Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([CH3:30])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>CN(C=O)C.CCOCC.Cl>[CH3:30][C:5]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:40][C:39]3[CH:38]=[CH:37][C:36]([C:35]([F:34])([F:44])[F:45])=[CH:43][CH:42]=3)[C:18](=[O:21])[N:17]2[CH3:22])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:31]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
To a mixture of 54 mg of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester in 2 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 10 mg of NaH (0.253 mmol) is added. The resulting solution is allowed to stand at ambient temperature for 20 min. Then 61 mg of 4-trifluoromethylbenzyl bromide is added and resulting mixture is allowed to stand at ambient temperature for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.3 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 35 mg (49%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, 2H, J=8.0 Hz), 7.35 (d, 2H, J=8.0 Hz), 7.28-7.18 (m, 4H), 7.05 (t, 1H, J=7.2 Hz), 6.91 (d, 2H, J=8.0 Hz), 6.74 (d, 2H, J=8.0 Hz), 5.49 (bs, 1H), 4.45, 4.39 (ABq, 2H, J=15.4 Hz), 3.98 (t, 2H, J=5.8 Hz), 3.77-3.65 (m, 1H), 3.42 (t, 1H, J=8.5 Hz), 3.28, 3.14 (ABq, 2H, J=14.0 Hz), 3.05 (t, 1H, J=8.5 Hz), 2.86 (s, 3H), 2.28-2.20 (m, 1H), 1.95-1.85 (m, 1H), 1.43 (s, 3H). HRMS (ES+) m/z exact mass calcd for C30H32N2O5F3 (m+1) 557.2263, found 557.2257.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:9]([CH3:10])[C:8]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:7]=2[N:6]=1)([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1>C1COCC1.C(O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:15][C:13]2[CH:12]=[CH:11][C:8]3[N:9]([CH3:10])[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:14]=2)[CH:25]=[CH:24][N:23]=1
Reactant: CC(C)Nc1nc2cc(N)ccc2n1C
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Nc1nc2cc(Nc3ccnc(Cl)n3)ccc2n1C
Temperature: 75 °C
Reaction time: 5 h

Procedure:
To a solution of N2-isopropyl-1-methyl-1H-benzimidazole-2,5-diamine (1.46 g, 7.2 mmol) in THF (7 ml) and ethanol (21 ml) was added NaHCO3 (1.81 g, 21.6 mmol) and 2,4-dichloropyrimidine (2.68 g, 18 mmol) and the reaction was heated to 75° C. After 5 h, the reaction was filtered hot and concentrated to a gray foam. Ether was added and the solid was filtered and dried to give N5-(2-chloro-pyrimidin-4-yl)-N2-isopropyl-1-methyl-1H-benzimidazole-2,5-diamine as an off-white solid. N5-(2-chloro-pyrimidin-4-yl)-N2-isopropyl-1-methyl-1H-benzimidazole-2,5-diamine was dissolved in DMF (21 ml) and cesium carbonate (6.84 g, 21 mmol) was added After 15 min, iodomethane (0.70 ml, 11.2 mmol) was added, and the reaction was stirred at rt. After TLC showed the starting material to be consumed, the reaction was diluted with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4 and concentrated to a red foam. The crude material was purified with silica gel to give the title compound as a white solid (1.10 g, 46% over two steps). 1H NMR (300 MHz, d6-DMSO) δ 7.87 (d, J=6.0 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.11 (1.8 Hz, 1H), 6.82 (dd, J=8.1 and 1.8 Hz, 1H), 6.53 (d, J=7.5 Hz, 1H), 6.09 (d, J=6.0 Hz, 1H), 4.04 (m, 1H), 3.51 (s, 3H), 3.37 (s, 3H), 1.23 (d, J=6.6 Hz, 6H). MS (ESI) m/z=331 [M+H]+.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8].O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:41]=[CH:40][C:31]([CH2:32][N:33]3[C:37](=[O:38])[NH:36][C:35](=[O:39])[O:34]3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[O:38]=[C:37]1[NH:36][C:35](=[O:39])[O:34][N:33]1[CH2:32][C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:26][CH2:27][CH:22]([NH:5][CH2:6][C@@H:7]([C:9]3[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=3)[OH:8])[CH2:23][CH2:24]2)=[CH:41][CH:40]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(Cn3oc(=O)[nH]c3=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(Cn4oc(=O)[nH]c4=O)cc3)CC2)ccc1O
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
Acetic acid (0.09 mL, 1.6 mmol) was added to a mixture of N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (197 mg, 0.8 mmol) (which was obtained in Example 10), 2-[4-(4-oxo-1-piperidinyl)benzyl]-1,2,4-oxadiazolidine-3,5-dione (231 mg, 0.8 mmol) (which was obtained in Example 55), and DMF(5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (203 mg, 0.96 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 4/1) to produce an off-white solid (296 mg, 71% yield); mp 193–195° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58–1.62 (m, 2H), 1.96–2.07 (m, 2H), 2.60–2.70 (m, 2H), 2.86–3.17 (m, 6H), 3.72–3.8 (m, 2H), 4.28 (s, 2H), 2.70–2.74 (m, 1H), 6.83–6.87 (m, 3H), 7.03–7.13 (m, 3H), 7.23 (m, 1H), 8.60 (brs, 2H); MS (ES) m/z: 518 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:10][N:11]1[CH2:19][CH2:18][CH2:17][CH:13]([C:14](O)=O)[CH2:12]1.[OH-].[Na+].C(Cl)Cl>O>[CH3:10][N:11]1[CH2:19][CH2:18][CH2:17][CH:13]([C:14]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[N:8]=2)[CH2:12]1
Reactant: CN1CCCC(C(=O)O)C1
Reactant: Nc1cccnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN1CCCC(c2nc3cccnc3[nH]2)C1

