Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:11]3[C:18]([C:19](O)=[O:20])=[C:17]([CH2:22][CH3:23])[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:58][C:59]1[CH:60]=[N:61][CH:62]=[CH:63][C:64]=1[NH2:65]>CN(C=O)C>[CH3:24][N:2]([CH3:1])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:11]3[C:18]([C:19]([NH:65][C:64]4[CH:63]=[CH:62][N:61]=[CH:60][C:59]=4[F:58])=[O:20])=[C:17]([CH2:22][CH3:23])[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:5][CH2:4]1
Reactant: CCc1sc2ncnc(OC3CCC(N(C)C)CC3)c2c1C(=O)O
Reactant: Nc1ccncc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1sc2ncnc(OC3CCC(N(C)C)CC3)c2c1C(=O)Nc1ccncc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a solution of 4-[[4-(dimethylamino)cyclohexyl]oxy]-6-ethylthieno[2,3-d]pyrimidine-5-carboxylic acid (100 mg, 0.29 mmol, 1.00 equiv) in distilled DMF (5 mL) was added HATU (217 mg, 0.57 mmol, 2.00 equiv), DIEA (110.9 mg, 0.86 mmol, 3.00 equiv) and 3-fluoropyridin-4-amine (32 mg, 0.29 mmol, 1.00 equiv) under nitrogen. The resulting solution was stirred for 1 h at room temperature. After evaporation under reduced pressure, the crude product (120 mg) was purified by Prep-HPLC with the following conditions (Waters): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (7.0% CH3CN up to 48.0% in 10 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the corresponding 4-[[4-(dimethylamino)cyclohexyl]oxy]-6-ethyl-N-(3-fluoropyridin-4-yl)thieno[2,3-d]pyrimidine-5-carboxamide (40 mg) as a white solid. MS (ES, m/z): 444 [M+H]+. 1H NMR: (400 MHz, CD3OD): 8.55-8.59 (2H, m), 8.50 (1H, d), 8.40 (1H, d), 5.19-5.24 (1H, m), 3.07 (2H, q), 2.28 (6H, s), 2.10-2.19 (3H, m), 1.89-1.92 (2H, m), 1.27-1.43 (5H, m), 1.22-1.25 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][CH2:10][O:11][C:12]([CH2:14]P(OCC)(OCC)=O)=[O:13].[H-].[Na+]>C1C=CC=CC=1>[CH2:10]([O:11][C:12](=[O:13])[CH2:14][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[CH3:9]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CN1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)CC1CCN(C)CC1

