product: O=C1CNCc2cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc2N1

Procedure:
A solution of (E)-2-chloropropyl 2-oxo-7-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-2,3-dihydro-1H-pyrido[2,3-e][1,4]diazepine-4(5H)-carboxylate (75 mg, 0.15 mmol) in methanol (3 mL) was refluxed for 2 hours. After concentration to dryness, the residue was triturated in methanol. The title product was obtained as a white solid (75 mg, 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[N:7](S(C)(=O)=O)[C:6]([C:19]([OH:29])([CH2:27][CH3:28])[CH2:20][S:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:5]2.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:13])([F:14])[F:12])[NH:7][C:6]([C:19]([OH:29])([CH2:27][CH3:28])[CH2:20][S:21][CH2:22][C:23]([F:25])([F:24])[F:26])=[CH:5]2
Reactant: CCC(O)(CSCC(F)(F)F)c1cc2cc(Cl)c(C(F)(F)F)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CCC(O)(CSCC(F)(F)F)c1cc2cc(Cl)c(C(F)(F)F)cc2[nH]1

Procedure:
This compound was prepared using the standard de-protection procedure from, as described in General Procedures Example B, reacting 2-(5-chloro-1-methanesulfonyl-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl)-butan-2-ol (0.24 g, 0.50 mmol) and using 4N sodium hydroxide as a base (0.37 mL, 0.50 mmol) to yield the title compound as a yellow sticky oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[S:13]1[CH:17]=[C:16]([CH:18]=O)[N:15]=[N:14]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[S:13]1[CH:17]=[C:16]([CH:18]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[N:15]=[N:14]1
Reactant: O=Cc1csnn1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2cccs2)=NC1=Cc1csnn1
Temperature: 90 °C
Yield: 38 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 1,2,3-thiadiazol-4-carboxaldehyde (37 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 30 mg of the above-captioned compound.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=O.[C:12]1([PH:18](=[O:20])[OH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[O:3]=[C:1]1[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([P:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:19])[OH:20])[O:7]1
Reactant: O=[PH](O)c1ccccc1
Reactant: O=Cc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Product: O=C1OC(P(=O)(O)c2ccccc2)c2ccccc21
Yield: 58 %

Procedure:
Into a suspension of 30.1 grams (0.2 moles) of 2-carboxybenzaldehyde in 240 mL of toluene is added 28.4 grams (0.2 moles) of phenylphosphinic acid. The resultant mixture is heated to reflux and 3.8 mL of water is collected by azeotropic distillation using a Dean-Stark receiver. Upon cooling the reaction mixture, the precipitated white solid is collected by filtration and dried. The crude solid is recrystallized from 240 mL of methanol to give 31.8 grams (58% yield) of (3-oxo-1,3-dihydro-isobenzofuran-1-yl)-phenyl-phosphinic acid as white crystals, mp 230-233° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=O)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:30]([C:32]1[N:36]=[C:35]([CH2:37][N:38]2[C:43]3[CH:44]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:46][C:42]=3[C:41](=[O:53])[N:40]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[C:39]2=[O:60])[O:34][N:33]=1)[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([C:19]([N:57]4[CH2:58][CH2:59][CH:54]([N:40]5[C:41](=[O:53])[C:42]6[S:46][C:45]([C:47]7[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:35]6[O:34][N:33]=[C:32]([CH2:30][CH3:31])[N:36]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[O:21])[CH:22]=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CC)no5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
The title compound is prepared analogously as described for example 1 using 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C8), 1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-phenyl-3-piperidin-4-ylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B32), HBTU (167 mg), DIPEA (0.28 ml) and DCM (3 ml). The crude product is purified by flash column chromatography (amino phase silica gel, eluent gradient: EtOAc/methanol, 98/2 to 95/5 (v/v)) and afterwards by preparative TLC [silica gel, eluent: EtOAc/MeOH/triethylamine, 92.5/5/2.5 (v/v/v)] to yield the title compound as a solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])=[C:5]([OH:20])[CH:4]=1.ClC[CH2:23][CH2:24][O:25][CH2:26]CCCl.C(=O)([O-])[O-].[K+].[K+].[Br-].[Na+]>CN(C)C=O>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])=[C:5]([O:20][CH2:23][CH2:24][O:25][CH3:26])[CH:4]=1
Reactant: ClCCCOCCCCl
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCOC
Yield: 87.7 %

