Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[C@@H:12]([CH2:22][O:23]CC2C=CC=CC=2)[O:11][C@H:10]1[N:31]1[CH:39]=[N:38][C:37]2[C:32]1=[N:33][C:34]([F:41])=[N:35][C:36]=2[NH2:40])C1C=CC=CC=1.C([O-])(O)=O.[Na+].C>C(Cl)Cl.CCO>[C@@H:10]1([N:31]2[CH:39]=[N:38][C:37]3[C:32]2=[N:33][C:34]([F:41])=[N:35][C:36]=3[NH2:40])[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@@H:9]1[OH:8]
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
BCl3 gas (72.9) was bubbled in CH2Cl2 (610 ml) at 0°in a 2-l., 3-necked flask equipped with a thermometer, magnetic stirrer, and addition funnel and the stirred solution then cooled to -72° (dry ice-acetone) before the dropwise addition (1 hr) of a cold solution of 9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-2-fluoroadenine (II, 7.0 g, 12.5 mmol) in CH2Cl2 (70 ml). After a total reaction time of 23/4 hr, the cooling bath was removed and the solvent and gas removed in vacuo. The residue was dissolved in CH2Cl2 (40 ml) and the solution evaporated to dryness (six times), or until a solid white residue is obtained, before adding 450 ml of 5% NaHCO3 followed by solid NaHCO3 to adjust the pH to 6-7. The mixture was diluted with EtOH, heated to boiling, treated with charcoal, filtered through Celite, and then allowed to stand at room temperature overnight. It was then chilled and the solid collected by filtration, washed with cold H2O and then ether, and dried in vacuo; yield 3.23 g (91%); mp 259°-260°; homogeneous according to TLC (19:1) and HPLC (23 H2O:2 MeCN); pmr; 3.7 (m, H4' and 2H5'), 4.15 (m, H2' and H3'), 5.1 (t, 5'-OH), 5.55 and 5.65 (2d, 2'-OH and 3'-OH), 6.14 (d, J1'2' 3Hz, H1'), 7.8 (broad s, NH2), 8.2 (s, H8); uv: pH 1--262 (13.2); ph 7, 13--261 (15.3).
Reaction SMILES: [OH:1][C@H:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[N:13]3[CH2:17][CH2:18][NH:19][C:12]3=[N:11][C:10]=2[N:9]([CH3:20])[C:8]1=[O:21].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C)C=O>[CH3:20][N:9]1[C:10]2[N:11]=[C:12]3[NH:19][CH2:18][CH2:17][N:13]3[C:14]=2[C:15](=[O:16])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([O:1][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH3:22])[C:8]1=[O:21]
Reactant: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.2 %

Procedure:
To the stirring solution of (R)-7,8-dihydro-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (CT-13430) (200 mg, 0.65 mmol) and imidazole (68 mg, 1.0 mmol) in dimethylformamide (1 ml) was added tert-butyidimethylsilyl chloride (127 mg, 1.30 mmol). After stirred at room temperature for 16 hours, the reaction mixture was treated with water and extracted with ethyl acetate (2×15 ml). The combined extracts were washed with water (2×5 ml), with saturated aqueous sodium chloride solution (5 ml), and dried over magnesium sulfate. Concentrating under reduced pressure to provide (R)-7,8-dihydro-1-methyl-3-(5-tert-butyldimethylsilyloxyhexyl)-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (280 mg, 100% yield) as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][NH:22][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([OH:23])=[CH:25][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Product: O=C(NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)c1ccc(O)cc1

Procedure:
The N-(1,4-Dibenzyl-piperazin-2-ylmethyl)-4-hydroxy-benzamide was prepared from C-(1,4-Dibenzyl-piperazin-2-yl)-methylamine and 4-hydroxybenzoic acid as described in EXAMPLE 1, Step 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:24])[CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35]I>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:12][CH2:13][CH:14]([CH2:17][C:18](=[O:24])[CH:19]([S:20]([CH3:23])(=[O:22])=[O:21])[CH3:35])[CH2:15][CH2:16]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CS(=O)(=O)CC(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)S(C)(=O)=O
Reaction time: 1.5 h
Yield: 44.7 %