Procedure:
2-(1-Methyl-piperid-4-yl)-ethanoic acid ethyl ester is prepared from 1-methyl-piperid4-one (1 equiv), triethyl phosphono acetate (1 equiv) and NaH (1.1 equiv) in benzene followed by reduction of the alkene bond according to the procedure of Cignarella etc. (J Heterocyclic Chem 1993, 30 (5), 1337-1340).
Reaction SMILES: [CH3:1][S:2][CH3:3].ClCl.[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:8]=1[NH2:9].N1C2C(=CC=CC=2)C=CC=1>ClCCl>[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:8]=1[N:9]=[S:2]([CH3:3])[CH3:1]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CSC
Agent: ClCl
Solvent: c1ccc2ncccc2c1
Solvent: ClCCl
Product: CS(C)=Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
A solution of 1.1 mL (15 mmol) of dimethyl sulfide in 170 mL of dichloromethane was cooled to -10° C. and 0.90 g (13 mmol) of chlorine was added through a sparge tube with cooling and stirring. Subsequently, 23.3 g (120 mmol) of 2,4,6-trichloroaniline and then 22 g (170 mmol) of quinoline were added with cooling and stirring. The resulting product was a mixture of the title compound and unreacted 2,4,6-trichloroaniline.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:1][C:2]2[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CS(=O)(=O)NCc1ccc(N)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1ccc(Nc2cc(Cl)ncn2)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
5.309 g N-(4-Amino-benzyl)-methanesulfonamide (obtained in Step 2, 26.5 mmol) and 4.739 g 4,6-dichloropyrimidine (31.81 mmol) was dissolved in 120 cm3 of isopropyl-alcohol, 6.93 cm3 N,N-diisopropyl-ethylamine (5.140 g, 39.76 mmol) was added and the mixture was refluxed for four days. The reaction mixture was cooled to room temperature and the precipitated compound was filtered off. The light yellow product was washed well with diethyl-ether and air-dried. 3.813 g N-[4-(6-Chloro-pyrimidin-4-ylamino)-benzyl]-methanesulfonamide was obtained above 98% purity in 46% overall yield. For analitical results and compound identification see Table 1. The compound was used as a starting material in the preparation of Example 34-58 and 76.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]#[N:11])[CH:3]=[CH:2]1.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:26][C:24]1([CH3:27])[CH2:25][CH:20]([NH:19][C:15]2[N:14]=[C:13]([C:3]3[C:4]4[C:9](=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH:18]=[CH:17][N:16]=2)[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: N#Cc1cccc2cc[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(C#N)cccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from SEM-protected 1H-indole-7-carbonitrile and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM-protecting group with TBAF. Yield: 10 mg (6%).
Reaction SMILES: C[N:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][C:21]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:22]3)=[CH:5][CH:4]=[N:3]1.S(Cl)(Cl)=O.[CH3:35]N(C=O)C>>[CH3:35][N:3]1[CH:4]=[CH:5][C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][C:21]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:22]3)=[N:2]1
Reactant: CN(C)C=O
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)O)ccc12
Solvent: O=S(Cl)Cl
Product: Cn1ccc(-c2cc(C(F)(F)F)ccc2-c2cccc3cc(S(=O)(=O)O)ccc23)n1

Procedure:
To a solution of 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonic acid (from Step 2) (0.093 g, 0.214 mmol) in DMF (0.428 mL) was added thionyl chloride (0.031 mL, 0.428 mmol) at 0° C. After 20 minutes LC/MS indicated that the sulfonic acid starting material was converted to the desired product. The reaction mixture was then transferred to a separatory funnel containing water and DCM. The layers were separated and the organic layer was washed twice with water. The resulting organic layer was dried with MgSO4, filtered and concentrated to an oil. m/z (ESI, +ve ion) 450.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>CN(C=O)C>[CH3:34][S:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:37])=[O:36]
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 1.40 mmol of methanesulfonyl chloride in 3 ml of DMF were added. The reaction solution was then stirred at room temperature for a further 6 h. The crude product was purified using chromatographic methods.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([CH3:12])[CH:3]=1.[O:13]1[C:18]2[CH:19]=[CH:20][C:21](B(O)O)=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N(C)C)=O>O>[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([C:2]3[N:7]4[N:8]=[C:9]([NH2:11])[N:10]=[C:6]4[CH:5]=[C:4]([CH3:12])[CH:3]=3)=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: Cc1cc(Br)n2nc(N)nc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2ccc3c(c2)OCCO3)n2nc(N)nc2c1
Temperature: 150 °C

Procedure:
5-Bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.19 g, 0.84 mmol), 1,4-benzodioxane-6-boronic acid (0.18 g, 1.00 mmol), palladium(tetrakis)triphenylphosphine (97 mg, 0.084 mmol), potassium phosphate (0.36 g, 1.67 mmol), dimethylacetamide (3 ml) and water (1 ml) were added to a microwave vial containing a stirrer bar. The reaction was heated to 150° C. for 10 min. Water was added to the reaction mixture and the product extracted into ethyl acetate (×2). The organics were combined, washed several times with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether and collected by filtration to give the desired product. LCMS RT: 2.82 min, MI: 283.17, Method: 2
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[CH2:17][CH:16]([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)=[CH:3][CH:2]=1.[NH2:20][NH2:21].C(Cl)(Cl)Cl>C(O)C>[CH3:18][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:20][NH:21][CH:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]2[CH2:17]1
Reactant: CC1CC(=Cc2ccncc2)C(=O)c2ccccc21
Reactant: NN
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC1CC2C(=NNC2c2ccncc2)c2ccccc21

