Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[CH2:16])=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3][CH3:4])=[O:2].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][Br:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].[Na].C(OCC)(=O)C1C=CC=NC=1.[K+].[Br-]>CO.CC(C)=O>[Br-:31].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N+:19]2[CH:20]=[CH:21][C:22]3=[C:5]([C:1]([O:3][CH3:4])=[O:2])[C:6]4[NH:7][C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=5[C:14]=4[C:15]([CH3:16])=[C:17]3[CH:18]=2)=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: C=C(c1cccnc1)c1c(CC(=O)OC)[nH]c2ccccc12
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: CCOC(=O)c1cccnc1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1c2cc[n+](Cc3ccc([N+](=O)[O-])cc3)cc2c(C)c2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Three grams (0.01 mol) of the ester 16 and 12.0 g (0.05 mol) of p-nitrobenzyl bromide in 140 mL of reagent grade acetone was stirred for 24 h. The crystals of 19 were collected, washed with ether, and dried; wt 4.72 g (92%). To a solution of 150 mg of metallic sodium in 40 mL of dry MeOH there were added 2.67 g (5.25 mmol) of crude 19 and 4.52 g (18.4 mmol) of ethyl nicotinate methobromide. The solution was stirred for 22 hours at room temperature in a nitrogen atmosphere. The crystallize solid that separated was filtered, washed with methanol, and dried; wt 2.31 g (80%) of the desired p-nitrobenzyl quaternary salt 22. The analytical sample was obtained by crystallization from CH2Cl2 -MeOH (1:1): mp 284°-289° C. dec; NMR (Me2SO-d6) δ12.13 (s, 1 H), 10.40 (s, 1 H), 9.31 (d, 1 H), 8.69 (d, 1 H), 8.49 (d, 1 H), 8.33 (d, 2 H), 7.86 (m, 3 H), 7.7-7.65 (m, 1 H), 7.50-7.47 (m, 1 H), 6.20 (s, 2 H), 4.13 (s, 3 H), 3.41 (s, 3 H); IR (KBr) 3240, 3045, 2945, 1717, 1590, 1420 cm-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.O>[CH2:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([O:17][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:20][C:19]=1[C:25]([F:26])([F:27])[F:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Solvent: O
Solvent: CO
Product: Fc1cnc(Nc2ccc(OCc3ccccc3)c(C(F)(F)F)c2)nc1Nc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 4-benzyloxy-3-trifluoromethylaniline (481 mg, 1.8 mmol) was added and the mixture was refluxed for 2 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis(4-benzyloxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.51 (s, 1H), 8.05 (s, 1H), 7.38-7.64 (m, 5H), 6.94-7.14 (m, 11H), 6.44-6.73 (m, 4H), 4.84 (s, 2H), 4.79 (s, 2H); LCMS purity: 94.7%; MS (m/e): 628.93 (M+, 100).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:15])[CH2:8][CH2:9][CH2:10][C:11](OC)=[O:12].[C:22]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1>>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:15]([CH2:28][C:24]2[CH:23]=[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:26][CH:25]=2)[C:11](=[O:12])[CH2:10][CH2:9][CH2:8]1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CCCC(N)c1ccccc1-c1ccccc1
Product: O=C1CCCC(c2ccccc2-c2ccccc2)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-([1,1′-biphenyl]-2-yl)-5-aminopentanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.03 min.; [M+H]+: 417.81 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:13][C:4]1[C:5]([OH:12])=[C:6]([CH:11]=[C:2]([F:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)cc(N)c1O
Yield: 101 %

Procedure:
A suspension of methyl 5-fluoro-2-hydroxy-3-nitrobenzoate (2.3 g, 10.7 mmol), acetic acid (2 mL) and 10% Pd/C (0.23 g) in ethyl acetate (50 mL) was stirred at 25° C. over 1 atm hydrogen for 4 hr. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=100:1 to 20:1) to give methyl 3-amino-5-fluoro-2-hydroxybenzoate (2.0 g, yield 100%) as a light yellow solid. 1H-NMR (400 MHz, CDCl3-d) δ 3.95 (s, 3H), 3.98-4.13 (s, br, 2H), 6.60-6.63 (dd, J1=9.4 Hz, J2=2.4 Hz, 1H), 6.86-6.89 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 10.70 (s, 1H); LC-MS (ESI) m/z 186 [M+1]+.
Reaction SMILES: [C:1](=[C:4]([CH2:6][CH:7]([CH2:13][CH:14]=[CH2:15])[CH2:8][O:9]COC)[F:5])([F:3])[F:2].CO.Cl>O>[C:1](=[C:4]([CH2:6][CH:7]([CH2:13][CH:14]=[CH2:15])[CH2:8][OH:9])[F:5])([F:3])[F:2]
Reactant: C=CCC(COCOC)CC(F)=C(F)F
Agent: Cl
Solvent: O
Solvent: CO
Product: C=CCC(CO)CC(F)=C(F)F
Temperature: 60 °C
Yield: 109.8 %