Procedure:
The product from Example 134 (28 mg, 0.056 mmol) in 1,2-dimethoxyethane (3 mL) was treated with sodium hydride (60% dispersion in mineral oil, 2 mg, 0.056 mmol) at room temperature. After stirring for 1.5 hours, methyl iodide (6 μL, 0.056 mmol) was added and the reaction stirred for 18 hours, then quenched with saturated aqueous ammonium chloride solution. The reaction was then extracted into ethyl acetate, dried (MgSO4) and evaporated to a white solid which was purified by column chromatography on silica eluting with 35% ethyl acetate/iso-hexane to yield the desired product as a white solid (13 mg).
Reaction SMILES: [OH:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6](OC)[C:3]=1[C:4]#[N:5].O.[NH2:13][NH2:14]>>[NH2:5][C:4]1[C:3]2[C:2]([OH:1])=[N:9][CH:8]=[CH:7][C:6]=2[NH:14][N:13]=1
Reactant: COc1ccnc(O)c1C#N
Reactant: NN
Solvent: O
Product: Nc1n[nH]c2ccnc(O)c12
Temperature: 140 °C

Procedure:
A mixture of 1.2 g of 2-hydroxy-4-methoxynicotinonitrile and 30 mL of hydrazine hydrate is maintained at 140° C. for 18 hours in a bomb. The reaction medium is then evaporated to dryness. The residue is taken up in ethyl ether, and the resulting suspension is filtered. 1.1 g of 3-amino-1H-pyrazolo[4,3-c]pyrid-4-ol are obtained in the form of a grey solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:11]([O:12]C)=[C:8]([O:9]C)[CH:7]=1)[CH3:2].[BrH:16]>C(O)(=O)C>[BrH:16].[CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:11]([OH:12])=[C:8]([OH:9])[CH:7]=1)[CH3:2]
Reactant: CCNCCc1ccc(OC)c(OC)c1
Agent: Br
Solvent: CC(=O)O
Product: CCNCCc1ccc(O)c(O)c1
Reaction time: 5 h

Procedure:
After dissolving 1.0 g of N-ethyl-homoveratrylamine in a solvent mixture consisting of 6 ml of a 48% aqueous hydrogen bromide solution and 4 ml of acetic acid, the solution was heated at 120°-130° C. with stirring for 5 hours. The solvent was distilled off and the residue was crystallized from ether to obtain 1.2 g of crude crystals. N-Ethyl-3,4-dihydroxyphenethylamine hydrobromide having a melting point of 149°-151° C. was obtained by recrystallizing from isopropyl alcohol. The yield was 0.68 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH3:24])[CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH3:24])[CH2:22][CH2:23]3)[C:17]([NH:28][C:29]3[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=3)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CC2(C)CC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
95.0 mg (246 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)propanoic acid (racemate), 47.5 mg (246 μmol) of tert-butyl 4-aminobenzoate, 34.9 mg (246 μmol) of Oxima and 38.3 μl (246 μmol) of DIC in 2.5 ml of dimethylformamide were reacted according to General Method 5B. Yield: 101 mg (66% of theory)
Reaction SMILES: C(OC([NH:8][CH:9]([P:19]([O:23][CH3:24])([O:21][CH3:22])=[O:20])[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=O)(C)(C)C.C(OC(=O)[NH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)=[CH:34][C:33]=1[NH2:43])(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][O:23][P:19]([CH:9]([NH2:8])[C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:43][C:33]2[CH:34]=[C:35]([C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)[CH:36]=[CH:37][C:32]=2[NH2:31])=[CH:17][CH:18]=1)(=[O:20])[O:21][CH3:22]
Reactant: COP(=O)(OC)C(NC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COP(=O)(OC)C(N)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[tert-Butoxycarbonylamino-(dimethoxy-phosphoryl)-methyl]-benzoic acid (76 mg, 0.212 mmol), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (74 mg, 0.254 mmol), EDC (61 mg, 0.317 mmol), HOBT (39 mg, 0.254 mmol), and DIPEA (82 mg, 0.635 mmol) were combined and diluted with DMF (0.85 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was purified directly by HPLC (20-85% MeCN in water w/0.025% TFA). Pure fractions were identified, combined, then concentrated in vacuo. The residue was diluted with 10:1 DCM:TFA and stirred at ambient temperature. After 2 h the mixture was concentrated in vacuo to give the title compound: 1H NMR (DMSO-d6, 600 MHz) 9.81 (s, 1H), 9.06 (br-s, 2H), 8.05 (d, J=9.0 Hz, 2H), 7.62 (d, J=9.0 Hz, 2H), 7.44-7.46 (m, 1H), 7.34-7.36 (m, 1H), 7.29-7.32 (m, 1H), 7.22-7.24 (m, 1H), 7.03-7.05 (m, 1H), 6.82 (d, J=7.8 Hz, 2H), 5.20 (d, J=17.4 Hz, 1H), 3.73 (d, J=10.8 Hz, 3H), 3.58 (d, J=10.8 Hz, 3H). MS: cal'd 432 (MH+), exp 432 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([OH:26])=O)=[N:13]2)=[O:10])=[CH:4][CH:3]=1.[CH3:27][C:28]([CH3:32])([CH3:31])[CH2:29][NH2:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[N:13]=[C:14]([CH2:23][C:24]([NH:30][CH2:29][C:28]([CH3:32])([CH3:31])[CH3:27])=[O:26])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]2=[O:22])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: CC(C)(C)CN
Product: CC(C)(C)CNC(=O)Cc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product of Example 114 and 2,2-dimethylpropan-1-amine were treated using a method similar to that described in Example 112 to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.48-8.41 (m, 1H), 8.30 (bs, 1H), 7.97 (d, J=8.0, 1H), 7.92-7.76 (m, 2H), 7.38 (bs, 4H), 6.11-5.98 (m, 1H), 3.89 (s, 2H), 3.80 (bs, 2H), 3.02 (d, J=6.3, 2H), 0.80 (s, 9H); MS (ESI−) M/Z 439 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1.C(N(CC)CC)C>CN(C=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:30])([F:31])[F:32])=[CH:12][N:11]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Temperature: 30 °C
Yield: 65.1 %