Procedure:
To a mixture of 25 grams of 2-(4-pyridylmethylene)-3,4-dihydro-4-methyl-1 (2H)-naphthalenone and 5 grams of hydrazine in 150 ml of ethanol is added sufficient chlorform to dissolve all the reactants. The solution is refluxed overnight under anhydrous conditions. After cooling, the reaction mixture is filtered and the solvent removed by evaporation to yield 5-methyl-3-(4-pyridyl)-3,3a,4,5-tetrahydro-2H-naphtho[1,2-c]Pyrazole. This is chromatographed on silica using benzene as the eluant to yield 4,5-dihydro-5-methyl-3l -(4-pyridyl)-2H-naphtho[1,2c]pyrazole.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=2)=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.[BrH:25]>C(O)(=O)C>[BrH:25].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccc(-c2c[nH]c(=O)cn2)cc1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: Nc1ccc(-c2c[nH]c(=O)cn2)cc1

Procedure:
A solution of 5-(4-benzyloxycarbonylaminophenyl)-2(1H)-pyrazinone (1.1 g) in 15% w/v hydrogen bromide in acetic acid solution (30 ml) was refluxed for 30 min. The yellow precipitate which formed was filtered off and it was washed with a little 1-propanol and then recrystallised from ethanol-water containing 2 drops of concentrated hydrobromic acid to give 5-(4-aminophenyl)-2(1H)-pyrazinone hydrobromide (1.03 m.p. >300° C.).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[C:13](=[O:14])[C:12]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])=[CH:16][C:17](Cl)=[N:18][C:11]=2[O:10][CH2:9][CH2:8]1.[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])[CH3:37]>>[C:36]([N:39]1[CH2:44][CH2:43][N:42]([C:17]2[CH:16]=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:12]3[C:13](=[O:14])[N:7]([CH2:6][C:5]4[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:3]([C:2]([F:1])([F:35])[F:34])[CH:4]=4)[CH2:8][CH2:9][O:10][C:11]=3[N:18]=2)[CH2:41][CH2:40]1)(=[O:38])[CH3:37]
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCO2
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2cc(-c3ccccc3C)c3c(n2)OCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Yield: 9.9 %

Procedure:
In a similar manner to Example 1, 4-[3,5-bis(trifluoromethyl)benzyl]-8-chloro-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (compound of Reference Example 19; 51.5 mg) was reacted with 1-acetylpiperazine (38.5 mg) to obtain 8-(4-acetylpiperazine-1-yl)-4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (6.0 mg, 10%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([CH:21]1[CH2:23][CH2:22]1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:32])=O>C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([Cl:32])[CH:21]1[CH2:23][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Cl)n2nc(C(O)C2CC2)n1Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1c2ccc(Cl)n2nc(C(Cl)C2CC2)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
To a stirred solution of 3-benzyl-7-chloro-2-(cyclopropyl-hydroxy-methyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (1.40 g, 4.24 mmol) and pyridine (1.5 mL, 18.5 mmol) in CH2Cl2 (20 mL) was added thionyl chloride (2 M, 4.5 mL, 9.0 mmol) at 0° C. under nitrogen and stirred for 20 min. The reaction mixture was then stirred at rt overnight, poured into ice water, and extracted with CH2Cl2 (3×40 mL). The organic layers were washed with brine and dried over MgSO4. Concentration and purification of the crude product by flash column chromatography (SiO2, EtOAc/hexane 1:9) gave the title compound as a white solid (0.96 g, 65%): 1H NMR (CDCl3) δ 7.22 (m, 3H), 7.04 (m, 3H), 6.48 (d, 1H, J=4.4 Hz), 6.05 (d, 1H, J=16.5 Hz), 4.68 (d, 1H, J=16.5 Hz), 3.81 (d, 1H, J=10.45 Hz), 1.96 (m, 1H), 1.19 (m, 1H), 0.72 (m, 1H), 0.57 (m, 1H), 0.22 (m, 1H), −0.35 (m, 1H); 3C NMR (CDCl3) δ 154.2, 148.2, 136.4, 129.2, 128.0, 125.8, 118.0, 117.6, 110.6, 109.0, 62.5, 44.1, 15.3, 7.22, 6.19; MS (ESI+) 348.02 (M++H), 370.01 (M++Na).
Reaction SMILES: C[O:2][CH:3]([O:20][CH3:21])[CH2:4][C:5]1[C:17]([CH3:18])=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([CH3:19])[CH:6]=1.Cl(O)(=O)(=O)=O.[C:27](#N)C>>[CH2:21]([O:20][CH:3]([OH:2])[CH2:4][C:5]1[C:17]([CH3:18])=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([CH3:19])[CH:6]=1)[CH3:27]
Reactant: CC#N
Reactant: CCOC(=O)COc1cc(C)c(CC(OC)OC)cc1C
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCOC(=O)COc1cc(C)c(CC(O)OCC)cc1C
Yield: 48.8 %