Procedure:
Grams 10.9 of 2,3-diaminopyridine and 17,9 g N-methylnipecotic acid hydrochloride are heated at 190° C. for 6 hours. The reaction mixture is cooled and diluted with a small amount of water, then is made alkaline to pH 10 by addition of NaOH and extraction is repeated several times with methylene chloride. The organic extracts, collected together, are evaporated to dryness. The obtained residue, is extracted several times with diethyl ether and the ethereal extracts are evaporated to dryness. The obtained residue, crystallized from acetonitrile, provides 5 g (23% of the theoretical value) 2-(1-methylpiperidin-3-yl)-3H-imidazo-[4,5-b] pyridine melting at 141°-144° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:21]([CH:17]1[C:18]([CH3:20])([CH3:19])[C:16]1([CH3:24])[CH3:15])=[O:22]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3ccc(F)cc23)C1(C)C
Yield: 40 %

Procedure:
A mixture of 5-fluoroindole (0.34 g. 2.5 mmol), ethylmagnesium bromide (1.0 M solution in THF, 3.0 mL, 3.0 mmol), zinc chloride (1.0 M solution in Et2O, 3.0 mL, 3.0 mmol) and the product of Example 1A (3.7 mmol) in 25 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.26 g, 1.0 mmol, 40% yield). MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:21]([O:32][CH3:33])=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:12]=2)[CH:8]=[N:7]1.[CH3:47][C@H:48]1[CH2:50][O:49]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:47][C@@H:48]([OH:49])[CH3:50])[CH2:28][CH2:27]5)=[N:22][C:21]=4[O:32][CH3:33])[CH:18]=3)[N:13]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1nc(N2CCNCC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Reactant: C[C@H]1CO1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(N2CCN(C[C@H](C)O)CC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Yield: 108.2 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (52 mg. 0.081 mmol) was alkylated using (S)-2-methyloxirane (8 mg, 0.137 mmol), DIPEA (18 mg, 0.137 mmol) and ethanol (5 mL) to get 61 mg (95.3%) of the titled compound.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[N:28]1([C:32]([C@@H:34]2[CH2:38][CH:37]([F:39])[CH2:36][NH:35]2)=[O:33])[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:32]([C@@H:34]2[CH2:38][CH:37]([F:39])[CH2:36][N:35]2[C:2]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=3)[NH:4][C:3]2=[O:12])=[O:33])[CH2:31][CH2:30][CH2:29]1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: O=C([C@@H]1CC(F)CN1)N1CCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N2CC(F)C[C@H]2C(=O)N2CCC2)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 2.37 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 10-3 (3.82 g, crude form) as starting materials, respectively 874 mg (Isomer A: colorless solid) and 1.45 g (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:18][C:19]1[NH:23][N:22]=[CH:21][CH:20]=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]([NH:18][C:19]2[NH:23][N:22]=[CH:21][CH:20]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccn[nH]1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1ccn[nH]1)c1cccnc1Cl

