Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:22])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nccc(-c2ccc(C(=O)N3CCOCC3)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 120 mg (0.33 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid (A-38) using 43 mg (0.50 mmoL) morpholine, 139 mg (0.37 mmol) HATU and 96 μL DIEA in 1.2 mL DMF. After completion of the reaction, DMF is removed under reduced pressure and the product is purified by chromatography on silica gel using a DCM/MeOH-gradient. Yield: 66 mg (46%).
Reaction SMILES: O[CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]4[N:20]([CH2:24][CH2:25][CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:21](=[O:23])[NH:22][C:17]4=[N:16][CH:15]=3)=[CH:10][CH:9]=2)[N:4]=1.O=C1NC2=NC=C(C3C=CC(C(=N)OCC)=CC=3)N=C2[N:34]1CCC1CCOCC1.OCC(NN)=O.C(N(CC)CC)C>C(O)C>[NH2:34][CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]4[N:20]([CH2:24][CH2:25][CH:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[C:21](=[O:23])[NH:22][C:17]4=[N:16][CH:15]=3)=[CH:10][CH:9]=2)[N:4]=1
Reactant: CCOC(=N)c1ccc(-c2cnc3[nH]c(=O)n(CCC4CCOCC4)c3n2)cc1
Reactant: O=c1[nH]c2ncc(-c3ccc(-c4n[nH]c(CO)n4)cc3)nc2n1CCC1CCOCC1
Agent: NNC(=O)CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: NCc1nc(-c2ccc(-c3cnc4[nH]c(=O)n(CCC5CCOCC5)c4n3)cc2)n[nH]1
Temperature: 110 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. Ethyl 4-(2-oxo-3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (See Example 195.B) (0.250 g, 0.63 mmol) in ethanol (20 mL) was treated with 2-hydroxyacetohydrazide (0.17 g, 1.9 mmol) and triethylamine (0.26 mL, 1.9 mmol), and the resulting reaction mixture was stirred in a sealed tube at 110° C. for 16 h. The cooled reaction solvent removed under reduced pressure. The resulting material was purified using reverse-phase semi-preparatory HPLC (15-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing clean product were passed through a Phenomenex Strata-X-C ion exchange column to remove TFA. The column was washed successively with water, methanol, and then 5% ammonium hydroxide in methanol. The product came off with the 5% ammonium hydroxide in methanol eluent and was concentrated on a rotary evaporator. The residue was triturated with ethyl ether in hexane to make a fine powder and dried under vacuum at 50° C. to give the desired product (0.130 g, 49%) as a white solid. MS (ESI) m/z 422.3[M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][C:14]4([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:13][C:14]4([CH2:20][CH2:19][N:18]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:17][CH2:16]4)[CH2:15]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CC4(CCNCC4)C3)cc2n1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a solution of 2-chloro-6-(2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (71 mg, 0.18 mmol) in anhydrous DCM (3 mL) was added triethylamine (160 μL, 1.46 mmol) and a solution of methanesulfonyl chloride (17 μL, 0.22 mmol) in anhydrous DCM (0.5 mL). The resulting mixture was stirred at RT for 18 h, then diluted with DCM and brine. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow oil (55 mg, 65%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:52])[NH:10][CH:11]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:43][CH:42]=1)[CH:12]([OH:39])[CH:13]([OH:38])[CH:14]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:55](OC)([CH3:57])[CH3:56].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[CH2:1]([O:8][C:9](=[O:52])[NH:10][CH:11]([CH:12]1[CH:13]([CH:14]([NH:27][C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[O:38][C:55]([CH3:57])([CH3:56])[O:39]1)[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:43][CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)Oc1ccc(CC(NC(=O)OCc2ccccc2)C(O)C(O)C(Cc2ccc(OC(C)(C)C)cc2)NC(=O)OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Product: CC(C)(C)Oc1ccc(CC(NC(=O)OCc2ccccc2)C2OC(C)(C)OC2C(Cc2ccc(OC(C)(C)C)cc2)NC(=O)OCc2ccccc2)cc1
Yield: 92 %

Procedure:
Diol 2.5 (5 g, 7 mmol) is dissolved in acetone (120 mL), 2,2-dimethoxypropane (20 mL), and pyridinium p-toluenesulfonate (120 mg, 0.5 mmol). The resulting solution is refluxed for 30 min., and then concentrated under reduced pressure to almost dryness. The resulting mixture is partitioned between methylene chloride and saturated NaHCO3 aqueous solution, dried, concentrated under reduced pressure, and purified by silica gel column chomatography to afford isopropylidene protected diol 2.6 (4.8 g, 92%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:26][NH2:27])[CH2:24][CH3:25]>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:27][N:26]([CH2:23][CH2:24][CH3:25])[C:15]=1[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)CC
Reactant: CCCNN
Product: CCCn1nc(CC)c(Cc2nccn2Cc2ccccc2)c1CC

