Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[C:29]1([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:38]3[CH:39]=[CH:40][C:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:36][CH:37]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3ccc(-c4ccccc4)cc3)C2=O)cc1
Yield: 81 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and (4-phenylphenyl)boronic acid instead of phenyl boronic acid, to obtain the title compound (81%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][O:4][CH2:3]1.CC([O-])(C)C.[K+].Cl[C:13]1[C:18]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[O:20])=[C:17]([CH3:30])[CH:16]=[C:15]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:14]=1.O>C1COCC1>[F:29][C:25]1[CH:24]=[C:23]([CH2:22][NH:21][C:19]([C:18]2[C:13]([O:1][CH:2]3[CH2:5][O:4][CH2:3]3)=[N:14][C:15]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:16][C:17]=2[CH3:30])=[O:20])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: OC1COC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)nc(OC2COC2)c1C(=O)NCc1cccc(F)c1
Temperature: 50 °C
Yield: 83.9 %

Procedure:
A solution of 209 mg (2.82 mmol) 3-hydroxy-oxetane in THF (6 ml) was treated with 316 mg (2.81 mmol) KOtBu and was heated at 50° C. for 15 min. After cooling to RT a solution of 205 mg (0.56 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 9) in THF (3 ml) was added and the mixture was heated at 80° C. for 8 h. The mixture was then poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 190 mg (0.47 mmol, 84%) N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-(oxetan-3-yloxy)-pyridine-3-carboxylic acid amide (example 317). [M+H]+402.2.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([O:12][CH:13]3[CH2:16][N:15]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH3:28][N:29]([CH3:39])[C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1>>[CH3:28][N:29]([CH3:39])[C:30]1[N:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([O:12][CH:13]4[CH2:16][N:15]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: CN(C)c1nc2ccccc2[nH]1
Reactant: CC(C)C(=O)N1CC(Oc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)C1
Product: CC(C)C(=O)N1CC(Oc2nc3c(N4CCOCC4)nc(-n4c(N(C)C)nc5ccccc54)nc3n2C)C1

Procedure:
The compound was prepared from 1-(3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yloxy)azetidin-1-yl)-2-methylpropan-1-one and N,N-dimethyl-1H-benzo[d]imidazol-2-amine following General Procedure of Buchwald coupling shown in Scheme 3. 1H NMR (400 MHz, CDCl3) δ 8.29 (s, OH), 7.58 (d, J=7.5 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.15 (dd, J=11.0, 4.3 Hz, 1H), 7.01 (dd, J=10.1, 4.2 Hz, 1H), 5.58-5.45 (m, 1H), 4.60 (d, J=7.2 Hz, 2H), 4.53-4.39 (m, 2H), 4.31 (d, J=9.6 Hz, 1H), 4.19 (s, 5H), 3.88-3.74 (m, 4H), 3.65 (s, 2H), 3.60 (s, 1H), 3.17 (s, 1H), 2.98 (s, 4H), 2.56-2.42 (m, 1H), 1.14 (d, J=6.8 Hz, 5H). LCMS: M+H+=520.2.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([C:12](=[O:16])[CH2:13][CH:14]=[CH2:15])[C:9]([CH3:11])=[CH2:10].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([C:12](=[O:16])[CH:13]=[CH:14][CH3:15])[C:9]([CH3:11])=[CH2:10]
Reactant: C=CCC(=O)C1(C(=C)C)CCC(C)=CC1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C1(C(=O)C=CC)CCC(C)=CC1C
Yield: 80 %

Procedure:
A solution of 1-(2,4-dimethyl-1-(prop-1-en-2-yl)cyclohex-3-enyl)but-3-en-1-one (2.5 g, 11.5 mmol) and triethylamine (2 g) in CH2Cl2 was stirred at room temperature over night. The solvent and excess of triethylamine were evaporated and the residue distilled bulb-to-bulb to yield the title compound (80%) as a slightly yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10](C([Sn])=C(CCCC)CCCC)[CH2:11]CC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>>[F:1][C:2]1[CH:8]=[C:7]([CH:10]=[CH2:11])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(I)cc1F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: C=Cc1ccc(N)c(F)c1