Procedure:
Ethyl 2-[4-(2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (43 g) was dissolved in acetonitrile (190 g) while stirring. To the resulting solution was added 10 perchloric acid (216 g), and the mixture was stirred for an hour at room temperature. The reaction mixture was partitioned between toluene (340 g) and water (200 g). The organic layer was washed with water, an aqueous solution of sodium bicarbonate and brine successively, and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was dissolved in ethanol (180 g), and the solvent was removed under reduced pressure. The residue was dissolved with hexane (86 g) and ethanol (37 g). After seed crystals were added, the solution was stirred at 0-10° C. for 2 hours. Hexane (220 g) was added, and the resulting suspension was stirred at 0-10° C. for 2 hours. The precipitated crystals were filtered to give ethyl 2-[4-(2-ethoxy-2-hydroxyethyl) -2,5-dimethylphenoxy]acetate (21 g).
Reaction SMILES: [CH3:1][C:2]12[O:10][B:9]([C@@H:11]([NH:28][C:29]([C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[CH2:36][NH:35][CH2:34]4)=[O:30])[CH2:12][C:13]3[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[O:8][CH:7]1[CH2:6][CH:5]1[CH2:40][CH:3]2[C:4]1([CH3:42])[CH3:41].C([O-])([O-])=O.[K+].[K+].Br[CH2:50][CH2:51][NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56].O>CN(C=O)C>[C:55]([O:54][C:53]([NH:52][CH2:51][CH2:50][N:35]1[CH2:34][C:33]2[C:37](=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C@H:11]([B:9]3[O:8][CH:7]4[C:2]([CH3:1])([CH:3]5[CH2:40][CH:5]([CH2:6]4)[C:4]5([CH3:42])[CH3:41])[O:10]3)[CH2:12][C:13]3[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=3)[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:30])[CH:32]=2)[CH2:36]1)=[O:59])([CH3:58])([CH3:57])[CH3:56]
Reactant: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CNC3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CN(CCNC(=O)OC(C)(C)C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-2-(isoindoline-5-carboxamido)ethyl)-2-methoxybenzoate from Example 9 step 2 (263 mg, 0.46 mmol) in DMF (5 mL) was added K2CO3 (252 mg, 1.84 mmol) and tert-butyl 2-bromoethylcarbamate (122 mg, 0.54 mmol). The resulting reaction was stirred at room temperature overnight. Water (15 mL) was added and the aqueous phase was extracted with EtOAc. The organic phase was washed with IN HCl, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Hexane/EtOAc, 2:1 to 1:2). ESI-MS m/z 718.1 (MH)+.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20]([C@@H:22]1[CH2:30][C@H:29]2[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[NH:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:38]([O:42][C:43]([NH:45][C@H:46]([C:48](O)=[O:49])[CH3:47])=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(OCC)(=O)C>[C:38]([O:42][C:43]([NH:45][C@@H:46]([CH3:47])[C:48]([N:23]1[C@@H:24]2[C@@H:29]([CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:30][C@H:22]1[C:20]([O:19][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:21])=[O:49])=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21
Temperature: 30 °C

