Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O[C:28]([C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[S:35]([C:38]1[N:42]2[C@:43]([CH3:68])([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([C:62]4[CH:63]=[N:64][CH:65]=[N:66][CH:67]=4)=[CH:58][CH:57]=3)[C:44](=[O:54])[N:45]([C:46]3[CH:51]=[C:50]([Cl:52])[CH:49]=[C:48]([Cl:53])[CH:47]=3)[C:41]2=[N:40][CH:39]=1)(=[O:37])=[O:36])=[O:29])(C)(C)C.Cl.C([O:74][C:75](=[O:79])[C@@H:76]([CH3:78])[NH2:77])(C)(C)C.CCN(C(C)C)C(C)C.Cl>CN(C=O)C.C(Cl)Cl.C(Cl)Cl>[Cl:53][C:48]1[CH:47]=[C:46]([N:45]2[C:41]3=[N:40][CH:39]=[C:38]([S:35]([N:31]4[CH2:32][CH2:33][CH2:34][C@H:30]4[C:28]([NH:77][C@H:76]([CH3:78])[C:75]([OH:79])=[O:74])=[O:29])(=[O:36])=[O:37])[N:42]3[C@:43]([CH3:68])([CH2:55][C:56]3[CH:57]=[CH:58][C:59]([C:62]4[CH:63]=[N:64][CH:65]=[N:66][CH:67]=4)=[CH:60][CH:61]=3)[C:44]2=[O:54])[CH:51]=[C:50]([Cl:52])[CH:49]=1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reaction time: 16 h
Yield: 44 %

Procedure:
TBTU (0.078 g) and (S)-1-[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-pyrimidin-5-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (Example 14) (0.10 g) were combined in 7% DMF-CH2Cl2 (3.2 mL) at room temperature. D-Alanine-tert-butyl ester hydrochloride (0.044 g), followed by DIPEA (0.07 mL), was then added and the reaction solution was stirred for 16 h. The reaction was diluted with CH2Cl2, poured into 1N HCl, and extracted with CH2Cl2. The organic layers were washed with saturated aqueous NaHCO3 followed by H2O. The combined organic phase was dried (MgSO4), filtered and concentrated. The resultant residue was re-dissolved dissolved in either 50% trifluoroacetic acid—CH2Cl2 or 4N HCl-dioxane (5 mL) and stirred at room temperature for 2 h. Following aqueous workup the residue was purified by silica gel chromatography to afford the title compound (0.045 g) as a foam (698.9, M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:70][CH2:71][CH2:72][OH:73]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:25](=[O:26])[NH:70][CH2:71][CH2:72][OH:73])([CH3:28])[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NCCO)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)phenyl]-2′-[5-fluoro-2-methylphenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (1 mL) was added 2-amino-ethanol (11 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (9 mg).
Reaction SMILES: [CH:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH2:2].[CH:16]([OH:18])=[CH2:17].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>N1C=CC=CC=1.C1C=CC=CC=1>[CH:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH2:2].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=1)[C:25]([O:18][CH:16]=[CH2:17])=[O:26])([O-:21])=[O:20]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C=CO
Agent: C=Cn1c2ccccc2c2ccccc21
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C=COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Copoly(N-vinyl carbazole-Vinyl alcohol) (II) (2.0 g) was dissolved in 50 ml of anhydrous pyridine. 3,5-Dinitrobenzoyl chloride (3.88 g) in 15 ml of anhydrous benzene was added with stirring to the pyridine solution. The resulting orange solution was stirred at room temperature for 4 hours. The small amount of solid remaining in the reaction mixture was collected on a filter and the filtrate was poured into 400 ml of methanol. The isolated polymer was purified by two precipitations from tetrahydrofuran into methanol to give 3.2 grams of a yellow powder. Nitrogen analysis demonstrated that the reaction of the alcohol groups with the acid chloride was nearly quantitative.