Procedure:
As depicted in above Scheme 20, 2-fluoro-4-iodoaniline is reacted with tertakis(triphenylphosphine)palladium and tributylvinyltin in the presence with catalitically amount of 2,6-di-tert-butyl-4-methylphenol to obtain 2-fluoro-4-vinylaniline (21-1). The resulting compound is reacted with sulfonylating agent such as methane sulfonyl chloride in the presence of pyridine solvent to produce N-(2-fluoro-4-vinylphenyl)methanesulfoneamide (20-2) and oxidized with oxidizing agent e.g., osmium tetroxide and sodium periodate in the presence of acetone-water mixture solvent to aldehyde intermediate (20-3). The aldehyde compound is reacted with Grignard reagent to obtain alcohol intermediate (2-4 to 20-7) and further reacted with DPPA (diphenylphosphorylazide) and DBU (1,8-diazabicyclo[5,4,0]undec-7-ene) in the presence with toluene solvent to produce azide compound (20-8 to 20-11). The azide intermediate is finally reduced with reducing agent such as Pd/C to produce purposed amine derivative (13-11 t 13-13) selectively.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.C([Li])CCC.CCCCCC.Cl>C1COCC1>[C:5]([C:4]1[CH:3]=[C:2]([B:10]([OH:15])[OH:11])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
3-Bromobenzonitrile (3.6 g, 20 mmol) in anhydrous THF (100 ml) is treated with triisopropyl borate (13 ml, 56 mmol) followed by 1.6 M butyllithium in hexane (14 ml, 22 mmol) over 15 min. at −78° C. The reaction is stirred at −78° C. for 45 min . then warmed to room temperature over 60 min. The reaction mixture is poured into 40 ml 2 N HCl and the precipitated solid is collected . The filter cake is washed with water (3×) and methylene chloride (3×) to yield 3-cyanophenyl boronic acid (2.3 g, 15.6 mmol). 1H NMR (CDCl3, 300 MHz) δ 8.4 (br, 2H), 8.13 (s, 1H), 8.07 (d, 1H), 7.85 (d, 1H), 7.55 (t, 1H). EI MS M+ 147.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])=[CH:10][C:5]=2[CH:4]=[CH:3]1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[O:33]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])=[CH:10][C:5]=2[CH2:4][CH2:3]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)C=CS3(=O)=O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)CCS3(=O)=O)cc(C(=O)Nc2ccn(C)n2)c1
Yield: 57.4 %

Procedure:
To a solution of 3-[(1,1-dioxido-1-benzothien-5-yl)oxy]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (113 mg, 0.24 mmol) in ethanol (2.5 mL) was added ammonium formate (152 mg, 2.40 mmol) and 10% palladium on charcoal (25 mg) and the resultant mixture heated at 140° C. for 10 minutes in a microwave reactor. The catalyst was filtered and the residue reduced, taken up in DCM plus a little methanol and transferred to a silica cartridge, eluted with 0-3% methanol in DCM, to give the desired compound as a clear foam (65 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1.C([Sn](CCCC)(CCCC)[C:29]1[O:30][CH:31]=[CH:32][N:33]=1)CCC>O1CCOCC1.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>[O:30]1[CH:31]=[CH:32][N:33]=[C:29]1[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]2[CH2:6][CH2:7][N:8]([CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:9](=[O:12])[C:10]=2[CH:11]=1
Reactant: CCCC(CCC)N1CCc2c(C(=O)OC)cc(Br)cc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCCC(CCC)N1CCc2c(C(=O)OC)cc(-c3ncco3)cc2C1=O
Temperature: 145 °C