Procedure:
4-(1-Benzyl-1H-imidazol-2-ylmethyl)-3,5-diethyl-1-propyl-1H-pyrazole was prepared from 4-(1-benzyl-1H-imidazol-2-ylmethyl)-heptane-3,5-dione and propylhydrazine in analogy to Example 190 b): light yellow viscous oil; MS (EI): 336.2 ((M+.), 100%), 245.3 ((M-PhCH2)+.).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[N:7][CH:8]=1)=O.[CH2:21]([S:23]([NH2:26])(=[O:25])=[O:24])[CH3:22]>>[C:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:20])[C:9]=1[C:5]1[CH:4]=[C:3]([CH2:1][NH:26][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])[CH:8]=[N:7][CH:6]=1)#[N:19]
Reactant: CCS(N)(=O)=O
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccccc21
Product: CCS(=O)(=O)NCc1cncc(-c2c(C#N)c3ccccc3n2C)c1

Procedure:
2-(5-Formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 127) and ethanesulfonamide are processed according to the method described in Example 170 to give ethanesulfonic acid [5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.3 Hz, 3H), 3.07 (q, J=7.4 Hz, 2H), 3.79 (s, 3H), 4.34 (d, J=6.1 Hz, 2H), 7.34-7.38 (m, 1H), 7.41-7.46 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.75-7.82 (m, 2H), 8.09 (t, J=2.1 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.1 Hz, 1H). HRMS (ESI) m/z 355.1247 [(M+H)+ Calcd for C18H19N4O2S: 355.1229].
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=[O:20])[CH:17]=[CH:18][C:4]1=2)[CH3:2].CC(=CC)C.P([O-])(O)(O)=[O:27].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([C:19]([OH:27])=[O:20])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a t-butanol (20 ml) and H2O (5 ml) solution of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (2.25 g) and 2-methyl-2-butene(3.25 ml) were added sodium dihydrogenphosphate (0.92 g) and sodium chlorite (2.081 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure to give the title compound (0.98 g) as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:28]1[C:29]2[C:36]([CH3:37])=[CH:35][NH:34][C:30]=2[N:31]=[CH:32][N:33]=1.C(N(CC)C(C)C)(C)C>C(O)C(C)C>[CH3:26][N:2]([CH3:1])[C:3](=[O:25])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH2:19][CH2:18][N:17]([C:28]3[C:29]4[C:36]([CH3:37])=[CH:35][NH:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CN(C)CCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCNCC1
Solvent: CC(C)CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(CCN(C)C)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 110 °C
Yield: 40.5 %

Procedure:
Impure 3-(4-(2-(dimethylamino)ethyl)piperidine-4-carboxamido)phenyl dimethylcarbamate from step D (173 mg) was combined with 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.30 mmol) and N,N-diisopropylethylamine (0.174 mL, 5 mmol) in isobutanol (0.4 mL) and heated at 110° C. for 7 hours. The reaction was cooled to room temperature and concentrated under vacuum. The residue was purified by prep HPLC (30×100 mm C18 column, 10-70% MeCN:H2O (10 mM NH4OAc), 12 min, 45 mL/min) and lyophilized to give the title compound (60 mg) as the di-acetate salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[CH:5][CH:4]=1.C[O-].[Na+].Cl.[C:17](#[N:19])[CH3:18]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH2:18][C:17]#[N:19])=[O:9])=[CH:11][CH:12]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(=O)CC#N)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-methoxybenzoate (7.2 kg) in dimethyl sulfoxide (21.6 L) were added sodium methoxide (3.046 kg) and acetonitrile (2.135 kg) and the mixture was stirred at 110° C. for 2 hours. Then, water (10.83 L) was added dropwise thereto at 15° C. or lower and further acetonitrile (14.4 L) was added to the mixture. Then, 6 N HCl was added thereto to adjust to pH 7.9 and the mixture was extracted with ethyl acetate (72 L). The aqueous layer was further extracted with ethyl acetate (36.32 L). The organic layers were combined and concentrated until the content became 17.39 kg. Methanol (17.84 L) was added thereto and water (17.84 L) was added dropwise. Then, the mixture was stirred at 5° C. for 1 hours and crystals deposited were filtered off and washed with methanol-water (1:1) to obtain the titled compound '6.40 kg, 82.7 g). 1H-NMR (CDCl3)δ: 3.90 (3H, s), 4.03 (2H, s), 6.98 (2H, d, J=11.25 Hz), 7.50 (2H, d, J=11.25 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].N[C@@H]1CCCC[C@H]1N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cu]I.O1CCOCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:25][CH:26]=1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2[nH]ccc2c1
Reactant: Fc1ccc(Br)cc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 56.4 %