Procedure:
A mixture of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (2.50 g, 7.76 mmoles), 2-chloro-ethylmethylether (1.47 g, 15.5 mmoles), potassium carbonate (2.14 g, 15.5 mmoles) and sodium bromide (0.80 g, 7.76 mmoles) in 40 ml of dimethylformamide (DMF) was stirred at reflux for four hours. The DMF was removed under vacuum and the residue was redissolved in methylene chloride and washed with water and dilute NaOH. The solvent was evaporated and the product was chromatographed using a gradient elution of methanol-methylene chloride containing 0.25% NH4OH. The appropriate fractions were combined and evaporated to yield 2.34 g (87.6%) of cream-colored solid. Recrystallization of the residue from ethyl acetate gave the title compound as a white solid, mp 108°-110.5°. The NMR spectrum (90MHz) in CDCl3 gave the following resonances: δ 8.19 (s, 1H); 6.35 (s, 1H); 4.5 (bs, 2H); 4.2 (m, 2H); 3.8 (m, 2H); 3.5 (m, 2H); 3.49 (s, 3H); 2.59 (m, 6H); 1.02 (t, 6H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][N:22]([C:32]1[O:36][N:35]=[C:34]([CH3:37])[C:33]=1[CH3:38])[S:23]([C:26]1[S:27][C:28](Br)=[CH:29][CH:30]=1)(=[O:25])=[O:24]>C(O)C.C1C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21][N:22]([C:32]1[O:36][N:35]=[C:34]([CH3:37])[C:33]=1[CH3:38])[S:23]([C:26]1[S:27][C:28]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:29][CH:30]=1)(=[O:25])=[O:24]
Reactant: OB(O)c1ccccc1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccc(Br)s1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: c1ccccc1
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccc(-c2ccccc2)s1
Yield: 61.9 %