Procedure:
40 g of CF2═CFCH2CH(CH2OCH2OCH3)CH2CH═CH2 obtained in Example 3 and 100 mL of methanol were put into a 300 mL glass reactor, and a catalytic amount of concentrated hydrochloric acid was added thereto, followed by heating at 60° C. for 19 hours. The reaction solution was cooled to room temperature, and 30 mL of water was added to carry out liquid separation. The organic layer was further washed with 50 mL of water and subjected to precision distillation to obtain 35.3 g of CF2═CFCH2CH(CH2OH)CH2CH═CH2 (59-60° C./0.5 kPa).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([N:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[OH:60])=[N:46][C:47]=1[CH2:48][CH3:49].Br[CH2:64][CH2:65][F:66]>>[Cl:32][C:33]1[CH:38]=[C:37]([N:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[O:60][CH2:64][CH2:65][F:66])=[N:46][C:47]=1[CH2:48][CH3:49]
Reactant: FCCBr
Reactant: CCc1nc(-c2ccc(N(C)C)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(N(C)C)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-({5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-ol and 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 2969, 2932, 2907, 2877, 1608, 1563, 1545, 1483, 1447, 1392, 1353, 1207, 1177, 1123, 1042 cm−1; OAMS supporting ions at: ESI+ 483.2; MS (EI) m/z 482 (M+); HRMS (FAB) calcd for C27H32CLFN4O+H1 483.2327, found 483.2324. [α]25D=−79 (c 0.52, methylene chloride); Anal. Calcd for C27H32ClFN4O: C, 67.14; H, 6.68; N, 11.60. Found: C, 67.19; H, 6.90; N, 11.63.
Reaction SMILES: [C:1]1([C:13](Cl)=[O:14])[CH:6]=[C:5]([C:7](Cl)=[O:8])[CH:4]=[C:3]([C:10](Cl)=[O:11])[CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:13]([C:1]2[CH:6]=[C:5]([C:7]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[O:8])[CH:4]=[C:3]([C:10](=[O:11])[C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:2]=2)=[O:14])=[CH:26][CH:25]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1cc(C(=O)c2ccc(F)cc2)cc(C(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5 g of 1,3,5-benzenetricarbonyltrichloride (18.8 mol), 6.7 g of aluminum chloride (50.0 mmol) and 50 mL of distilled dichloromethane (DCM) were put in a 250 mL round flask, which was stirred for 30 minutes at 25° C. for reaction in the presence of nitrogen. 20 mL of dichloromethane and 4.5 g of fluorobenzene (48.8 mmol) were added in 100 mL of Dropping funnel, and the fluorobenzene solution was dropped in the round flask drop by drop. The reaction mixture was stirred for 4 hours in the presence of nitrogen, to which 20 mL of distilled water was added. The reaction mixture was stirred further for more than 12 hours. The organic layer of the reaction mixture was extracted by using dichloromethane, and the organic solvent was eliminated, resulting in a crude product. The crude product was re-crystallized using ethanol to give white brancher [3,5-bis(4-fluorobenzoyl)phenyl](4-fluorophenyl) methanone (yield: 70%). The structure of the [3,5-bis(4-fluorobenzoyl)phenyl](4-fluorophenyl)methanone was confirmed by 1H-NMR, 13C-NMR spectrometry and elemental analysis.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([CH2:11][OH:12])=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([CH:11]=[O:12])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)c2nsnc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(Br)c2nsnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a solution of (7-bromo-benzo[1,2,5]thiadiazol-4-yl)-methanol (20.22 g) (Example I2) in dichloromethane (185 ml) was added manganese(IV) oxide (71.7 g). The suspension was stirred at ambient temperature for 16 hours. The reaction mixture was filtered through a plug of Celite®. The filtrate was concentrated to give 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde (16.65 g) as an orange solid. 1H-NMR (400 MHz, CDCl3): 10.74 (s, 1H), 8.11-8.05 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:24]2([CH3:29])[CH2:28]CC[CH2:25]2)[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1.ClC1N=C(N[C@@H](C(C)(C)C)CC(OC)=O)C(F)=CN=1.C(O)=O>C(#N)C>[F:1][C:2]1[C:3]([NH:18][C@@H:19]([C:24]([CH3:29])([CH3:28])[CH3:25])[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: CC1(C(CC(=O)O)Nc2nc(-c3n[nH]c4ncc(F)cc34)ncc2F)CCCC1
Agent: COC(=O)C[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Solvent: O=CO
Solvent: CC#N
Product: CC(C)(C)[C@@H](CC(=O)O)Nc1nc(-c2n[nH]c3ncc(F)cc23)ncc1F