Procedure:
A mixture of 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (Example 101(d), 31 mg, 0.11 mmol), 1-bromo-4-fluorobenzene (0.014 mL, 0.13 mmol), copper(I) iodide (4 mg, 0.02 mmol), potassium carbonate (50 mg, 0.36 mmol), trans-1,2-diaminocyclohexane (0.01 mL, 0.08 mmol), tetrabutylammonium iodide (18 mg, 0.05 mmol), and dioxane (0.6 mL) was stirred at 110° C. for 24 h. Concentration and purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 3-(1-(4-fluorophenyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (24 mg, 0.062 mmol, 56% yield) as a liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)=[CH:7][C:4]=1[CH:5]=O.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)=[CH:7][C:4]=1/[CH:5]=[CH:20]/[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=[O:21]
Reactant: COc1cc(OC)c(-c2csc(C)n2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OC)c(-c2csc(C)n2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-(2-methyl-thiazol-4-yl)-benzaldehyde (Ex-69A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 201–202° C. (dec.). 1H-NMR (DMSO-d6) δ 8.47 (s, 1H), 8.14–7.97 (m, 5H), 7.76 (s, 1H), 7.65 (d, J=15.8 Hz, 1H), 6.81 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.69 (s, 3H). MS m/z=409 (M+, 70%), 378 ([M−OCH3]+, 100%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][N:20]([CH2:22][CH2:23][OH:24])[CH3:21].[H-].[Na+].O(C1C2N=C(C3C=CC(F)=CC=3)C=CC=2N=CN=1)C1C=CC=CC=1>>[CH3:19][N:20]([CH2:22][CH2:23][O:24][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[CH3:21]
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Reactant: CN(C)CCO
Agent: Fc1ccc(-c2ccc3ncnc(Oc4ccccc4)c3n2)cc1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOc1ncnc2ccc(-c3ccc(F)cc3)nc12
Yield: 20 %

Procedure:
was synthesized from 4-chloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine and 2-(N,N-dimethylamino)ethanol/NaH, in 20% yield, using the procedure described for the synthesis of 4-phenoxy-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine. The mass spectrum characterising data was as follows: MS (m/z): 313 ([M+H]+, 100).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH3:12][O-:13].[Na+]>CO>[Br:1][C:2]1[C:3]([O:13][CH3:12])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cc1Br
Temperature: 25 °C