Procedure:
Added to a solution of 0.8 g of methyl 7-bromo-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate in 8 cm3 of dioxane, under an argon atmosphere at a temperature close to 20° C. are 308 mg of tetrakis(triphenylphosphine)palladium and 3.2 g of 2-(tri-n-butylstannyl)oxazole. The reaction medium is heated at 145° C. in a microwave oven for 15 minutes, then left to return to a temperature close to 20° C. The reaction medium is concentrated to dryness under reduced pressure (5 kPa). The residue is taken up by 5 cm3 of dichloromethane and purified by flash chromatography over silica (column: 110 g; spherical silica of BP-SUP type particle size: 20-40 μm; eluent: 90% heptane/10% ethyl acetate then 100% ethyl acetate). After concentrating the fractions under reduced pressure, 320 mg of methyl 7-(2-oxazolyl)-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are obtained.
Reaction SMILES: [BH4-].[Na+].Br[CH2:4][C:5]([C:7]1[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=1)=[O:6].O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:27])=[CH:21][CH:20]=1>CO>[OH:6][CH:5]([C:7]1[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=1)[CH2:4][N:28]([CH:26]([CH3:27])[CH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(C(=O)CBr)s1
Reactant: COc1ccc(CC(C)NCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(O)CN(Cc2ccccc2)C(C)Cc2ccc(OC)cc2)s1
Temperature: 0 °C

Procedure:
Sodium borohydride (3.14 g) was added to an ice-cold suspension of methyl 5-(bromoacetyl)thiophene-2-carboxylate (4.14 g) in methanol (250 ml). After 15 min the reaction mixture was poured into iced water (1000 ml) and extracted with ethyl acetate (5×200 ml). The dried (MgSO4) organic phase was evaporated to give a yellow oil, which was heted with [2-(4-methoxyphenyl)-1-methylethyl](phenylmethyl)amine (5.18 g) at 100° for 16 h. The cooled reaction mixture was partitioned between water (400 ml) and ethyl acetate (3×400 ml), and the dried (MgSO4) organic phase was evaporated, giving the crude product as an oily brown solid (9.75 g). This was applied on silica to a short-path silica column (1000 g) eluted with cyclohexane 15% diethyl ether. The appropriate fractions (Rf 0.15) were combined and evaporated to give the ethanolamine (slightly impure) as an oily beige solid (2.4 g). TLC SiO2 (Et2O/cyclohexane, 1:1 ) Rf 0.39.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=O)[NH:6][N:7]=1)[CH3:2].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([NH2:18])[CH:12]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:8]2[NH:17][C:14]3[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][C:13]=3[N:18]=2)[NH:6][N:7]=1)[CH3:2]
Reactant: CCc1cc(C=O)[nH]n1
Reactant: Nc1ccc(Br)cc1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(-c2nc3cc(Br)ccc3[nH]2)[nH]n1

Procedure:
Starting with 20 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 30 mg of 4-bromo-1,2-phenylenediamine and 30 mg of sodium metabisulphite, in 1 ml of ethanol and 2 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a reverse-phase HPLC (5 mm C18 phase, dimensions: 100×25 mm, flow rate 20 ml/min, elution gradient: acetonitrile/0.07% TFA-water/0.07% TFA from 5-95 to 95-5 (v/v)), and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 21 mg of 2-(5-ethyl-2H-pyrazol-3-yl)-5-bromo-1H-benzimidazole are obtained in the form of a yellow powder, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1.Br[CH2:32][CH2:33][O:34][CH3:35]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[CH2:32][CH2:33][O:34][CH3:35])=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: COCCBr
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)[nH]c3cc2Br)CC1
Product: COCCn1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc21

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 1, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (Example 6, step 4) and (2-bromoethyl)-methylether. The desired product was obtained in a yield of 70% as white foam. MS (m/e): 556.3 (M+H, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12]>C(O)C>[OH:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)CCl
Reactant: Nc1ncccc1O
Solvent: CCO
Product: Cc1cn2cccc(O)c2n1
Reaction time: 8 h

