Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:23]([N:15]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([NH2:22])=[C:21]2[C:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:14]1)([CH3:25])[CH3:24]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: COc1cccc(B(O)O)c1
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Temperature: 80 °C

Procedure:
A solution of 3-Methoxyphenylboronic acid (17 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA49. ESI-MS (M+H)+ m/z calcd 284.1, found 284.0.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8](=[O:11])[CH2:9][Cl:10])[N:6]=1.C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[Cl:10][CH2:9][C:8]([NH:7][C:5]1[N:6]=[CH:2][S:3][CH:4]=1)=[O:11]
Reactant: [H][H]
Reactant: O=C(CCl)Nc1csc(Br)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CCl)Nc1cscn1
Yield: 57.9 %

Procedure:
A solution of 2-bromo-4-chloroacetamidothiazole (4 g) and sodium acetate (1.15 g) in methanol (100 ml) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst (1 g) until theoretical uptake of hydrogen had occurred. The catalyst was removed by filtration and washed with methanol and the extracts evaporated to dryness in vacuo. The residue was recrystallised twice from carbon tetrachloride to give the title compound (1.6 g) m.p. 115°-119° C. (Found: C, 33.7; H, 2.9; N, 15.5. C5H5ClN2OS requires C, 34.0; H, 2.9; N, 15.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[NH:7])=[CH:4][CH:3]=1.C([Li])CCC.Cl[P:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[N:7][P:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:17][CH:18]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(=N)Nc2c(C)cccc2C)cc1
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(c2ccccc2)c2ccccc2)Nc2c(C)cccc2C)cc1
Reaction time: 1 h

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.19 g of 4-methyl-N1-(2,6-dimethylphenyl)benzamidine (Amidine III, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, the oily product was treated with 20 mL of pentane. After 1 hour stiffing at room temperature, a white solid formed. The solution was concentrated to approximately 10 mL and filtered while cold, yielding 1.64 g (78%) after drying.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:15])[NH:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:15])[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: Cc1c[nH]c(=O)c(-c2ccc(Cl)cc2)c1
Product: Cc1cc(-c2ccc(Cl)cc2)c(=O)n(-c2ccccc2)c1
Yield: 82 %

Procedure:
3-(4'Chlorophenyl)-5-methyl-1-phenyl-2-(1H)-pyridone is prepared in 82% yield by the reaction of 3-(p-chlorophenyl) -5-methyl-2-(1H)-pyridone (B. E. Witzel et al. Brit. Pat. No. 1,238,959) with iodobenzene as described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:15][NH:16][CH:17]([CH:30]([CH3:32])[CH3:31])[C:18]([N:20]([CH3:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:19])=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(O)(C)C.[N:37]#[C:38]Br.[Cl:40]CCl>>[ClH:40].[NH2:37][C:38]1[N:16]([CH:17]([CH:30]([CH3:32])[CH3:31])[C:18]([N:20]([CH3:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:19])[CH2:15][C:3]2[CH:4]=[C:5]([O:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CC(C)C(NCc1cc(Oc2ccccc2)ncc1N)C(=O)N(C)CCc1ccccc1
Reactant: ClCCl
Reactant: N#CBr
Solvent: CC(C)O
Product: CC(C)C(C(=O)N(C)CCc1ccccc1)N1Cc2cc(Oc3ccccc3)ncc2N=C1N
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-[(5-amino-2-phenoxy-pyridin-4-ylmethyl)-amino]-3,N-dimethyl-N-phenethyl-butyramide (1.69 g, 3.9 mmol) and isopropyl alcohol (10 mL) was added cyanogen bromide in dichloromethane (1.3 mL, [3M]) and the resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated to yield a brown solid. The brown solid was purified by reverse phase chromatography. The solvent was evaporated from the desired fractions, and the solute was treated with 1N HCl to yield the title compound as a solid, as its corresponding hydrochloride salt.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][C:7]2=O)([OH:3])=[O:2].P(Cl)(Cl)([Cl:23])=O.CN(C)[CH:28]=[O:29]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]([CH:28]=[O:29])=[C:7]2[Cl:23])([OH:3])=[O:2]
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC(c1ccccc1)O2
Product: O=CC1=C(Cl)c2cc(C(=O)O)ccc2OC1c1ccccc1
Reaction time: 3 h