Procedure:
To a cloudy mixture of 3-bromo-2-chloro-5-nitropyridine (Atlantic Scitech, Linden, N.J., 5.10 g, 21.48 mmol) in 50 mL anhydrous methanol at 0° C. (ice/water bath) was added sodium methoxide 5.4 M in methanol (7.96 mL, 43.0 mmol) dropwise by addition funnel The reaction became clear then a thick precipitate formed. The ice/water bath was removed and the reaction warmed to ambient temperature, quenched with water and sat'd aq. NH4Cl and DCM. The aqueous layer was extracted with DCM 2 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 3-bromo-2-methoxy-5-nitropyridine (5.07 g, 21.76 mmol, quantitative yield) as a light yellow solid. m/z (ESI, +ve ion) 233 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.02 (d, J=2.3 Hz, 1H), 8.63 (d, J=2.5 Hz, 1H), 4.15 (s, 3H).
Reaction SMILES: C(Cl)CCl.[Br:5][C:6]1[C:7]([C:12]([OH:14])=O)=[N:8][CH:9]=[CH:10][CH:11]=1.N1C2C(=NC=CC=2)N(O)N=1.Cl.[F:26][C:27]([F:42])([F:41])[C:28]1[N:29]=[CH:30][C:31]([NH:34][C@H:35]2[CH2:39][CH2:38][CH2:37][C@@H:36]2[NH2:40])=[N:32][CH:33]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:5][C:6]1[C:7]([C:12]([NH:40][C@H:36]2[CH2:37][CH2:38][CH2:39][C@@H:35]2[NH:34][C:31]2[CH:30]=[N:29][C:28]([C:27]([F:42])([F:41])[F:26])=[CH:33][N:32]=2)=[O:14])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1ncccc1Br
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (509 mg, 2.65 mmol) was added to a solution of 3-bromopyridine-2-carboxylic acid (429 mg, 2.12 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (361 mg, 2.65 mmol), (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 500 mg, 1.77 mmol) and triethylamine (0.74 ml, 5.31 mmol) in DCM (5.9 ml). The reaction was stirred at room temperature overnight. The reaction was diluted with DCM, washed with water, brine, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][Li].ClCCCC#C.C([Li])CCC.[CH:19]([B:23](OC(C)C)[O:24][CH:25]([CH3:27])[CH3:26])([CH2:21][CH3:22])[CH3:20].Cl.C(OCC)C>O1CCCC1>[CH:19]([B:23]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][Cl:1])[O:24][CH:25]([CH3:27])[CH3:26])([CH2:21][CH3:22])[CH3:20]
Reactant: [Li]C#CCCCCl
Reactant: CCC(C)B(OC(C)C)OC(C)C
Agent: C#CCCCCl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(C)B(C#CCCCCl)OC(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran (THF) solution of 5-chloro-1-pentynyllithium prepared from 5-chloro-1-pentyne (5.43 g, 53 mmol) and n-butyllithium (20.4 mL, 53 mmol) cooled to -78° C. was added sec-butyldiisopropoxyborane (8.74, 48 mmol) in 48 mL THF. The reaction mixture was stirred at -78° C. for an additional 1 h, then quenched with hydrogen chloride in ethyl ether (15.5 mL, 53 mmol). The cooling bath was removed and the reaction mixture allowed to warm to room temperature. The lithium chloride was allowed to settle and the clear supernatant was decanted via a double-ended needle into a distillation flask. The remaining solid lithium chloride was washed with THF, 2×15 mL, and added to the distillation flask. Volatiles were removed with reduced pressure, followed by high vacuum distillation. Yield: 9.5 g (92%), bp 72°-74° C. (0.1 mm Hg); n20D 1.4496; proton NMR (CDCl3)δ4.63 (septet, J=18 Hz, 1H), 3.60 (triplet, J=18 Hz, 2H), 2.47 (triplet, J=18 Hz, 2H), 1.17 (d, J=18 Hz, 6H), 0.87 (m, 6H); boron NMR (EE)δ+41.3 ppm (s); mass spectrum (chemical ionization, isobutane), m/e 213 (M+H, 8%). IR (thin film) 2185, 1325 cm-1. Anal. Calcd. for C12H28BClO: C, 63.06; H, 9.70; B, 4.73. Found: C, 63.14; H, 9.60; B, 4.48.
Reaction SMILES: CC([N:5]([C@H:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=2)=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:28][CH:26]([C:22]1[CH:21]=[C:20]([O:19][C:16]2[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:29])[NH2:5])=[CH:18][CH:17]=2)[CH:25]=[CH:24][CH:23]=1)[CH3:27]
Reactant: CC(C)c1cccc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
1,1-dimethylethyl{(1R)-1-methyl-2-[(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)amino]-2-oxoethyl}carbamate (Intermediate 25, 56 mg) was dissolved in 3 mL of dry dichloromethane. To this solution at 0° C. were added dropwise 30 equivalents of TFA (0.324 mL). The reaction was stirred at 0° C. for 3 hours. The reaction mixture was evaporated. The crude obtained was purified by SCX on a 5 g cartridge. 3 CV of methanol were used first, then the residue was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N). Evaporation of the volatiles, afforded the title compound (38 mg).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC(C)([O-])C.[K+].[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:27]=[C:28]2[O:32][C:31](SC)=[N:30][C:29]2=[O:35])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14]>C(O)C>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([CH:27]=[C:28]2[O:32][C:31]([NH:4][C:3]([NH2:5])=[NH:2])=[N:30][C:29]2=[O:35])[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]=1[OH:22])([CH3:12])[CH3:14]
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)O1
Reactant: N=C(N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2OC(NC(=N)N)=NC2=O)cc(C(C)(C)C)c1O
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A solution of 2.0 g (0.021 mole) of guanidine hydrochloride in 75 mL of ethanol is cooled in ice and treated in portions with 2.2 g (0.020 mole) of potassium tert-butoxide. The mixture is stirred for 15 minutes, and then rapidly filtered into a suspension of 4.6 g (0.013 mole) of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-(methylthio)-4(5H)-oxazolone in 75 mL of ethanol. The new reaction mixture is stirred at reflex for 3 hours, then cooled and filtered. The filtrate is evaporated 50% and added to 500 g of ice and water. The precipitated solid is filtered, washed with water, and dissolved in 200 mL of ethyl acetate. The solution is washed with brine (3×200 mL), dried (anhydrous sodium sulfate), and evaporated. The residue is chromatographed over silica gel, using elution with 10% acetonitrile in ethyl acetate. The purified product, [5-[[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]methylene]-4,5-dihydro- 4-oxo-2-oxazolyl]guanidine, is 2.6 g (55% yield). A sample recrystallized from aqueous acetonitrile has mp 258°-dec.