Procedure:
200 g of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester para-toluene-sulphonate, 65 ml of triethylamine and 1 litre of ethyl acetate are introduced into a stirred reactor, followed, after stirring for 10 minutes at ambient temperature, by 87 g of N-[tert-butyloxycarbonyl]-(S)-alanine and 175 g of O-(benzotriazol-1-yl)-1,1,3,3-bis(tetra-methylene)uronium hexafluorophosphate. The heterogeneous mixture is then heated at 30° C. for 3 hours whilst stirring well and is then cooled to 0° C. and filtered.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH3:23].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH3:23]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: CC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 2.25 g (7.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.35 g (7.0 mmol) of acetaldehyde in 30 ml of ethanol, 0.07 ml (0.7 mmol) of piperidine was added, followed by refluxing for 5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/1→1/2) to yield 0.48 g (19.7%, yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1.Cl.O1CCOCC1.[Na]>O>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:17][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]2[CH2:16][CH:14]3[CH2:15][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6]2)=[N:20][CH:21]=1
Reactant: COCCN1CC2CC(C1)c1cc(N)ccc12
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(CCOC)C2)ncc1Cl
Temperature: 120 °C
Yield: 46.5 %

Procedure:
10-(2-Methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (45 mg, 0.19 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (58 mg, 0.19 mmol) and 4N HCl in dioxane (53 μl, 0.21 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 12 g Isco silica gel column using 0-15% methanol in methylene chloride as the eluent to yield 2-[5-Chloro-2-(10-(2-methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (43.6 mg, 43%) as a yellow foam. MP: 104.5-105.5° C.; 1H-NMR (CDCl3) δ 9.68 (d, J=7.8 Hz, 1H), 8.12 (s, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.42 (m, 2H), 7.21 (s, 1H), 7.08 (d, J=8.1 Hz, 2H), 6.91 (s, 1H), 6.20 (br s, 1H), 3.33 (t, J=5.8 Hz, 2H), 3.20 (s, 3H), 3.11-2.98 (m, 6H), 2.86 (br s, 2H), 2.59-2.46 (m, 4H), 2.39 (m, 1H), 1.73 (d, J=10.36, 1H); LC/MS (ESI+): 493 (M+H).
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([CH:10]=[N+:11]=[N-:12])([CH3:9])[CH3:8].[F:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[CH:29]=[N:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[C:23]=1[C:24]#[N:25]>C1COCC1.CCOC(C)=O>[F:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[CH:29]=[N:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[C:23]=1[C:24]1[N:25]=[N:12][NH:11][C:10]=1[Si:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#Cc1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1[nH]nnc1-c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Reaction time: 0.33 h
Yield: 36.5 %

Procedure:
n-Butyllithium (28 μL, 2.5 M in THF, 0.07 mmol) was added to a solution of (trimethylsilyl)diazomethane (35 μL, 2.0 M in THF, 0.07 mmol) in THF (1 mL) at 0° C., and stirred for 20 minutes. 3-(2-Fluoro-4-iodo-phenylamino)-5-(2-fluoro-phenyl)-isonicotinonitrile (20 mg, 0.05 mmol) was added, and the resulting solution was stirred overnight at room temperature. The reaction solution was diluted with EtOAc and satd. NH4Cl, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 75% EtOAc in hexanes to afford the desired product (10 mg, 40%). LC-MS (M+H=548, obsd.=548).