Procedure:
Compound 5 was synthesized in a manner similar to compound 12, starting with compound 6a: 1H NMR (400 MHz, d6-DMSO) δ 12.65 (s, 1H), 9.43 (s, 1H), 9.15 (s, 1H), 8.44 (d, J=4.7 Hz, 1H), 8.41-8.29 (m, 2H), 3.93 (s, 1H), 3.54 (s, 1H), 1.19 (d, J=20.0 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.70 min, (M+H) 393.32.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:6])[CH:2]=[CH2:3].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[Br:29][CH2:30][C:31](Br)=[O:32]>ClCCl>[Br:29][CH2:30][C:31]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:5](=[O:6])[O:4][CH2:1][CH:2]=[CH2:3])=[O:32]
Reactant: C=CCOC(=O)NCCCCN
Reactant: O=C(Br)CBr
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Product: C=CCOC(=O)NCCCCNC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
4-((Allyloxycarbonyl)amino)butan-1-amine (87c, 1.18 g, 6.852 mmol, prepared according to Synthesis, 2002, 15, 2195) and proton sponge (1.468 g, 6.850 mmol) were dissolved in 14 mL of dichloromethane followed by the dropwise addition of 0.6 mL (6.908 mmol) of bromoacetyl bromide. After overnight stirring at room temperature, the mixture was diluted with dichloromethane, washed with water (2×) and brine (1×) and dried over sodium sulfate. The concentrated crude material was subjected to a Biotage™ flash chromatography system on a silica gel column with 40:1 (v/v) dichloromethane/methanol as the eluent. Product 88c (1.52 g, 76% yield) was obtained as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.69 (m, 4H), 3.22 (q, J=6.2, 2H), 3.32 (q, J=6.2, 2H), 3.88 (s, 2H), 4.56 (d, J=5.1, 2H), 4.80 (broad s, 1H), 5.21 (dd, J=1.1, 10.6, 1H), 5.30 (dd, J=1.8, 17.2, 1H), 5.92 (octet, J=5.6 Hz, 1H), 6.58 (broad s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]([NH2:24])=S)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1.O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]#[N:24])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[CH:19][CH:18]=[N:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(NC(N)=S)ccc1-n1cccn1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(NC#N)ccc1-n1cccn1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 87 %

Procedure:
A mixture of the compound (315 mg) obtained in Example 2c, p-toluenesulfonyl chloride (190 mg) and pyridine (2 ml) was stirred at room temperature for 70 minutes. Water was added to the reaction mixture and extraction with methylene chloride was conducted. The organic layer was washed with brine, dried with anhydrous sodium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1) to give the titled compound (yield, 87%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)=[O:30]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:35]=[CH:36][C:31]([C:29]([NH:28][CH3:27])=[O:30])=[N:32][CH:33]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNC(=O)c1ccc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (Peak 2, Example 49, Step 7) and N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Frontier, Cat. No. M10074). LCMS (M+H)+: m/z=473.4.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:40]O)[CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=1>C1(C)C=CC=CC=1>[N:15]([CH2:40][C:33]1[CH:34]=[C:35]([N+:37]([O-:39])=[O:38])[CH:36]=[C:31]([O:30][CH3:29])[CH:32]=1)=[N+:16]=[N-:17]
Reactant: COc1cc(CO)cc([N+](=O)[O-])c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(CN=[N+]=[N-])cc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 100 %

Procedure:
Diphenylphosphoryl azide (0.316 ml, 0.4 g, 1.46 ml, 1.1 eq) and 1,8-Diazabicyclo(5.4.0)undec-7-ene (0.219 ml, 0.22 g, 1.46 mmol, 1.1 eq) were added to a stirred solution of (3-methoxy-5-nitrophenyl)methanol in 10 ml anhydrous toluene under Ar. After stirring overnight the solvent was removed in vacuo. Purification via flash chromatography yielded 0.278 g (1.34 mmol, 100% yield) of 1-(azidomethyl)-3-methoxy-5-nitrobenzene.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=3)[C:15]([F:29])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([OH:27])=[O:26])[CH:20]=3)[C:15]([F:29])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)OC)c3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)O)c3)n2)c1
Yield: 58.6 %