Procedure:
A mixture of 2-amino-3-hydroxypyridine (1,000 g) and chloroacetone (845 g) in 7.57 liters of ethanol was heated under reflux for 20 hrs. Most of the ethanol was removed by distillation and the residual material was dissolved in 7.57 liters of water. This solution was extracted four times with 1.2 liter portions of dichloromethane. The combined extracts were washed with 1 liter of water and this was combined with the aqueous solution. This solution was then adjusted to pH 11.5-12 with 850 ml of 50%sodium hydroxide. This basic solution was extracted three times with 1.2 liters of dichloromethane. The combined dichloromethane extracts were washed with 1 liter of H2O and this was added to the basic solution.This solution was chilled in an ice bath and the pH adjusted to 7 with 1.45liters of 6 N hydrochloric acid. After standing overnight, the product was collected, washed with water, and dried. The product was recrystallized from dichloromethane/methanol to give the intermediate.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:14]([C:25]([OH:27])=O)[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[NH:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:14]([C:25]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:27])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
4.72 g (24.6 mmol) of EDCl was added to 100 ml of THF solution of 5.00 g (16.4 mmol) of Boc-Trp-OH (manufactured by Tokyo Chemical Industry Co., Ltd), 1.50 ml (16.4 mmol) of aniline and 1.89 g (1.64 mmol) of HO-Su, followed by stirring for 16 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), the organic layer was dried over sodium sulfate. After the drying agent was separated by filtration, the filtrate was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1 (volume ratio)), thereby obtaining 3.10 g of the product with a yield of 49.8%.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13]3[C:19]4[C:20]([NH:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]6[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=6)=[C:27]([Cl:40])[CH:26]=5)=[N:21][CH:22]=[N:23][C:18]=4[S:17][C:14]=32)=[N:9]1)(=O)=O.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C>CC#N>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]3[S:17][C:14]4[C:15]5[C:10]([CH2:11][CH2:12][C:13]=4[C:19]=23)=[N:9][N:8]([CH2:7][CH2:6][N:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)[CH:16]=5)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1
Reactant: Cc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3nn(CCOS(C)(=O)=O)cc3-5)cc2Cl)n1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3nn(CCN4CCN(C)CC4)cc3-5)cc2Cl)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 42.1 %

Procedure:
To 4 mL CH3CN were sequentially added 2-[6-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]ethyl methanesulfonate (100 mg, 0.17 mmol), 1-methylpiperazine (0.06 mL, 0.5 mmol), and diisopropylethylamine (0.06 mL, 0.33 mmol). The mixture was stirred at 70° C. for 16 h after which time the mixture was removed from heating, and allowed to cool to rt. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and purified by prep HPLC. The combined fractions were treated with saturated Na2CO3 and dried to afford free base product (43 mg, 43%) as a white solid. 1H-NMR (DMSO-d6) δ 8.43 (s, 1H), 8.34 (s, 1H), 7.95 (s, 1H), 7.77 (d, 1H), 7.73 (d, 1H), 7.51 (dd, 1H), 7.35 (d, 1H), 7.22 (s, 1H), 7.19 (s, 1H), 5.22 (s, 2H), 4.17 (t, 2H), 3.38 (t, 2H), 2.91 (t, 2H), 2.70 (t, 2H), 2.48 (s, 3H), 2.40-2.48 (br s, 4H), 2.25-2.35 (br s, 4H), 2.13 (s, 3H); LCMS RT=2.07-2.24 min, [M+H]+=601.4.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.OS(O)(=O)=O.O=S(=O)=O.[CH2:22]=O>>[C:6]([C:5]1[CH:9]=[C:10]2[C:2](=[CH:3][CH:4]=1)[C:1](=[O:12])[O:11][CH2:22]2)([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 125 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
Terephthalic acid (10 kg) is charged into a reactor. Oleum (20% (18-24% SO3); 6 kg/kg terephthalic acid ) is added and then paraformaldehyde (1.33 equivalents, 0.24 kg/kg terephthalic acid) is added. The mixture is agitated at 125° C. for 17 hours. Water (13 kg/kg terephthalic acid and filter aid is added, the temperature is adjusted to about 70° C. The precipitate is filtered of, washed with water and suspended in water. The pH of the suspension is adjusted to about 7 with NaOH, activated carbon, 0.07 kg/kg terephthalic acid is added, and then the mixture is filtered, the precipitate is rinsed with water. The temperature of the filtrate is adjusted to about 65° C. and the pH is adjusted to about 2 with 50% sulfuric acid. The 5-carboxyphthalide precipitated is separated by filtration washed and dried. Yield 83%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)C(C)C)(C)C.Cl[C:25]1[C:26]2[C:33]([CH3:34])=[CH:32][NH:31][C:27]=2[N:28]=[CH:29][N:30]=1>C(O)(C)C>[CH3:1][C@H:2]1[CH2:7][N:6]([C:25]2[C:26]3[C:33]([CH3:34])=[CH:32][NH:31][C:27]=3[N:28]=[CH:29][N:30]=2)[CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9]
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCN(C(=O)OC(C)(C)C)[C@@H](C)C3)c12
Temperature: 120 °C
Yield: 37.5 %