Reaction SMILES: [CH3:1][C:2]1(C)C[CH:6]([OH:8])[CH2:5][C:4](C)(C)N1.[CH3:12][N:13]1[C:18]([CH3:20])([CH3:19])[CH2:17][CH:16]([OH:21])[CH2:15][C:14]1([CH3:23])[CH3:22].C=C.C(OCC)(=O)C=C>>[CH2:1]=[CH2:2].[C:6]([O:21][CH:16]1[CH2:17][C:18]([CH3:19])([CH3:20])[N:13]([CH3:12])[C:14]([CH3:23])([CH3:22])[CH2:15]1)(=[O:8])[CH:5]=[CH2:4]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: C=C
Agent: C=CC(=O)OCC
Product: C=CC(=O)OC1CC(C)(C)N(C)C(C)(C)C1

Procedure:
The above-named copolymer was prepared by the general procedure of Example 1 by substituting for the 2,2,6,6-tetramethylpiperidin-4-ol an equivalent amount of 1,2,2,6,6-penta-methylpiperidin-4-ol, and reacting with an ethylene/ethyl acrylate copolymer (77/23).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])[N:5]=[C:4]([NH:16][N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:39][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([Cl:47])=[N:45][CH:46]=1>O1CCOCC1.C(Cl)(Cl)Cl>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[C:6]1[N:5]=[C:4]([NH:16][N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=2)[N:3]=[C:2]([NH:39][CH2:40][C:41]2[CH:46]=[N:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[N:7]=1
Reactant: Fc1cccc(Cl)c1-c1nc(Cl)nc(NN=Cc2ccc(OC(F)(F)F)cc2)n1
Reactant: NCc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Fc1cccc(Cl)c1-c1nc(NCc2ccc(Cl)nc2)nc(NN=Cc2ccc(OC(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of 2-chloro-4-(2-chloro-6-fluorophenyl)-6-(2-(4-(trifluoromethoxy)benzylidene)hydrazinyl)-1,3,5-triazine (XVII) (250 mg, 0.56 mmol) in 1,4-dioxane (2 mL) was treated with a solution of iPr2NEt (144.8 mg, 1.12 mmol) in 1,4-dioxane (1 mL). The mixture was treated with a solution of 5-aminomethyl-2-chloropyridine (80.37 mg, 0.564 mmol) in 1,4-dioxane (1 mL). The reaction was stirred overnight at room temperature. The reaction was concentrated on a rotary evaporator and the residue was taken up in ethyl acetate and washed with brine. The aqueous layer was extracted twice with ethyl acetate. The combined organics was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield a white solid. The solid was taken up in chloroform and loaded onto 100 g of silica gel. The silica gel was eluted with ethyl acetate/hexanes (30%, 40%, 50%, 70%). The appropriate fractions were concentrated on a rotary evaporator to yield 4-(2-chloro-6-fluorophenyl)-N-((6-chloropyridin-3-yl)methyl)-6-(2-(4-(trifluoromethoxy)benzylidene)hydrazinyl)-1,3,5-triazin-2-amine (Example 22) as a white solid (305 mg). ESI/MS 552.3, 554.2 (M+H), 550.4, 552.4 (M−H).
