Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(N=N[CH:9]2[C:13](=O)[N:12]([C:15]3[CH:20]=[CH:19][C:18](S([O-])(=O)=O)=[CH:17][CH:16]=3)N=[C:10]2[C:25]([O-:27])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+]>O>[CH:15]1([N:12]2[CH2:13][CH2:9][CH2:10][C:25]2=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: O=C1CCCN1C1CCCCC1

Procedure:
An ink composition comprising 2.5 percent by weight of Tartrazine FD&C Yellow #5, a yellow dye obtained from Buffalo Color, West Patterson, N.Y., 15 percent by weight of cyclohexyl pyrrolidone (obtained from GAF Corporation, Wayne, N.J.), and 82.5 percent by weight of deionized water was prepared by mixing together the ingredients at room temperature, stirring to obtain a homogeneous solution, and filtering. An additional ink was also prepared, said ink being of the same composition as the first except that it contained 0.3 percent by weight of Carbowax M20. The Carbowax M20 was added to the ink at room temperature and the resulting mixture was stirred for about 5 minutes to obtain a homogeneous solution.
Reaction SMILES: C([C@H:3]([S:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.Cl.[NH2:34][CH2:35][C:36]([NH2:38])=[O:37]>>[NH2:38][C:36](=[O:37])[CH2:35][NH:34][C:4](=[O:6])[CH2:3][S:7](=[O:8])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Reactant: NCC(N)=O
Agent: Cl
Product: NC(=O)CNC(=O)CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Yield: 49.4 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (75 mg, 0.17 mmol) and glycinamide hydrochloride (95 mg, 0.84 mmol) were reacted to give the title compound as colorless oil (40 mg, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O=S(Cl)[Cl:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)ccc1F
Product: O=C(Cl)c1cc(Br)ccc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-2-fluorobenzoic acid (1.1 g, 5.2 mmol) in SOCl2 (11.8 g, 99 mmol) was warmed to 90° C. and was stirred for 2 h. The mixture was cooled to ambient temperature and was concentrated under reduced pressure. The residue was diluted with toluene (5 mL) and was concentrated under reduced pressure. This dilution with toluene and concentration was repeated two additional times to remove excess SOCl2. The crude acid chloride was carried on without purification or characterization.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][N:10]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:5][CH:4]=1>ClCCl.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:12][CH2:11][N:10]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:7][CH:8]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(CO)cc2)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(C=O)cc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 94 %

Procedure:
Di tert-butyl 2-[4-(hydroxymethyl)phenyl]piperazine-1,4-dicarboxylate (750 mg, 1.911 mmol) was dissolved in dichloromethane (12.00 mL) and dioxomanganese (1.993 g, 396.5 μL, 22.93 mmol) was added. The reaction was stirred at ambient temperature for 22 hours. Reaction followed by TLC. Reaction mixture was filtered through a pad of celite and washed with dichloromethane. Purified by column chromatography (ISCO Companion, 40 g column) dry loaded and eluted with 5 to 50% ethyl acetate/petroleum ether. Product fractions were combined and concentrated in vacuo to give the sub-title product. (699 mg, 94% yield). 1H NMR (400.0 MHz, CDCl3) δ 1.43-1.47 (m, 18H), 3.01 (br s, 2H), 3.43-3.44 (m, 1H), 3.98-4.01 (m, 2H), 4.44 (br s, 1H), 5.32 (br s, 1H), 7.49-7.51 (m, 2H), 7.87 (d, 2H) and 10.03 (s, 1H) ppm; TLC (petroleum ether: ethyl acetate, 1:1 v/v) Rf=0.61
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][N:3]=1.[CH3:22][C:23](OC(C)=O)=[O:24]>C1COCC1.O>[C:23]([N:11]1[C:12]([CH:14]2[CH2:15][CH2:16]2)=[CH:13][C:9]([NH:8][C:6]2[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][N:3]=[C:2]([Br:1])[N:7]=2)=[N:10]1)(=[O:24])[CH3:22]
Reactant: CCOC(=O)c1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc(Br)nc1Nc1cc(C2CC2)n(C(C)=O)n1
Reaction time: 2 h
Yield: 83 %