Procedure:
tert-Butyl 4-(3-methoxy-4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I28) (5.52 g, 8.84 mmol) was dissolved in DMF (250 mL) then triethylamine (1 mL) and Pd/C (2.50 g) were added and the mixture stirred at 30° C. under hydrogen. After 16 hours the mixture was filtered through celite and the celite washed with DMF (250 mL). Triethylamine (1 mL) and Pd/C (2.50 g) were added to the combined filtrates and the mixture stirred at 30° C. under hydrogen. After 18 hours the resulting mixture was filtered through celite washing with ethyl acetate (300 mL). The filtrate was divided into two lots; each was poured into water (800 mL) and the resulting mixture extracted with ethyl acetate (3×300 mL). The ethyl acetate extracts from each lot were combined, washed with water (2×500 mL) and brine, dried (sodium sulfate) and evaporated. The two workups were combined and chromatographed (120 g silica cartridge, 0-20% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I21) (3.620 g, 65% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.37 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 7.29-7.18 (m, overlaps with CHCl3), 6.85 (dd, J=8.3, 1.8 Hz, 1H), 6.77 (d, J=1.8 Hz, 1H), 4.26 (s, 2H), 3.93 (s, 3H), 3.68 (s, 3H), 3.19-3.01 (m, 4H), 2.81 (t, J=12.7 Hz, 2H), 2.64 (tt, J=12.0, 3.5 Hz, 1H), 1.85 (d, J=13.3 Hz, 2H), 1.70-1.57 (m, overlaps with water), 1.49 (s, 9H). LCMS Method C: rt 7.14 min; m/z 629.2 [M+H]+, 573.1 [M-tBu+2H]+; m/z 627.2 [M−H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:17][CH2:18][CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:8][CH2:7]1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
A solution of the product from Example 1 step (ii) (2.0 g), 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione (1.61 g) and triethylamine (2.5 ml) in dichloromethane (40 ml) was heated under reflux for 48 h. The reaction mixture was partitioned between ethyl acetate/water, the organic layer dried and evaporated under reduced pressure. Purification was by chromatography eluting with 4% methanol/dichloromethane. Yield 0.839 g
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([C:19]2[C:20](=[S:25])[NH:21][CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1.[C:26]([NH:29][C:30]1[N:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=1)(=[O:28])[CH3:27].C(OCC)(=O)C>CN(C)C=O>[C:26]([NH:29][C:30]1[N:35]=[C:34]([CH2:36][S:25][C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH3:8])[CH:10]=3)=[O:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][N:31]=1)(=[O:28])[CH3:27]
Reactant: Cc1cc(C)cc(NC(=O)c2ccc[nH]c2=S)c1
Reactant: CC(=O)Nc1nccc(CCl)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nccc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)n1
Yield: 52 %

