Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([CH3:31])([CH3:30])[CH2:27][NH:28][CH3:29])[CH2:22][CH2:21]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+].CC1C=CC(S([O-])(=O)=O)=CC=1>ClCCl.C(N(CC)CC)C>[CH3:29][N:28]([CH2:27][C:26]([CH3:31])([CH:23]1[CH2:24][CH2:25][N:20]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22]1)[CH3:30])[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCN1CCC(C(C)(C)CNC)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCN1CCC(C(C)(C)CN(C)C(C)=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.2 %

Procedure:
3.4 ml (3.6×10-2 mole) of acetic anhydride was added to a solution of 8 g (2.4×10-2 mole) of 1-dodecyl-N,β,β-trimethyl-4-piperidineethanamine in 100 ml of dichloromethane and 16.8 ml of N,N-diethylethanamine. The reaction mixture was stirred for 12 hours at room temperature. The solution was poured into a 1N sodium hydroxide solution and extracted with trichloromethane. The organic phase was washed with water, dried and filtered and the solvents were evaporated off under reduced pressure. 8.7 g of N-methyl-N-[2-methyl-2-[(1-dodecyl)-4-piperidinyl]propyl]acetamide (yield: 97%) was obtained, from which the 4-methylbenzene sulphonate was prepared and recrystallised from ethyl acetate. M Pt=102°-103° C.
Reaction SMILES: [CH3:1][C:2]([O:11][OH:12])([CH2:4][CH2:5][C:6]([CH3:10])([O:8][OH:9])[CH3:7])[CH3:3].Cl[Si:14](Cl)([CH3:16])[CH3:15].N>CCOCC>[CH3:15][Si:14]1([CH3:16])[O:12][O:11][C:2]([CH3:1])([CH3:3])[CH2:4][CH2:5][C:6]([CH3:10])([CH3:7])[O:8][O:9]1
Reactant: C[Si](C)(Cl)Cl
Reactant: CC(C)(CCC(C)(C)OO)OO
Agent: N
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)OO[Si](C)(C)OO1
Temperature: 5 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
Into a one liter flask equipped with a motorized stirrer is added 0.15 mole (25.17g, 98.47% pure) of 2,5-dimethyl-2,5-dihydroperoxyhexane and 0.15 mole (19.35g) of dichlorodimethylsilane in 400 ml of anhydrous ether. This mixture is cooled to about 5° C., and ammonia gas is introduced cautiously. Reaction temperature is maintained between 5° and 10° C. by use of an ice bath and by adjusting the rate of gas introduction. Ammonia addition is continued for 30 to 40 minutes until the exothermic reaction has stopped. The reaction mixture is then stirred at room temperature for an additional 3 hours. The salts are removed by filtration and the ether is removed by distillation. The crude yield of a colorless solid was 26.7 grams. To purify the crude product hexane is added and the mixture is filtered to remove a small amount of insoluble, unreacted 2,5-dimethyl-2,5-dihydroperoxyhexane. Evaporation of the hexane yields 21.9 grams (62.4%) of 3,3,6,6,9,9-hexamethyl-1,2,4,5-tetraoxa-3-silacyclononane having a melting point of 44.5°-48° C. The product is 95.5% pure based upon active oxygen (A.O.) analysis wherein theoretical A.O. is 13.67% and A.O. found is 13.05%. Analysis of the product supports the structure ##STR4## as follows: (1) I.R. spectrum indicates no terminal hydroperoxy (--OOH) groups; (2) the molecular weight corresponds to a cyclic structure; and (3) various chromatographic analyses verify a very non-polar species.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:10]([CH:12]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:4]1)[CH3:2].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=2)[C:10]([CH:12]2[CH2:13][CH2:14][CH2:15][C:16]3[C:17]([O:22][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:18][CH:19]=[CH:20][C:21]2=3)=[O:11])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCn1cc(CN(C(=O)C2CCCc3c(O)cccc32)c2ccc(C(C)C)cc2)cn1
Product: CCOC(=O)COc1cccc2c1CCCC2C(=O)N(Cc1cnn(CC)c1)c1ccc(C(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.00 g) and ethyl bromoacetate (0.40 mL) as starting materials, ethyl 2-(5-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoyl}-5,6,7,8-tetrahydronaphthalene-1-yloxy)acetate (1.09 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([Cl:20])[C:4]=2[CH:3]=1.Cl.CO>C(Cl)(Cl)Cl.CCOCC>[ClH:20].[F:1][C:2]1[CH:18]=[CH:17][C:16]2[NH+:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([Cl:20])[C:4]=2[CH:3]=1
Reactant: Cn1c2c3ccccc3nc-2c(Cl)c2cc(F)ccc21
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: C[NH+]1C2=c3ccccc3=NC2=C(Cl)c2cc(F)ccc21
Yield: 178.5 %