Procedure:
To the mixture of ethyl 2-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-5-carboxylate (495 mg, 1.41 mmol) in THF (100 mL) and water (10 mL) was added Ac2O (2.0 mL). The reaction mixture was stirred for 2 h and water was added. The mixture was filtered and the solid was washed with water and concentrated with ethanol to remove the residual water to obtain ethyl 4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-2-bromopyrimidine-5-carboxylate (460 mg, 83%). LC-MS (m/z)=394.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[C:14]([OH:22])[CH:13]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1)(O)[C:31]#[CH:32]>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1([C:34]2[CH:35]=[CH:36][C:37]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:38][CH:39]=2)[O:22][C:14]2[CH:13]=[C:12]([C:10]3[S:11][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8][CH:9]=3)[C:21]3[C:16]([C:15]=2[CH:32]=[CH:31]1)=[CH:17][CH:18]=[CH:19][CH:20]=3
Reactant: Oc1cc(-c2ccc(-c3ccccc3)s2)c2ccccc2c1
Reactant: C#CC(O)(c1ccc(N2CCCC2)cc1)c1ccccc1F
Solvent: Cc1ccccc1
Product: Fc1ccccc1C1(c2ccc(N3CCCC3)cc2)C=Cc2c(cc(-c3ccc(-c4ccccc4)s3)c3ccccc23)O1

Procedure:
A stirred solution of 4-(5-phenyl-2-thienyl)-2-naphthol, (0.52 g, 1.73 mmol) and 1-(2-fluorophenyl)-1-(4-pyrrolidinophenyl)prop-2-yn-1-ol (0.51 g, 1.73 mmol) in toluene (50 ml) was warmed to 50° C. Acidic Al2O3 (1 g) was then added and the mixture heated to reflux for 1.5 h. After cooling, the solution was filtered, washed with hot toluene (100 ml) and the solvent removed. The resulting residue was then flash chromatographed eluting with EtOAc-hexane (1:9). The fractions were combined and the solvent removed. After precipitation from acetone-MeOH, the title compound (0.52 g, 52%) was collected as dark green crystals.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]([F:35])([F:36])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:33][CH:34]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(OC(CC)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(C(=O)NCCC(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
A solution of ethyl 3-{4-[1-(4′-trifluoromethylbiphenyl-4-yl)propoxy]benzoylamino}propionate (Isomer 1) (51 mg, 0.105 mmol) in THF (1.05 mL) is treated with 5 N NaOH (0.106 mL) and shaken at RT overnight. The reaction is neutralized with 1 N HCl (0.53 mL), and extracted into dichloromethane (3×). The combined organic layers are dried and concentrated, giving the title compound (10.1 mg).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH:25]=[C:24]4[CH2:32][CH2:33][C:34]([O:36]CC(C)C)=[O:35])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:28][CH:29]([CH3:30])[CH3:31])[CH:25]=[C:24]4[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)COC(=O)CCc1cn(CC(C)C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1cc(CCC(=O)O)c2cccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Sodium hydroxide (114 mg) was added to a solution of 2-methylpropyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-(2-methylpropyl)-1H-indol-3-yl]propanoate (D124) (77 mg) in THF (5 mL), isopropanol (4 mL) and water (2 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-(2-methylpropyl)-1H-indol-3-yl]propanoic acid (E30) (42 mg). δH (DMSO-d6, 400 MHz): 0.52 (6H, d), 1.37 (6H, d), 1.51 (1H, m), 2.61 (2H, t), 2.99 (2H, t), 3.99 (2H, d), 4.89 (1H, m), 7.19 (1H, t), 7.22 (1H, s), 7.45 (2H, m), 7.82 (1H, dd), 8.14 (1H, dd), 8.21 (1H, d), 12.04 (1H, br s); MS (ES): C26H28ClN3O4 requires 481; found 482.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2C)=NC=1.[CH:53]1([NH2:56])[CH2:55][CH2:54]1>>[CH:53]1([NH:56][C:3](=[O:2])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:14][O:15][C:16]=3[C:17]([F:19])([F:18])[F:20])=[N:6][CH:5]=2)[CH2:55][CH2:54]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Product: O=C(NC1CC1)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Yield: 94 %

Procedure:
As described for example 89, 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol), instead of 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted, using cylopropylamine instead of morpholine, to the title compound (100 mg, 94%) which was obtained as a white solid. MS: m/e=404.5 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[Cl:11]NC(=O)CCC(N)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11]
Reactant: NC(=O)CCC(=O)NCl
Reactant: Brc1ccc2[nH]ncc2c1
Solvent: CC#N
Product: Clc1n[nH]c2ccc(Br)cc12
Temperature: 60 °C
Yield: 95 %

Procedure:
To a solution of 5-bromoindazole 162 (0.234 g, 1.19 mmol.) in anhydrous acetonitrile (8 mL) was added N-chlorosuccinamide (0.174 g, 1.31 mmol.). The reaction mixture was heated at 60° C. for 2 hours. The organic solvent was evaporated under reduced pressure. Ethyl acetate (100 mL) was added. The organic layer was washed was 1N sodium hydroxide solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to yield 5-bromo-3-chloroindazole 163 (0.26 g, 1.13 mmol.). The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][O:21]1>CN(C=O)C>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:20]([OH:21])([CH3:22])[CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH:15]([CH3:16])[CH2:14][C:5]2=3)[CH:24]=1
Reactant: CC1(c2cccnc2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CC(C)N(C)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 6.6 %