Procedure:
Triethylamine (45 mL, 0.32 mmol) was added to a solution of N-(3,5-dimethylphenyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide (28 mg, 0.11 mmol, Reference Compound No. 13-1) and 2-acetylamino-4-(chloromethyl)pyrimidine (18 mg, 0.10 mmol, Reference Compound No. 11-1) in anhydrous N,N-dimethylformamide (1.0 mL) at room temperature, and the mixture was stirred for 16 hours. Ethyl acetate (30 mL) was added thereto, then the whole was washed with saturated aqueous sodium hydrogencarbonate solution (30 mL) and brine (30 mL), and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the precipitated solid was filtered off with diethyl ether and washed. The solid was dried at 50° C. under reduced pressure to give 21 mg of the target compound as a light orange solid (Yield: 52%).
Reaction SMILES: [N:1]1(C(N2C=CN=C2)N)C=CN=[CH:2]1.[CH3:13][O:14][C:15](=[O:25])[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([OH:23])[C:17]=1[NH2:24]>C1COCC1>[NH2:1][C:2]1[O:23][C:18]2[C:17](=[C:16]([C:15]([O:14][CH3:13])=[O:25])[CH:21]=[C:20]([F:22])[CH:19]=2)[N:24]=1
Reactant: COC(=O)c1cc(F)cc(O)c1N
Reactant: NC(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)cc2oc(N)nc12
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a solution of di(1H-imidazole-1-yl)methanamine (1.05 g, 6.52 mmol) in THF (30 mL) was added methyl-2-amino-5-fluoro-3-hydroxybenzoate (0.96 g, 5.22 mmol) at room temperature and the resulting reaction mixture was heated to reflux for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with H2O (4×100 mL), saturated aqueous ammonium chloride (2×100 mL), brine (2×100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford methyl 2-amino-6-fluorobenzoxazole-4-carboxylate (0.95 g, 87%). 1H NMR and MS consistent.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][CH:15]=O)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:2].Cl>C1COCC1.CO>[CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccccc2NC=O)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Oc2ccccc2NC)c(OC)c1
Temperature: 0 °C
Yield: 122.1 %

Procedure:
To a solution of N-[2-(4-ethyl-2-methoxyphenoxy)phenyl]formamide (0.21 mmol; 72 mg), under argon, in dry THF was added at 0° C., borane dimethylsulfide complex (0.51 mmol, 49 μL). The reaction was stirred at reflux for 3 h 30. After cooling to 0° C., the mixture was diluted with 1 mL of dry methanol and stirred 1 hour. HCl (4M in dioxane) was added at 0° C. until pH 2, then the mixture was refluxed 1 hour. After cooling to room temperature, the reaction was diluted with 5 mL of methanol and concentrated in vacuo. The crude was treated with 5 mL of NaOH (1N), until pH 12, and extracted with ethyl acetate (3*2 mL). Combined organic phases were dried over Na2SO4 and concentrated in vacuo to yield the title compound (66 mg, quantitative) as a red oil used without further purification.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]=[CH:6][C:7]([NH:10]C(=O)C(C)(C)C)=[N:8][CH:9]=1)[CH3:3].C(=O)([O-])[O-].[K+].[K+]>CO.[Cl-].[Na+].O>[NH2:10][C:7]1[N:8]=[CH:9][C:4]([CH:2]([OH:1])[CH3:3])=[N:5][CH:6]=1
Reactant: CC(O)c1cnc(NC(=O)C(C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(O)c1cnc(N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of N-[5-(1-hydroxyethyl)pyrazin-2-yl]-2,2-dimethylpropanamide (394 mg) in methanol (10 mL) was added potassium carbonate (249 mg) at room temperature, followed by stirring at room temperature overnight and stirring at 60° C. for 5 hours. Further, potassium carbonate (249 mg) was added thereto, followed by stirring at 60° C. for 3 hours. After leaving it to be cooled to room temperature, saturated brine was added to the reaction mixture, followed by extraction with a solvent (chloroform:isopropyl alcohol=4:1). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained solid was collected by filtration while washing with a solvent (hexane:diisopropyl ether=1:1), to obtain 1-(5-aminopyrazin-2-yl)ethanol (187 mg) as a pale yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19]([CH3:32])[C:18](=[O:33])[N:17]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH2:38]([O:37][C:35](=[O:36])[CH2:34][N:17]1[C:16]2[N:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]=2[C:20](=[O:31])[N:19]([CH3:32])[C:18]1=[O:33])[CH3:39]
Reactant: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2CC(=O)OCC
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1ccccc1-n1c(N2CCNCC2)nc2c1c(=O)n(C)c(=O)n2CC(=O)OCC