Procedure:
As in example 1, but using 6 g 6-carboxy-flavanone, 60 ml dimethylformamide and 15 ml phosphorous oxychloride. Reaction time is three hours at 50° C. After hydrolysis a precipitate formed which is filtered, washed with water and dried over phosphorous pentoxyde. The residual solid is dissolved in a 10% sodium bicarbonate aqueous solution, which is then washed with methylene chloride. The aqueous phase is acidified with a 10% hydrochloric acid solution and the precipitate which formed is filtered, washed and dried. The residual solid is recrystallised in a mixture of hexane and ethyl acetate and pure 6-carboxy-4-chloro-3-formyl-flav-3-ene is obtained; m.p. 262°-267° C.
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][O:20][C:21]1[S:25][C:24]([C:26](O)=[O:27])=[N:23][CH:22]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:26]([C:24]3[S:25][C:21]([O:20][CH3:19])=[CH:22][N:23]=3)=[O:27])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: COc1cnc(C(=O)O)s1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: COc1cnc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)s1
Yield: 9 %

Procedure:
(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (86 mg, 0.33 mmol) was coupled with 5-methoxythiazole-2-carboxylic acid (90 mg, 0.40 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: silica, eluent: 0-10% MeOH in DCM) to yield 12 mg (9%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 3.99 (s, 3H), 4.26 (dd, 1H), 4.40-4.46 (m, 1H), 4.49-4.59 (m, 1H), 6.63 (d, 1H), 7.22 (s, 1H), 7.49 (d, 1H), 7.68 (d, 1H), 7.78 (dd, 1H), 8.10 (broad d, 1H) overlapping with 8.13 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:5]([N:8]([CH2:19][C:20](=O)[CH3:21])[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])([CH3:7])[CH3:6].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:5]([N:8]1[CH2:19][C:20]([CH3:21])=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:9]1=[O:18])([CH3:7])[CH3:6]
Reactant: CC(=O)CN(C(=O)Cc1ccccc1F)C(C)(C)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2cc(Cl)cc(Cl)c2)C1
Yield: 48.2 %

Procedure:
6.8 g (17 mmol) of N-(3,5-dichloro-α,α-dimethylbenzyl)-N-(2-oxopropyl)-2-fluorophenylacetamide (having a melting point of from 167 to 170° C.) prepared in accordance with the method of Reference Example 8, was dissolved in 30 ml of ethanol, and 0.7 g (11 mmol) of sodium hydroxide powder was-added thereto. The mixture was refluxed under heating for 10 minutes. The reaction solution was cooled, and then ethanol was distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The crude crystals thereby obtained was recrystallized from methanol to obtain 3.1 g (yield: 49%) of the desired compound as colorless crystals.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OCC)(=[O:24])[CH:22]=[CH2:23].CCCCCCC>C(O)C.C(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4=[N:18][C:21](=[O:24])[CH2:22][CH2:23][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NCC(COc2ccc(C3CCCCC3)cc2)O1
Reactant: C=CC(=O)OCC
Solvent: CCO
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=C1CCN2CC(COc3ccc(C4CCCCC4)cc3)OC2=N1
Temperature: 150 °C
Yield: 26.2 %