Procedure:
2,3,8-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (214 mg, 1 mmol) was dissolved in DMF (3 mL) and NaH (80 mg, 3.33 mmol) was added portionwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min. The solution of 3-(2-methyloxiran-2-yl)pyridine (270 mg, 2 mmol) in DMF (2 mL) was added dropwise at 0° C. and the reaction mixture was stirred at 0° C. for 10 min and at RT for 16 h. Completion of reaction was monitored by LCMS. The reaction mixture was poured onto crushed ice slowly and extracted with EtOAc (3×30 mL). The organic layer was washed with water (7×40 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product that was purified by reverse HPLC to give 23 mg of 2-(pyridin-3-yl)-1-(2,3,8-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.73 (s, 1H), 8.47 (d, 1H), 7.2 (d, 1H), 7.11 (s, 1H), 7.04 (d, 2H), 6.90 (d, 1H), 4.15 (dd, 2H), 3.78 (dd, 1H), 3.6 (dd, 1H), 2.9 (m, 2H), 2.7 (dd, 1H), 2.43 (s, 3H), 2.4 (s, 3H), 1.6 (s, 3H), 1.14 (d, 3H). Separation by chiral HPLC provided diastereomers II-146a-d.
Reaction SMILES: [NH2:1][CH:2]([C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=1)[CH2:3][N:4]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33])C(=O)OC(C)(C)C.FC(F)(F)C1C=C(C(NC(=O)OC(C)(C)C)CNCC2C=C(C(F)(F)F)C=CC=2C2C=C(C(C)C)C=CC=2OC)C=C(C(F)(F)F)C=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[F:41][C:40]([F:42])([F:43])[C:38]1[CH:39]=[C:34]([CH:2]([NH2:1])[CH2:3][NH:4][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:14]=2[C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])[CH:35]=[C:36]([C:44]([F:45])([F:47])[F:46])[CH:37]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Agent: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(NC(=O)OC(C)(C)C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 283.5 mg (0.418 mmol) of the mixture of tert-butyl {2-amino-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate and tert-butyl [1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl]carbamate in CH2Cl2 (15 mL) was added TFA (1.5 mL). The reaction was stirred at room temperature for 5 hours and then poured into 1 N NaOH (50 mL). The mixture was extracted with CH2Cl2 (3×50 mL) and the organic extracts were combined, dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 5 to 10% MeOH/CH2Cl2 gave 1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine. Rf=0.46 (10% MeOH/CH2Cl2). LCMS=579.2 (M+1)+. 1H NMR (CD2Cl2, 500 MHz) δ 7.83 (s, 2H), 7.77 (s, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.24 (dd, J=8.4, 2.3 Hz, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 4.06 (m, 1H), 3.59-3.76 (m, 2H), 3.69 (s, 3H), 2.88 (m, 1H), 2.67 (dd, J=11.9, 4.3 Hz, 1H), 2.51 (m, 1H), 1.22 (d, J=6.9 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CCC(=O)O)c1

Procedure:
3-Nitrocinnamic acid (50 g) was suspended in ethanol (600 cm3) and reduced in the presence of palladium catalyst until no further hydrogen uptake was observed. After filtering the solvent was evaporated under reduced pressure to give the pure product in quantitative yield as a brown oil which slowly crystallised.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:26])[C:5]2[CH:6]=[CH:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]CC4C=CC=CC=4)=[C:13]([F:25])[CH:12]=3)[C:9]=2[CH:10]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([OH:26])[C:5]2[CH:6]=[CH:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[C:9]=2[CH:10]=1
Reactant: Oc1cc(F)cc2c1ccn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(-n2ccc3c(O)cc(F)cc32)cc1F
Yield: 75.4 %