Reaction SMILES: [H][H].[CH2:3]([NH2:5])[CH3:4].Cl[C:7]1[N:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@@H:27]1[O:39][C@H:38]([CH2:40][O:41]C(=O)C)[C@@H:33]([O:34]C(=O)C)[C@H:28]1[O:29]C(=O)C>>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][O:16][C:14]2[N:15]=[C:7]([NH:5][CH2:3][CH3:4])[C:8]3[N:9]=[CH:10][N:11]([C:12]=3[N:13]=2)[C@@H:27]2[O:39][C@H:38]([CH2:40][OH:41])[C@@H:33]([OH:34])[C@H:28]2[OH:29])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: [H][H]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(OCc4ccc([N+](=O)[O-])cc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCN
Product: CCNc1nc(OCc2ccc([N+](=O)[O-])cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 60 %

Procedure:
A compound having a structure of the above formula was prepared where the substituent R1 is —CH2CH3, R2 is hydrogen, and R3 is 4-nitrobenzyl (—CH2(4-nitro)C6H4). The compound (C19H22N6O7) was prepared by reaction of ethylamine with 6-chloro-2-(4-nitrobenzyl)oxy-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (Example 4) as described in Example 2, Step E. The final product was isolated in 60% yield as a solid with a melting point of 210-213° C. 1H-NMR (DMSO-d6): δ 1.05 (1, 3H, J=8); 3.4 (m, 2H); 3.5 (m, 1H); 3.6 (m, 1H); 3.85 (m, 1H); 4.05 (m, 1H); 4.6 (m, 1H); 5.2 (m, 2H); 5.4 (d, 1H, J=6); 5.45 (s, 2H); 5.8 (d, 1H, J=6); 7.8 (d, 2H, J=8); 8 (bt, 1H); 8.2 (s, 1H); 8.25 (d, 2H, J=8).
Reaction SMILES: II.[CH:3]12[C:15](=[O:16])[CH:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH:10]1[CH:4]2[C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=13.[CH3:21][N:22]([CH3:27])[C:23](=[O:26])[CH2:24]Br>[Zn].C1C=CC=CC=1.CO.C(O)(=O)C>[CH3:21][N:22]([CH3:27])[C:23](=[O:26])[CH2:24][C:15]1([OH:16])[CH:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH:10]3[CH:3]1[CH:4]3[C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=12
Reactant: CN(C)C(=O)CBr
Reactant: O=C1C2c3ccccc3C3C1C3c1ccccc12
Agent: II
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Solvent: c1ccccc1
Product: CN(C)C(=O)CC1(O)C2c3ccccc3C3C(c4ccccc42)C31

Procedure:
An amount of 3.6 g (0.055 mole) of zinc chips and a trace of iodine are placed into a dry reaction vessel; additions are then made of 2 ml of a solution of 7.0 g (0.03 mole) of 1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cyclohepten-11-one and 7.1 g (0.039 mole) of N,N-dimethyl-bromoacetamide in 50 ml of abs. benzene, and the whole is refluxed while stirring is maintained; the remainder of the benzene solution is added dropwise in the course of 30 minutes and refluxing subsequently performed for a further hour. After cooling, the reaction mixture is decomposed with 6 ml of glacial acetic acid and 6 ml of methanol. The formed organic precipitate is taken into solution by the addition of benzene and zinc residues still present are filtered off. The benzene solution is washed with 2N acetic acid, then with 2N sodium bicarbonate solution and finally with water; it is then dried over sodium sulphate and concentrated in a water-jet vacuum. The residue crystallises from benzene/petroleum ether to yield N,N-dimethyl-11-hydroxy-1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e] cyclopropa[c]cycloheptene-11-acetamide; M.P. 203°-204°.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[CH3:34][C:35](=O)[CH3:36]>CO.[Pd]>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([CH:35]([CH3:36])[CH3:34])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Agent: [Pd]