Procedure:
175 g. of 2-chloro-3-pyridinecarboxylic acid chloride are dissolved in 750 ml. of anhydrous dioxane containing 110 g. of triethylamine. At 10°, 83 g. of 5-aminopyrazole dissolved in 100 ml. of dioxane are added dropwise with stirring. After the addition is completed, the mixture is stirred overnight at room temperature, filtered and the precipitate washed with dioxane. The solvent is removed in vacuo and the oily residue crystallized with ethyl acetate. The product, 2-chloro-N-(1H-pyrazol-5-yl)-3-pyridinecarboxamide, is recrystallized from ethyl acetate, yield: 103 g. (46%); m.p. 162.8°.
Reaction SMILES: Br[C:2]([CH3:17])([CH3:16])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].[P:18]([O:23]C)([O:21][CH3:22])[O:19][CH3:20]>>[P:18]([O:21][CH3:22])([O:19][CH3:20])([O:4][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[C:2]([CH3:17])[CH3:16])=[O:23]
Reactant: COP(OC)OC
Reactant: COc1ccc2c(C(=O)C(C)(C)Br)n[nH]c2c1
Product: COc1ccc2c(C(OP(=O)(OC)OC)=C(C)C)n[nH]c2c1

Procedure:
The title compound was prepared from 2-bromo-1-(6-methoxy-1H-indazol-3-yl)-2-methylpropan-1-one from the above by heating in excess trimethyl phosphite at 62° C. for 21 hours. Excess trimethyl phosphite was removed by vacuum distillation. The residue was purified on RP-HPLC using 10-90% MeCN gradient in water without TFA. Fractions containing the title compound were pooled, evaporated to dry, and recrystallized from ethyl acetate to give the title compound as colorless crystals. 1H NMR (CDCl3, 500 MHz) δ 11.41 (br s, 1NH), 7.63 (d, 9.0 Hz, 1H), 6.815 (dd, 2.2 & 8.8 Hz, 1H), 6.77 (d, 1.8 Hz, 1H), 3.83 (s, 3H), 3.65 (d, JP-H=11.2 Hz, 6H), 2.04 (d, JP-H=2.5 Hz, 3H), 1.81 (d, JP-H=3.5 Hz, 3H). LC-MS: 2.79 min. (m/Z=201.1, 327.0, 349.2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].O1CCCC1>[C].[Pd].CO>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc([N+](=O)[O-])cc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(N)cc32)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 69.9 %

Procedure:
To a solution of 4-(3-cyano-6-nitroindol-1 yl)benzoic acid ethyl ester (0.11 g) in a mixed solvent of tetrahydrofuran (2 mL) and methanol (2 mL) was added palladium-carbon powder (0.04 g) under an argon atmosphere, and this mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.070 g).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O.[OH-].[Na+].Cl>CO.O>[C:1]1([CH:7]2[O:25][CH:8]2[C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: O=C1NC(=O)C(Cc2ccc(C(=O)/C=C/c3ccccc3)cc2)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1NC(=O)C(Cc2ccc(C(=O)C3OC3c3ccccc3)cc2)S1
Yield: 79.2 %