Procedure:
To a solution of 5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (350 mg, 1.28 mmol) in ethanol (6 mL) was added ethyl acrylate (255.8 mg, 2.56 mmol). The reaction mixture was heated in a microwave oven at 150° C. for 40 min. The solvent was removed under vacuum, and the residue purified via flash column chromatography (silica gel, 0.5-12% EtOH/CH2Cl2) to afford an oil, which was dissolved in a small amount of methylene chloride and to which was then added heptane. A white solid precipitated to afford 110 mg of 2-(4-cyclohexyl-phenoxymethyl)-2,3,5,6-tetrahydro-oxazolo[3,2-a]pyrimidin-7-one.
Reaction SMILES: [OH-].[Na+].[ClH:3].[CH3:4][N:5]([CH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)[C:9]1=O)[CH3:6]>>[ClH:3].[CH3:6][N:5]([CH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)[CH2:9]1)[CH3:4]
Reactant: COc1ccc2c(c1)C(=O)C(CN(C)C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)CC(CN(C)C)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
1 N Sodium hydroxide was added to 2-(N,N-dimethylamino)methyl-7-methoxy-1-tetralone hydrochloride (8.46 g) to convert it into a free compound, which was extracted with ethyl acetate. The extract was dried, and then concentrated. Sodium borohydride (2.32 g) was added to a methanol solution (150 ml) of the resulting residue, with cooling with ice, which was then stirred at room temperature for 12 hours. Water was added to the reaction mixture, which was concentrated under reduced pressure, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried, and concentrated. Concentrated hydrochloric acid (6.4 g) and 10% palladium-carbon (0.7 g) were added to an ethanol solution (100 ml) of the resulting residue, which was thus catalytically reduced under a hydrogen pressure of 5 atmospheres at 60° C. for 8 hours. The catalyst was removed from the reaction mixture through filtration, and the filtrate was concentrated. The residue was recrystallized from methanol-ethyl acetate to obtain the entitled compound (6.53 g).
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1.[NH2:18][C@@H:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[CH2:39]([O:38][CH2:37][C@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][O:2]2)[CH2:13][CH2:12]1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)CN1CCN(CC2CCCO2)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCN(CC2CCCO2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 48.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 110, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)acetamido)propanamide (23.1 mg, 48.9%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.92 (d, 1H), 7.60 (d, 2H), 7.29 (m, 5H), 7.21 (t, 2H), 7.03-6.97 (m, 4H), 4.69 (m, 1H), 4.52 (s, 2H), 3.89 (m, 1H), 3.79-3.68 (m, 3H), 3.59 (m, 1H), 2.96 (s, 2H), 2.45 (m, 5H), 2.34 (m, 5H), 1.89 (m, 1H), 1.76 (m, 2H), 1.44 (m, 1H). MS (EI) for C33H39FN4O5. found 591.7 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:8]2[N:9]([C:13]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][NH2:32])[CH2:27][CH2:26]3)=[N:14][C:15]=2[C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:11][N:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:6][C:7]1[C:8]2[N:9]([C:13]([CH:25]3[CH2:26][CH2:27][CH:28]([CH2:31][NH:32][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:29][CH2:30]3)=[N:14][C:15]=2[C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:11][N:12]=1
Reactant: NC[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NCC1CCC(c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (4.40 μL, 0.057 mmol was added to a mixture of 1-{trans-4-[8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanamine (20.5 mg, 0.057 mol) and PS-DIEA (3.90 mmol/g loading; 60 mg, 0.2mmol) in DCM (1.14 mL). The reaction mixture was stirred for 30 min at r.t. for 18 h. The crude reaction mixture was then concentrated and residue purified by mass directed preparative HPLC to afford 4 mg of desired product. MS (ES+): m/z 439.10 (100) [MH+]. 1H NMR (CD3OD, 400 MHz): δ 8.24 (br s, 2H), 7.61 (m, 2H), 7.46 (dd, J=8.4, 0.8 Hz, 1H), 7.19 (ddd, J=7.2, 1.2, 1.2 Hz, 1H), 7.08 (ddd, J=7.2, 1.2, 1.2 Hz, 1H), 6.75 (d, J=0.8 Hz, 1H), 3.14 (m, 1H), 2.07 (m, 4H), 1.85 (m, 2H), 1.64 (m, 1H), 1.26 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[CH2:29][CH2:28]3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[CH2:31][CH2:32]3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-(4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.052 g, 0.088 mmol) in dichloromethane (2 mL) and the resulting solution was stirred at room temperature for 30 min. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 30% methanol in dichloromethane) to give the title compound as a white solid (0.025 g, 0.052 mmol, 57%). 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1 H), 7.58 (d, J=9.2 Hz, 1 H), 7.38 (d, J=2.0 Hz, 1 H), 7.16-7.09 (m, 2 H), 6.86 (dd, J=2.0, 8.0 Hz, 1 H), 6.64 (s, 1 H), 6.10 (q, J=6.8 Hz, 1 H), 4.35 (dd, J=6.4, 8.4 Hz, 1 H), 3.91-3.85 (m, 1 H), 3.80-3.60 (m, 3 H), 3.31-3.11 (m, 6 H), 2.36-2.28 (m, 1 H), 1.99 (d, J=6.8 Hz, 3 H), 1.87-1.80 (m, 3 H); MS: (ES) m/z calculated for C24H28Cl2N5O [M+H]+472.2, found 472.4.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])[CH2:22]2)=[N:18][C:19]=1[NH2:20].O1CCOCC1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[NH:20][C:19]3=[N:18][C:17]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:28])[CH2:22]4)=[CH:16][CH:15]=[C:14]3[N:13]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(C1CCCN(c2ccc3nc(COc4ccc(Cl)cc4)[nH]c3n2)C1)N1CCCC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
2-(4-Chlorophenoxy)acetic acid (75 μmol) was added into an 8-mL vial followed by a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone in anhydrous dioxane (600 μL, 127.5 μmol, 0.21M). Triethylamine (90 μL, 648 μmol) and 1-propanephosphonic acid cyclic anhydride (120 μL, 50% in ethyl acetate, 202 μmol) were added. The vial was capped and the reaction mixture was shaken at 140° C. for 16 h. The solvent was removed by Speedvac and the residue was purified via HPLC to afford the title compound. MS API-ES+ (M+H) 440; HPLC retention time 2.473 min (Method D).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][C:22]([CH3:28])([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>CO>[CH3:21][C:22]([CH3:28])([CH3:27])[CH2:23][CH2:24][CH2:25][NH:26][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: CC(C)(C)CCCN
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCCC(C)(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 37.3 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 4,4-dimethylpentylamine (0.310 g, 2.69 mmol) and 3 Å molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, then add EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate. Dissolve the product in ether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and then concentrate to about a quarter of the volume. Filter the precipitate to give the title compound (0.356 g, 37.3%): TOF MS ES+ 373.2 (M+H)+, HRMS calcd for C20H29N4O3 373.2240 (M+H)+, found 373.2245, time 0.39 man; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 min, 10-20% over 5 min, 20-95% over 18], tR=12.0 min, 98.7% purity.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10](I)=[CH:9][C:8]=1[O:16][CH:17]([CH3:19])[CH3:18].[N:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[C:21]=[O:22]>C1COCC1>[Cl:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:21]([NH:20][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)=[O:22])=[CH:9][C:8]=1[O:16][CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)c1ccc(N=C=O)cc1
Reactant: COc1cc(I)cc(OC(C)C)c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)c2cc(OC)c(Cl)c(OC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 6.4 %