Solvent: CO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C(C)C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (553 mg, 1.23 mmol) and propan-2-one (1.0 mL) in MeOH (20 mL) was added 10% Pd/C (30 mg) as a slurry in MeOH (0.5 mL) and the resulting mixture stirred under an atmosphere of H2 for 1.5 h at r.t. The reaction mixture was filtered through Celite®, washing with MeOH, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, 2M NH3/MeOH:EtOAc, 0-12%) then (C18, MeOH:H2O, 5-25%). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/MeOH. The resulting colourless foam was recrystallised from iPrOAc and pentane affording 739 as colourless crystals (166 mg, 28%). LCMS (method I): RT 2.48 min, [M+H]+ 491.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-8.02 (1 H, m), 7.64-7.63 (1 H, m), 7.29-7.28 (2 H, m), 4.40 (4 H, s), 4.05 (2 H, d, J=8.89 Hz), 3.86 (4 H, s), 3.81 (3 H, s), 3.57-3.55 (2 H, m), 3.31-3.30 (2 H, m), 3.10 (3 H, s), 2.54-2.53 (1 H, m), 1.40 (3 H, t, J=7.50 Hz), 1.02 (6 H, d, J=6.24 Hz)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:32][C:33](Cl)=[O:34].C(N(C(C)C)C(C)C)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C)C=O.O>[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([CH2:32][C:33]([NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][C:12]4[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=4)[C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=4)=[O:16])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:34])[CH2:48][CH2:47]1
Reactant: O=C(Cl)CCl
Reactant: CN1CCNCC1
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cccc(C(=O)Nc5ccc(C(F)(F)F)cc5)c4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[4-(trifluoromethyl)phenyl]benzamide (215 mg, 0.50 mmol) produced in Example A25(v), chloroacetyl chloride (225 mg, 2.00 mmol) and N-ethyl-N-isopropylpropane-2-amine (518 mg, 4.00 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1) to give a colorless oil. This was dissolved in N,N-dimethylformamide (5 mL), 1-methylpiperazine (400 mg, 4.00 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel chromatography (eluent:ethyl acetate/methanol=10:1), and triturated with diethyl ether to give the title compound (180 mg, 63%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH:14]1[CH2:19][OH:20].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH:14]2[CH2:19][OH:20])[N:3]=1
Reactant: NC(=O)c1cc(Cl)nc(Cl)n1
Reactant: OCC1COCCN1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(N2CCOCC2CO)nc(Cl)n1
Temperature: 50 °C
Yield: 92 %

Procedure:
To a mixture of 2,6-dichloropyrimidine-4-carboxamide (0.384 g, 2.00 mmol) in acetonitrile (10 mL) was added morpholin-3-ylmethanol hydrochloride (0.310 g, 2.02 mmol) and iPr2NEt (0.77 mL, 4.4 mmol). The mixture was heated at 50° C. overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 25-75% acetone in hexanes. The product fractions were evaporated in vacuo to yield 2-chloro-6-(3-(hydroxymethyl)morpholino)pyrimidine-4-carboxamide as a pale tan solid (0.501 g, 1.84 mmol, 92% yield). LC/MS: m/z=273.2 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:13][CH:12]3[N:14]([CH3:15])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH:6]=1.[Cl:16][C:17]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:18]=1[CH:19]=[C:20]([C:28]1[C:29]([NH2:43])=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=1)[N:21]=[CH:22]2.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC.O>[Cl:16][C:17]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:18]=1[CH:19]=[C:20]([C:28]1[C:29]([NH2:43])=[N:30][CH:31]=[C:32]([C:2]3[CH:3]=[N:4][N:5]([CH:7]4[CH2:13][CH:12]5[N:14]([CH3:15])[CH:9]([CH2:10][CH2:11]5)[CH2:8]4)[CH:6]=3)[CH:33]=1)[N:21]=[CH:22]2
Reactant: CN1C2CCC1CC(n1cc(I)cn1)C2
Reactant: CC1(C)OB(c2cnc(N)c(-c3cc4c(Cl)ccc(F)c4cn3)c2)OC1(C)C
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: O
Solvent: COCCOC
Product: CN1C2CCC1CC(n1cc(-c3cnc(N)c(-c4cc5c(Cl)ccc(F)c5cn4)c3)cn1)C2
Temperature: 100 °C

Procedure:
A solution of 3-(4-iodopyrazol-1-yl)-8-methyl-8-azabicyclo[3.2.1]octane (42.7 mg, 0.135 mmol), 3-(5-chloro-8-fluoroisoquinolin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (0.070 g, 0.18 mmol), potassium carbonate (55.9 mg, 0.404 mmol), and Pd(PPh3)4 (9 mg, 0.008 mmol) in previously degassed DME/Water (4:1) (3.0 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was diluted with EtOAc and washed with H2O (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 10% MeOH in CHCl3], passing through an SCX cartridge, and finally by the MDP. The fractions containing product were combined, concentrated in vacuo, and partitioned between CHCl3 and sat. NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo resulting in the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=1.64-1.72 (m, 2H), 1.77-1.86 (m, 2H), 1.97-2.06 (m, 2H), 2.07-2.17 (m, 2H), 2.26 (s, 3H), 3.20 (br. s., 2H), 4.47 (tt, J=11.7, 5.9 Hz, 1H), 6.89 (br. s., 2H), 7.54 (dd, J=9.9, 8.4 Hz, 1H), 7.87 (s, 1H), 8.03 (dd, J=8.4, 4.8 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.25 (s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.37 (s, 1H), 9.64 (s, 1H). MS (ES+): m/z=463.13/465.15 (76/24) [MH+]. HPLC: tR=1.88 min (ZQ2, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.C(Cl)[Cl:17].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([Cl:17])=[O:15]
Reactant: ClCCl
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 2-(2-fluoro-4-(trifluoromethyl)phenyl)acetic acid (5 g, 22.509 mmol, CASRN 209991-64-0) in DCM (112 mL, 22.509 mmol) was added oxalyl chloride (2.94 mL, 33.8 mmol) and 3 drops of DMF. The solution was stirred at RT overnight and concentrated to dryness to afford 5.2 g (88.2%) of 2-(2-fluoro-4-(trifluoromethyl)phenyl)acetyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH:13]=[C:14]([CH3:16])[CH3:15])[N:7]=1)=[O:5])[CH3:2]>C1COCC1.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][CH:14]([CH3:15])[CH3:16])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)cc(C=C(C)C)n1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)cc(CC(C)C)n1
Temperature: 50 °C
Reaction time: 15 h
Yield: 98.3 %

Procedure:
To a solution of 4-methyl-6-(2-methyl-propenyl)-pyridine-2-carboxylic acid ethyl ester (175 mg, 0.80 mmol) in THF (5 mL) and ethanol (5 mL), Pd/C (50 mg, 10% Pd) is added. The mixture is stirred at 50° C. for 15 h under 1 bar of H2. The catalyst is filtered off over celite and the solvent of the filtrate is evaporated to give 6-isobutyl-4-methyl-pyridine-2-carboxylic acid ethyl ester (174 mg) as a colourless oil; LC-MS: tR=0.84 min, [M+1]+=222.48.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1
Yield: 90 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow foam (90%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:34])[CH2:12][CH2:13][C:14]1[CH:33]=[CH:32][C:17]([C:18]([NH:20][C:21]2[C:22]([OH:31])=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])=O)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]([CH3:34])[CH2:12][CH2:13][C:14]1[CH:33]=[CH:32][C:17]([C:18]2[O:31][C:22]3[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=[CH:30][C:21]=3[N:20]=2)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(CCN(C)C(=O)OCc3ccccc3)cc2)c1O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2nc(-c3ccc(CCN(C)C(=O)OCc4ccccc4)cc3)oc12
Temperature: 110 °C
Yield: 26 %

Procedure:
A mixture of methyl 3-(4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)benzamido)-2-hydroxybenzoate (800 mg, 1.73 mmol) in anhydrous toluene (10 mL) was added anhydrous pyridine (0.76 mL, 9.5 mmol), then thionyl chloride (0.7 ml, 9.5 mmol) was added. The mixture was heated to 110° C. for 2 h. The mixture was cooled to room temperature and poured into ice water (100 mL) carefully with vigorous stirring, then extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give methyl 2-(4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)phenyl)benzo[d]oxazole-7-carboxylate 200 mg, yield 22%). LC-MS (ESI) m/z: 445 (M+1)+.