Procedure:
A solution of 6-fluoro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indol-4-ol (D18) (380 mg, 1.082 mmol) in ethyl acetate (30 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated. The product was purified by silica gel chromatography eluting with 10-100% ethyl acetate in hexane to yield the title compound (E9), (213 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH2:10][CH3:11])[CH:3]=1.[CH3:12][NH:13][CH3:14]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:13]([CH3:14])[CH3:12])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CNC
Reactant: CCc1cc(Br)ccc1CBr
Solvent: CO
Product: CCc1cc(Br)ccc1CN(C)C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-ethyl-benzene (1.12 g, 4.03 mmol) in MeOH (20 mL) was added dimethylamine (2.5 mL, 40% solution in water). The mixture was stirred for 1 hour, at which time the volatiles were removed in vacuo. The residue was dissolved in EtOAc, washed with H2O, dried over MgSO4, and concentrated to a clear oil (0.910 g, 93%). 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 3 H), 2.21 (s, 6 H), 2.69 (q, J=7.5 Hz, 2 H), 3.32 (s, 2 H), 7.14 (m, 1 H), 7.28 (m, 2 H).
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(C(C)C)CC)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[S:20]([O:9][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
To 130 g (0.995 mol) of 2-octanol and 207 ml (1.19 mol, 1.2 equiv) of diisopropylethylamine in 1.5 L dichloromethane at 0° C. under a CaSO4 drying tube was added dropwise 84.4 ml (1.09 mol, 1.1 equiv.) of methanesulfonyl chloride over 1 hour while keeping the internal temperature at less than 5° C. The faintly yellow solution was stirred at 0° C. for an additional 1.5 h. The cold reaction solution was then washed with 2×1 L ice-cold 1M HCl and 1 L of ice-cold H2O and brine and dried over MgSO4. The residue was filtered through Celite and concentrated in vacuo below 35° C. to afford 208 g of a yellow oil. The yellow oil was placed under high-vacuum for 2 h at 25° C. to give 205 g of yellow oil. NMR spectra confirmed the desired title-product having only trace amounts of solvents present.
Reaction SMILES: [CH:1]1([N:7]([CH2:30][CH:31]([O:34][CH3:35])[O:32][CH3:33])[C:8](=[O:29])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:43]1[N:44]([CH3:49])[CH:45]=[C:46]([CH3:48])[N:47]=1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:7]([CH2:30][CH:31]([O:32][CH3:33])[O:34][CH3:35])[C:8](=[O:29])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:43]3[N:44]([CH3:49])[CH:45]=[C:46]([CH3:48])[N:47]=3)[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cn(C)c(Br)n1
Reactant: COC(CN(C(=O)CCOCCc1cccc(B2OC(C)(C)C(C)(C)O2)c1)C1CCCCC1)OC
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: [K+]
Solvent: CO
Product: COC(CN(C(=O)CCOCCc1cccc(-c2nc(C)cn2C)c1)C1CCCCC1)OC
Temperature: 120 °C

Procedure:
N-Cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethoxy)propanamide [Example 34, Step i)] (390 mg), potassium carbonate (220 mg), Pd(Ph3P)4 (46 mg) and 2-bromo-1,4-dimethyl-1H-imidazole (279 mg) in MeOH (3 mL) was loaded into a microwave vial, flushed with nitrogen and sealed. The vial was heated within a Discover microwave at 120° C. for 30 min. After cooling, the reaction and the filtrate washed with DCM. Volatiles were removed and the residue purified on silica using 20%-100% EtOAc/iso gradient to afford the subtitled compound (358 mg). MS [M+H]+=458 (MultiMode+) 1H NMR (400 MHz, CDCl3) δ 7.51-7.47 (m, 1H), 7.43-7.40 (m, 1H), 7.37-7.30 (m, 1H), 7.27-7.22 (m, 1H), 6.67 (s, 1H), 4.61 and 4.37 (2×t, J=5.2 Hz, 1H), 4.25-4.16 and 3.61-3.51 (2×m, 1H), 3.81-3.74 (m, 2H), 3.73-3.65 (m, 2H), 3.68 (s, 3H), 3.41 (s, 3H), 3.39 (s, 3H), 3.37 and 3.29 (2×d, J=4.9 Hz, 2H), 2.96-2.89 (m, 2H), 2.73-2.65 (m, 2H), 2.26 (s, 3H), 1.85-1.74 (m, 2H), 1.73-1.05 (m, 8H); a ˜2:1 mixture of rotamers is observed.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH3:13])=[CH:7]2.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)=[N:26][N:25]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][C:2]4[C:11]5[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][N:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:39][CH:40]=3)=[N:26][N:25]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(-c2nnc(Nc3ccc(O)cc3)c3ccccc23)cc1
Reactant: COc1cnc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5ccc(C(C)(C)C)cc5)c5ccccc45)cc3)ccnc2c1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
In a nitrogen purged sealed tube, 8-chloro-3-methoxy-1,5-naphthyridine (0.053 g, 0.271 mmol) was dissolved in DMF (2.00 mL). 4-(4-(4-Tert-butylphenyl)phthalazin-1-ylamino)phenol (0.100 g, 0.271 mmol) and cesium carbonate (0.176 g, 0.541 mol) were added, and the mixture in the tube was stirred at 90° C. for 17 h. Upon cooling to RT, the mixture was concentrated in vacuo, and purified by silica gel chromatography using 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2 to yield 4-(4-tert-butylphenyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine as off-white solid. MS [M+H]=528.1; Calc'd 527.6 for C33H29N5O2.