Procedure:
(S)-tert-butyl 2-methylpiperazine-1-carboxylate (3 g, 15 mmol), N,N-diisopropylethylamine (3 ml), and 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (2 g, 12 mmol) were added to isopropanol (10 ml). The solution was heated at 120° C. in a sealed pressure tube for 12 hours. The reaction was concentrated under vacuum, and the residue was purified by flash chromatography (80 g SiO2, 0-5% MeOH: CH2Cl2, 50 min) to give clean (S)-tert-butyl 2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.5 g, 4.5 mmol, 38%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1.O=[C:24]1[CH2:27][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25]1.C(O)(=O)C.ClCCCl>ClCCCl.CC(O)C.CC(O)C>[NH2:22][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[CH:21][N:13]2[C@H:5]1[C@@H:6]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]2[C@@H:3]([CH2:2][NH:1][CH:24]2[CH2:27][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:25]2)[O:4]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CN)O[C@H]2n1cnc2c(N)ncnc21
Reactant: O=C1CC(CCC(=O)OCc2ccccc2)C1
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of the 9-[(3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-amine (1.45 g, 4.736 mmol), benzyl 3-(3-oxocyclobutyl)propanoate (1.21 g, 5.209 mmol) and acetic acid (246.45 μl, 4.31 mmol) in DCE:iPrOH (4:1, 50 ml) was stirred at RT for 1 h. A further aliquot of DCE (40 ml) and iPrOH (5 ml) was added to the reaction mixture and continued for 1 hour. STAB (1.28 g, 6.03 mmol) was then added and the reaction mixture was stirred for 18 hours. The reaction mixture was quenched with 1N Na2CO3 (10 ml), and the product was extracted with DCM (2×30 ml). This was dried over Na2SO4, filtered and evaporated to dryness. Purification by silica gel column chromatography, eluting with 7N NH3 in MeOH:DCM (1:99-3:97) gave the desired product as a colourless oil, 1.51 g (58%); MS (ESI+) for C27H34N6O5 m/z 523.65 [M+H]+; HPLC purity 97% (ret. time, 1.43 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 8.35 (d, J=5.3 Hz, 1H), 7.87 (d, J=33.8 Hz, 1H), 7.40-7.29 (m, 5H), 6.08-5.94 (m, 1H), 5.59-5.42 (m, 3H), 5.10 (d, J=4.0 Hz, 2H), 5.03-4.96 (m, 1H), 4.33 (dq, J=7.3, 3.9 Hz, 1H), 3.12 (ddd, J=23.0, 14.6, 7.5 Hz, 1H), 2.85-2.77 (m, 1H), 2.74 (dd, J=12.5, 6.6 Hz, 1H), 2.39-2.07 (m, 4H), 1.90-1.64 (m, 5H), 1.61 (s, 4H), 1.38 (s, 3H), 1.28-1.06 (m, 1H).