Procedure:
A solution of N2,N4-bis(3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (100 mg, 0.25 mmol) and NaOH (140 mg, 3.5 mmol) in THF:H2O (5 mL, each) was stirred at room temperature overnight. The reaction mixture was diluted with water (60 mL) and ethyl acetate (60 mL). The aqueous layer was separated, acidified with 1N HCl solution to pH 3 The formed precipitate was collected by filtration and recrystallized from methanol to give N2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (54 mg, 58%) as a white solid. 1H NMR (CD3OD): δ 7.31 (t, J=8.1 Hz, 1H), 7.42 (t, J=8.1 Hz, 1H), 7.61 (dm, J=7.8 Hz, 1H), 7.76 (dm, J=8.4 Hz, 1H), 7.89 (dm, J=7.2 Hz, 1H), 7.98 (d, J=3.6 Hz, 1H), 8.01 (m, 1H), 8.20 (m, 1H), 8.37 (m, 1H); LCMS: ret. time: 15.77 min.; purity: 98.84%; MS (m/e): 369.03 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:45]=[CH:44][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[CH:20][C:19]=3[N:35]([CH3:43])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1>FC(F)(F)C(O)=O>[CH3:43][N:35]1[C:19]2[CH:20]=[C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH:22]=[CH:23][C:18]=2[N:17]=[C:15]1[CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:45][CH:44]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(C(F)(F)F)cc3)cc21
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A solution of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-trifluoromethylphenoxy)phenyl}-N-methylcarbamate (0.95 g) in trifluoroacetic acid (20 ml) was stirred at 60° C. for 3 hours and allowed to stand at ambient temperature overnight. The reaction mixture was concentrated and to the residue was added water and neutralized with aqueous sodium bicarbonate solution (5%). The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then evaporated. The residue was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=1/2 as the eluant to give the title compound (0.60 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:28]2[S:29][C:30]([CH3:33])=[CH:31][CH:32]=2)O1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:28]3[S:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Product: Cc1ccc(-c2cc3c(cn2)C(C)(C)CN3C(=O)OC(C)(C)C)s1

Procedure:
Prepared from 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester and 4,4,5,5-tetramethyl-2-(5-methyl-thiophen-2-yl)-[1,3,2]dioxaborolane using a procedure similar to Preparation 379. MS: [M+H]+=345.
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1C(OC(C)(C)C)=O)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].[C:28]([CH2:30][CH2:31][NH:32][C:33]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)=[O:34])#[N:29]>>[C:1]([C@@H:3]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1)=[O:14])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([C:33](=[O:34])[NH:32][CH2:31][CH2:30][C:28]#[N:29])[CH:40]=2)=[CH:9][CH:10]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(I)cc1
Reactant: N#CCCNC(=O)c1cccc(B(O)O)c1
Product: N#CCCNC(=O)c1cccc(-c2ccc(C[C@@H](C#N)NC(=O)[C@@H]3CCCCN3)cc2)c1

Procedure:
Prepared by a process analogous to that described in Method 2 Example 2 using (S)-tert-butyl 2-((S)-1-cyano-2-(4-iodophenyl)ethylcarbamoyl)piperidine-1-carboxylate and 3-(2-cyanoethylcarbamoyl)phenylboronic acid. NMR appeared to show the product was a free base.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)cc1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution of 4-fluorophenol (2.00 g, 17.84 mmol) in DMF (10 mL) was added dropwise to a stirred suspension of NaH in DMF (2.0 mL) at around 10° C. Ethyl bromoacetate (2.483 mL, 22.30 mmol) was added dropwise and then the reaction mixture was allowed to warm up to room temperature for 4 hours. The solvent was removed under vacuum and the residue was dissolved in methylene chloride and washed 2 times with water, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on silica gel using (4:1 heptane:EtOAc as eluent) to give ethyl 2-(4-fluorophenoxy)acetate (3.12 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[NH:31][C:30]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29]4)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCOC(=O)c1cc2cc(NC(=O)C(CC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)ccc2[nH]1

Procedure:
87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 56 mg (0.28 mmol, 1.1 eq.) of ethyl 5-amino-1H-indole-2-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 94 mg (70% of theory)