Procedure:
To a solution of title product of Example 39 (0.5 g, 1.5 mmol) in methanol (4 ml), cooled to 0° C., was added 30% H2O2 (0.5 ml, 4.8 mmol), followed by 2N NaOH (1.6 ml, 3.2 mmol). After 30 minutes at 0° C. the solution was acidified with 2N HCl, diluted with water (15 ml) and extracted with ethyl acetate (2×15 ml). The combined extracts were washed with brine (15 ml), dried over magnesium sulfate and concentrated in vacuo, leaving present title product as an oil (420 mg, 80%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]2[CH2:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][Si](C(C)C)(C(C)C)C(C)C)=[CH:15][N:14]=3)([CH3:12])[O:11][C:7]=2[CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:31]=[CH:30][C:8]2[CH2:9][C:10]([C:13]3[N:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)([CH3:12])[O:11][C:7]=2[CH:6]=1
Reactant: COCOc1ccc2c(c1)OC(C)(c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cn1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCOc1ccc2c(c1)OC(C)(c1ccc(O)cn1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A mixture of 2-(6-(methoxymethoxy)-2-methyl-2,3-dihydrobenzofuran-2-yl)-5-(triisopropylsilyloxy)pyridine (8 g) and tetrabutylammonium fluoride (5.66 g) in THF (30 mL) was stirred at ambient temperature for 30 min. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to afford the title compound (4.66 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]2[C:23]([O:28][CH3:29])=[N:24][CH:25]=[CH:26][CH:27]=2)[N:16]=1>CN(C=O)C>[CH3:29][O:28][C:23]1[C:22]([NH:21][C:17]2[N:16]=[CH:15][N:20]=[C:19]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=4)[CH:3]=[N:2]3)[N:18]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: N#Cc1ccc2cn[nH]c2c1
Reactant: COc1ncccc1Nc1ncnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncccc1Nc1ncnc(-n2ncc3ccc(C#N)cc32)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1H-indazole-6-carbonitrile (70 mg, 0.49 mmol) in DMF (5 mL) was added NaH (60% oil dispersion, 39.12 mg, 0.98 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes before the addition of 4-chloro-N-(2-methoxypyridin-3-yl)-1,3,5-triazin-2-amine (139.45 mg, 0.59 mmol). Stirring at RT was continued for 2 hr. The reaction mixture was then quenched with water and EtOAc was added. Precipitate formed was collected by suction filtration, then redissolved in DCM and washed with water. Further trituration (9:1 mixture of heptane/Et2O) gave the title compound: 1H (250 MHz, CDCl3, VT @ 323K) δ 4.10 (3H, s), 7.06 (1H, br. s.), 7.60 (1H, dd, J=8.22, 1.37 Hz), 7.91 (1H, dd, J=8.22, 0.76 Hz), 7.97 (2H, d), 8.42 (1H, d, J=0.76 Hz), 8.74 (1H, dd, J=7.84, 1.60 Hz), 8.86 (1H, s), 9.20 (1H, s); m/z=+345.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:23]=O.C[O-].[Na+].[BH4-].[Na+]>CO.CC(C)=O>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:23])=[CH:3][CH:4]=2)[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 1,1-dimethylethyl (2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D22) (4.14 g, 13.56 mmol) in dry MeOH (80 mL) at 50° C. under an argon atmosphere was added paraformaldehyde (1.22 g, 40.67 mmol) and sodium methoxide (3.65 g, 67.78 mmol). The mixture was stirred for ˜24 h then sodium borohydride (1.54 g, 40.67 mmol) was added portion-wise and the reaction stirred at 50° C. overnight. After cooling to room temperature, acetone (10 mL) was added and the solvent removed in vacuo. The residue was partitioned between DCM and water and the organic phase was washed with brine, then dried and concentrated. Column chromatography gave the title compound as a colourless, crystalline solid (3.73 g). δH (CDCl3, 400 MHz) 7.13 (2H, d), 6.57 (2H, d), 4.16 (1H, br.s), 3.78 (1H, d), 3.67 (1H, br.s), 3.42 (1H, d), 3.30 (1H, d), 3.08 (1H, td), 2.83 (3H, s), 2.75 (1H, m), 2.59 (1H, m), 2.06 (1H, dd), 1.94 (1H, m), 1.45 (9H, s), 1.21 (3H, d).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8]C(=O)O[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.CN(C=O)C>O>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([Br:14])=[CH:16][CH:17]=1)=[O:12]
Reactant: Nc1ccc(Br)cc1
Reactant: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Cl)cccc1C(=O)Nc1ccc(Br)cc1
Temperature: 130 °C