Procedure:
A solution of 2-fluoro-5-methylquindoline from Example 24 (100 mg) in chloroform (50 mL) was treated at room temperature with a 1M solution of HCl in ether until a yellow solution/precipitate formed. Methanol was added to homogenize the mixture and then the solution was concentrated. The resulting solid was recrystallized from hot CHCl3 (50 mL)/EtOH (5 mL), with a minimum amount of ether being added to facilitate the crystallization process. Filtration, followed by washing the product with diethyl ether and drying afforded 101 mg (90.2%) of the title compound as yellow crystals, mp 211.8°-212.5° C.; 1H NMR (DMSO-d6) δ 13.55 (s, 1H), 8.99 (dd, J=10.0, J=4.4, 1H), 8.82 (d, J=8.4, 1H), 8.40 (dd, J=9.2, J=2.8, 1H), 8.25-8.18 (m, 1H), 7.99 (dt, J=8.4, J=0.8, 1H) , 7.88 (d, J=8.0, 1H), 7.56 (dt, J=8.4, J=0.8, 1H), 5.04 (s, 3H); 13C NMR (DMSO-d6) 160.48 (d, J=250.5), 146.01, 138.95, 134.75, 132.85, 132.53, 127.58 (d, J=5.6), 126.71, 124.94 (d, J=10.6), 122.51 (d, J=9.3), 122.33 (d, J=27.5), 122.20, 114.42, 113.56, 108.44 (d, J=25.4), 40.02; MS (EI, m/z) 285 (M+), 287 (M+2+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([OH:12])[CH:8]=[C:7]2O.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1Cl)[NH2:18].[ClH:23]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([OH:12])[CH:8]=[C:7]2[NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([Cl:14])[C:16]=1[Cl:23]
Reactant: Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Oc1cc(O)c2cccc(Br)c2n1
Solvent: CN1CCCC1=O
Product: Oc1cc(Nc2cccc(Cl)c2Cl)c2cccc(Br)c2n1
Yield: 55 %

Procedure:
Prepared using general procedure 1; 8-Bromo-2,4-quinolinediol (4 g, 16.66 mmol), 3,4-dichloroaniline (8 g, 49.38 mmol), 2.78 mL of 6 M HCl (16.68 mmol) and 20 mL NMP were irradiated to achieve 200° C. (400 W max) for 30 min. Cooling and precipitation by pouring onto 100 mL water afforded 3.52 g of product (9.16 mmol, 55%). 1H NMR (300 MHz, DMSO): 9.77(s, 2H), 8.95(s, 1H), 8.11(dd, 1H, J=8.48, 0.81 Hz), 7.89(dd, 1H, J=7.67, 0.81 Hz), 7.66(d, 1H, J=8.88 Hz), 7.58(d, 1H, J=2.42 Hz), 7.36(dd, 2H, J=8.48, 2.42 Hz), 7.20(t, 1H, J=8.07 Hz), 5.88(s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[O:8][C:9]3[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][CH2:19][CH3:20])=[C:13]([O:21][C:22](=[O:24])[CH3:23])[C:10]=3[C:11]=2[CH3:12])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:33])[CH2:31]Br)[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:30]([CH2:31][O:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[O:8][C:9]3[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][CH2:19][CH3:20])=[C:13]([O:21][C:22](=[O:24])[CH3:23])[C:10]=3[C:11]=2[CH3:12])=[CH:4][CH:3]=1)([O:29][CH2:27][CH3:28])=[O:33]
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(O)cc3)c(C)c2c1OC(C)=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OCC(=O)OCC)cc3)c(C)c2c1OC(C)=O

Procedure:
A mixture of 2-(p-hydroxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran (107 mg; 0.28 mmole), ethylbromoacetate (100 mg, 0.60 mmole), potassium carbonate (100 mg, 0.73 mmole) in acetone (10 mL) was refluxed for 30 minutes. The solids were filtered off, the filtrate was concentrated in vacuo to yield a residue that was purified by chromatography on silica gel. Elution with 20% ethylacetate in hexane yielded 133 (100%) of 2-(p-carboethoxymethoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][CH:12]([NH:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[CH3:13].ClC(C)[CH2:25][NH:26]C1C(C)=CC(C)=CC=1C.CC1C=CC=C(C)C=1N.Cl>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:11][CH:12]([CH3:13])[N:14]([C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:22])[C:25]1=[NH:26]
Reactant: Cc1cc(C)c(NCC(C)Nc2c(C)cccc2C)c(C)c1
Reactant: Cc1cc(C)c(NCC(C)Cl)c(C)c1
Agent: Cc1cccc(C)c1N
Agent: Cl
Product: Cc1cc(C)c(N2CC(C)N(c3c(C)cccc3C)C2=N)c(C)c1
Yield: 65.6 %

Procedure:
1-(2',4',6'-Trimethylphenyl-amino)-2-(2',6'-dimethylphenyl-amino)-propane, applied as starting substance, is obtained with a yield of 65.6% by reacting N-(β-chloropropyl)-2,4,6-trimethyl-aniline, a compound prepared according to Example 16, point (b), with 2,6-dimethylaniline under the conditions given in Example 16, point (c). The hydrochloride of the product melts at 174°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][O:28]C2C=NC=CC=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.OC1C=NC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][O:28][S:8]([CH3:5])(=[O:10])=[O:9])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(NC(=O)C(COc2cccnc2)NS(=O)(=O)c2ccc(Cl)cc2)c1
Agent: Oc1cccnc1
Product: CCOC(=O)c1cccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)c1
Yield: 185.6 %