Procedure:
n-Butyllithium (364 μl, 0.909 mmol) was slowly added to a solution of 2-chloro-5-iodo-1-isopropoxy-3-methoxybenzene (3) (270 mg, 0.827 mmol) in anhydrous THF (5 mL) at −78° C. After stirring for 15 min at this temperature a solution of methyl 4-isocyanatobenzoate (176 mg, 0.992 mmol) in anhydrous THF (5 mL) was added dropwise. The solution was allowed to warm to RT and stirred for a further 20 h. The reaction mixture was partitioned between DCM (40 mL) and brine (100 mL). The phases were separated and the organic solution was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (40 g, 0-40% EtOAc in isohexane) to afford methyl 4-(4-chloro-3-isopropoxy-5-methoxybenzamido)benzoate (5) (20 mg, 6%) as a colourless oil: m/z 376 [M−H]− (ES−).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][CH:27]=[C:17]([O:16][CH3:15])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1cccc(C=CC(=O)O)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3)nc2n(CC)c1=O
Yield: 49 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.48 g (13.9 mmol) of 3-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 2.10 g (yield 49%) of Compound 102 as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.C=O.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:9][CH2:10][CH2:11][N:12]([C:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:22])[CH2:25][C:7]=2[CH:8]=1
Reactant: COc1ccc(SCCNC(=O)OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CCS2
Temperature: 70 °C
Reaction time: 8 h
Yield: 295.6 %

Procedure:
A mixture of compound 2 (7.3 g, 23 mmol), paraformaldehyde (6.9 g 0.23 mol) and p-toluenesulfonic acid (1.45 g, 7.6 mmol) in 250 mL of toluene was stirred at 70° C. overnight. After cooling to r.t., the solid was filtered off. The solution was extracted with sat. sodium carbonate (100 mL), and the organic layer was dried over anhydrous sodium sulfate. The target product (7.4 g) was obtained as a liquid after removal of the solvent in 97% yield.