Procedure:
4-[3-Ethoxycarbonylmethyl-1-methyl-2,6-dioxo-7-(2-vinylphenyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (8 mg) was dissolved in trifluoroacetic acid and the solution was concentrated. The residue was purified by reversed phase high performance liquid chromatography to give 2.68 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[N:6]=[N:7][CH:8]=1.C(=O)(O)[O-].[Na+].[CH2:17](O)[CH3:18]>O>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[N:7][N:6]2[CH:17]=[CH:18][N:9]=[C:5]2[CH:4]=1
Reactant: Nc1cc(C(F)(F)F)cnn1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1cnn2ccnc2c1
Temperature: 130 °C

Procedure:
5-(Trifluoromethyl)pyridazin-3-amine (6.79 g, 41.6 mmol) was dissolved in a mixture of ethanol (133 mL) and water (33.3 mL) and 50% aq. solution of chloroacetylaldehyde (26.9 mL, 208 mmol) and sodium bicarbonate (17.5 g, 208 mmol) was added. The reaction was sealed in a pressure vessel and heated to 130° C. for 6 h. The reaction was then cooled to room temperature. Water was added and the mixture filtered through celite. The aqueous layer was extracted with a 3:1 mixture of CHCl3:Isopropanol (×3). The organic layers were collected, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound as an orange solid. 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H); 8.27 (s, 1H); 8.13 (s, 1H); 7.97 (s, 1H). LRMS (APCI) calc'd for (C7H4F3N3) [M+H]+, 187.1. found 187.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[N:11]([CH2:22][C:23](O)=[O:24])[C:10](=[O:26])[C@H:9]1[CH2:27][CH:28]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=O)(C)(C)C.[NH2:35][C:36]1[CH:37]=[C:38]2[C:51](=[CH:52][CH:53]=1)[CH2:50][C@:40]1([C:48]3[C:43](=[N:44][CH:45]=[CH:46][CH:47]=3)[NH:42][C:41]1=[O:49])[CH2:39]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH:28]1([CH2:27][C@H:9]2[NH:8][CH2:13][CH:12]([C:14]3[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=3)[N:11]([CH2:22][C:23]([NH:35][C:36]3[CH:37]=[C:38]4[C:51](=[CH:52][CH:53]=3)[CH2:50][C@:40]3([C:48]5[C:43](=[N:44][CH:45]=[CH:46][CH:47]=5)[NH:42][C:41]3=[O:49])[CH2:39]4)=[O:24])[C:10]2=[O:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)[C@H]1CC1CCCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)[C@@H](CC2CCCCCC2)NCC1c1cc(F)cc(F)c1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
0.20 g (0.42 mmol) 2-((3R)-4-(tert-butoxycarbonyl)-3-(cycloheptylmethyl)-6-(3,5-difluorophenyl)-2-oxopiperazin-1-yl)ethanoic acid (isomer 4.1.1.1), 0.11 g (0.45 mmol) (R)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 0.11 g (0.55 mmol) 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 74 mg (0.55 mmol) HOBT, 0.06 ml (0.45 mmol) TEA and 2.0 ml DMF were stirred overnight at RT. The reaction mixture was concentrated by rotary evaporation. The residue was stirred with 15 ml of a 1.25M methanolic hydrochloric acid for 1 h at 50° C. The mixture was concentrated by rotary evaporation and the residue was purified by HPLC. The product-containing fractions were combined and lyophilised.