Procedure:
Sodium carbonate (2 ml of a 2 M aqueous solution) followed by phenyl boronic acid (86 mg, 0.71 mmol) in 2 ml of 95% ethanol were added to a solution of N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (200 mg, 0.47 mmol) and tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol) in dry benzene (4 ml) under argon. The mixture was refluxed for 12 h, diluted with 5 ml of water and extracted into ethyl acetate (3×25 ml). The combined organic extracts was washed with brine (1×25 ml), dried and evaporated. The residue was flash chromatographed on silica gel using 25% ethylacetate/hexanes to afford 123 mg (62%) of the sulfonamide as a colorless gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=3)[CH:9]=[C:10]2[NH:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:5][CH:4]=1.[Br:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2Cl)[NH:29][N:28]=1.C(OCC)(=O)C>O1CCCC1.C(N(CC)CC)C>[Br:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=3)[CH:9]=2)[NH:29][N:28]=1
Reactant: CNc1nccc(-c2cc(NCCCN)c3cc(OC)ccc3c2)n1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNc1nccc(-c2cc(NCCCNc3ncnc4[nH]nc(Br)c34)c3cc(OC)ccc3c2)n1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a slurry of 182 in tetrahydrofuran (10 ml) and triethylamine (0.3 ml) was added 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (63 mg). The mixture was shaken at 50° C. for 24 hours. After cooling to room temperature the mixture was poured into ethyl acetate (150 ml) washed with water (2×200 ml) and the organic layer dried over anhydrous magnesium sulfate. Evaporation to dryness gave a yellow solid which was purified by silica gel chromatography eluting with 60-100% ethyl acetate in hexanes to 1% methanol in ethyl acetate yielding N1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N3-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)propane-1,3-diamine 183 as a yellow powder (43 mg). M.p.=145-148° C. 1H NMR (DMSO-d6) 400 MHz δ 8.26 (s, 1H), 7.84-7.8 (m, 2H), 7.63-7.52 (m, 1H), 7.22-7.0 (m, 5H), 7.15-7.12 (m, 1H), 5.16 (m, 1H), 4.56-4.53 (m, 2H), 3.9 (s, 3H), 3.75 (m, 2H), 3.52-3.4 (m, 2H), 2.87-2.86 (m, 3H), 2.11 (m, 2H), LCMS m/e 534 and 536 (M+) Calculated for C24H24BrN9O 0.72 H2O-0.32 C4H8O2: C 52.75, H 4.9, N 21.9; found C, 52.76; H, 4.44; N, 21.92.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.Br[CH2:28][C:29]#[CH:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:30][C:29]#[CH:28])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: C#CCBr
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: C#CCC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
309 mg (0.8 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate and 155 mg (1.04 mmol) of 3-bromoprop-1-yne were reacted according to General Method 7A. Yield: 288 mg (87% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([O:17][CH2:16][C:13]1[CH:12]=[C:11]([C:18]([OH:20])=[O:19])[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:15][CH:14]=1)=[O:32]
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C(=O)O)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2C(=O)O)c1
Temperature: 12.5 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a 0° C. mixture of 29.1 (2.2 g, 7.9 mmol) in THF (20 mL) was added pyridine (1.56 g, 19.8 mmol) followed by pivaloyl chloride (0.96 g, 7.9 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA). The resulting solution was stirred at 0-25° C. overnight and was then quenched with water and treated with 2.0 N HCl (15 mL). The mixture was extracted with EtOAc (3×30 mL). The organic layers were combined and washed with water (10 mL) and brine (10 mL). After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0-65% EtOAc/hexanes for elution gave 29.2 as white solid (1.60 g, 56%).
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:11][C:12]1[CH:13]=[C:14]([O:19][CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:15]([NH2:18])=[N:16][CH:17]=1>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:19][CH2:20][C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:15]2[N:16]([C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH3:10])[N:18]=2)[CH:17]=1
Reactant: Nc1ncc(Br)cc1OCc1c(F)cccc1F
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Br)cn12
Reaction time: 0.5 h

Procedure:
16 g of powdered molecular sieve 3 Å and 52.7 ml of ethyl 2-chloroacetoacetate (380.8 mmol; 5 equivalents) were added to 24 g of 5-bromo-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 17A; 76.2 mmol; 1 equivalent) in 400 ml of ethanol, and the mixture was heated at reflux overnight. A further 8 g of molecular sieve were added, and the mixture was heated at reflux for a further 24 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in dichloromethane and chromatographed on silica gel (dichloromethane/methanol 20:1 as mobile phase). The product-containing fractions were concentrated and the residue was stirred with 100 ml of diethyl ether for 30 min. The product was then filtered off, washed with a little diethyl ether and dried. This gave 15 g (45% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:7](=O)[CH2:6][CH2:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[O:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH2:1])=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)[CH2:15][CH2:16]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2CCN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)CCCN2CCN1CCOCC1
Temperature: 0 °C
Yield: 35.6 %

Procedure:
A mixture of compound 3 (0.800 g, 2.905 mmol) in THF (25 mL) was stirred at 0° C. and was treated with solid lithium aluminum hydride (0.4352 g, 11.62 mmol). The mixture was brought to room temperature at which point it was heated to reflux for 1 hour. The reaction was quenched with H2O (1 mL), 3N NaOH solution (1 mL) and an additional aliquot of H2O (1 mL). The solution was filtered over celite and was rinsed with diethyl ether. The concentrated crude product was subject to flash chromatography on silica gel 5% 2M NH3 methanol/CH2Cl2, which resulted in a dark brown viscous liquid, compound 4 (0.27 g, 36%).