Procedure:
A mixture of 8-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (0.80 g, 4.05 mmol) and 4-bromoaniline (0.70 g, 4.05 mmol) with anhydrous DMF (1 mL) was heated at 130° C. for 2 hours. Water (50 mL) was added, and the product was extracted with ethyl acetate (200 mL). The organic phase was separated, washed with water (100 mL), brine (100 mL) and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo, and the crude material was washed with ether, to give 2-amino-N-(4-bromophenyl)-3-chlorobenzamide as an off-white solid. Yield 1.17 g (89%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Ni]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(OCc2ccc(F)cc2)cc1

Procedure:
1-Nitro-4-(4-fluorobenzyloxy)-benzene (2.37 g) was dissolved in 200 ml of methanol and catalytic amount of Raney Ni was added. The mixture was stirred at room temperature under atmospheric pressure in a hydrogen atmosphere for 3 hours. After filtering off Raney Ni over Celite and washing with methanol, the obtained filtrate was concentrated under reduced pressure to give a solid product 4-(4-fluoro-benzyloxy)-aniline, which is pure enough for next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.[CH2:10](OC(OCC)OCC)C>>[Cl:1][C:2]1[N:3]2[CH:10]=[N:9][N:8]=[C:4]2[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Cl)n1
Reactant: CCOC(OCC)OCC
Product: Clc1cccc2nncn12
Temperature: 25 °C
Yield: 53.8 %

Procedure:
Charge a 125 mL round-bottomed flask with 2-chloro-6-hydrazinylpyridine (3.0 g, 20.9 mmol), triethoxymethane (20 mL, 120.2 mmol). The mixture was heated at reflux for 4 hours and allowed to cool to ambient temperature overnight. The mixture was concentrated to dryness and 50 ml POCl3 was added. The mixture was refluxed overnight. The reaction was quenched over ice and washed with CH2Cl2. The aqueous layer was adjusted to pH 6 with 1N NaOH and extracted with CH2Cl2 and the organics concentrated and purified on Si gel eluting with 100% EtOAc (500 ml) followed by 5% MeOH/CH2Cl2 to give 5-chloro-[1,2,4]triazolo[4,3-a]pyridine (1.73 g, 11.25 mmol, 53% yield) as a solid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N:22]1([CH2:31]O)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1>CCO>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:31][N:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=[N:23]3)[CH2:17]2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: OCn1nnc2ccccc21
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Solvent: CCO
Product: CCCCCCCCOc1ccc(C2CN(Cn3nnc4ccccc43)CCO2)cc1
Temperature: 50 °C

Procedure:
To a solution of 2-(4-octyloxy-phenyl)-morpholine (0.75 g; 2.6 mmol) in EtOH (10 mL) was added 1H-benzotriazole-1-methanol (0.38 g; 2.6 mmol), and the reaction mixture was heated at 50° C. for 20 minutes. After cooling to RT, the solvent was removed in vacuo to afford 1-[2-(4-octyloxy-phenyl)-morpholin-4-ylmethyl]-1H-benzotriazole; which was used as such.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=1)[CH:17]=[CH2:18]>>[CH2:16]([O:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:11]=[C:12]2[CH3:15])[N:21]=1)[CH:17]=[CH2:18]
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: C=CCOc1cncc(Cl)n1
Product: C=CCOc1cncc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)n1

Procedure:
The title compound, white cristalline solid, MS: m/e=351.2, 353.2 (M+H+), was prepared in accordance with the general method of example 1b from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-Allyloxy-6-chloro-pyrazine (CAS: [107466-49-9].