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(pyridin-3-yloxy)propanamide (100 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (93.0 mg).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:39][NH2:40]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([NH:40][CH3:39])=[O:35])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CN
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: CNC(=O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and a saturated solution of methylamine (1.0 ml in DMF) were combined to give 11 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 544 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Li+].CC([N-]C(C)C)C.[CH3:19][S:20](=S)(OC)=O>C1COCC1>[Cl:1][C:2]1[C:3]2[S:10][C:9]([S:20][CH3:19])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COS(C)(=O)=S
Reactant: Clc1ncnc2ccsc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1cc2ncnc(Cl)c2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of compound 6.2 (5 mmol) in dry THF (25 mL) was added LDA (6 mmol, 2.0 M in heptane/THF/ethylbenzene) at −78° C. under an atmosphere of N2. After stirring at −78° C. for 30 minutes, the mixture was transferred to a pre-cooled solution of methyl methanethiosulfonate (8 mmol) in of dry THF (10 mL) at −78° C. The resulting mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of several portions of sat. aq. NH4Cl, concentrated and partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was separated, dried and concentrated to give a residue that was purified by flash column chromatography on silica gel to give 4-chloro-6-methylsulfanyl-thieno[3,2-d]pyrimidine (compound 63.1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])/[C:6](/[NH:18][C:19](=[O:38])[C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[O:27])=[CH:22][C:21]=1[Cl:37])=[CH:7]/[C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]([F:17])([F:16])[F:15].[CH3:40]O>>[NH2:13][C:11]1[S:12][C:8](/[CH:7]=[C:6](\[NH:18][C:19](=[O:38])[C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=3)=[O:27])=[CH:22][C:21]=2[Cl:37])/[C:5]([OH:39])=[O:4])=[C:9]([C:14]([F:15])([F:16])[F:17])[N:10]=1.[Cl:37][C:21]1[CH:22]=[C:23]([C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[O:27])[CH:24]=[CH:25][C:20]=1[C:19]([NH:18]/[C:6](=[CH:7]\[C:8]1[S:12][C:11]([NH:13][CH3:40])=[N:10][C:9]=1[C:14]([F:17])([F:15])[F:16])/[C:5]([OH:4])=[O:39])=[O:38]
Reactant: COC(=O)/C(=C/c1sc(N)nc1C(F)(F)F)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: CNc1nc(C(F)(F)F)c(/C=C(\NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)O)s1
Product: Nc1nc(C(F)(F)F)c(/C=C(\NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)O)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An aqueous 3N solution of sodium hydroxide (0.5 mL, 1.5 mmol) was added to a solution of (Z)-3-(2-amino-4-trifluoromethylthiazol-5-yl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid methyl ester (Example 234; 90 mg, 0.16 mmol) in methanol (0.5 mL). The solution was stirred at room temperature for 16 h and then at 50° C. for 2 h. The reaction mixture was evaporated to dryness and the residue was dissolved in water (2 mL). 1N Hydrochloric acid solution (1.5 mL) was added and the resulting yellow solid was filtered off and washed well with water. The mixture of crude acids was purified by reverse phase HPLC and lyophilized to give (Z)-3-(2-amino-4-trifluoromethylthiazol-5-yl)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid (15 mg) and (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2-methylamino-4-trifluoromethylthiazol-5-yl)propenoic acid (15 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: CCOC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and ethyl chloroformate by using the same method as in Example 107.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH3:10][O:11][CH2:12][CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:10][O:11][CH2:12][CH2:13][N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: O=C1CCNCC1
Reactant: COCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCN1CCC(=O)CC1

Procedure:
To a solution of 4-piperidone monohydrate hydrochloride salt (2.2 g, 14.32 mmol, 1 eq) in acetonitrile, 2-bromoethyl methyl ether (5.9 ml, 28.6 mmol, 2 eq), and K2CO3 (2 eq) was added and heated at reflux overnight. Reaction extracted into dichloromethane (50 ml), washed with water (2×50 ml), dried (MgSO4), and evaporated in vacuo to give 1-(2-methoxy-ethyl)piperidin-4-one as a yellow oil.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)s1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 46.3 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 54, 100 mg, 0.231 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (48.65 mg, 0.254 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 46% (65 g, 0.107 mmol) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:19][C:20]1[C:21](I)=[CH:22][C:23](=[O:44])[N:24]([CH2:26][CH2:27][C@@:28]([CH3:43])([S:39]([CH3:42])(=[O:41])=[O:40])[C:29]([NH:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[O:30])[CH:25]=1>O1CCOCC1.O.[Pd]>[F:19][C:20]1[C:21]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([F:7])[CH:9]=2)=[CH:22][C:23](=[O:44])[N:24]([CH2:26][CH2:27][C@@:28]([CH3:43])([S:39]([CH3:42])(=[O:40])=[O:41])[C:29]([NH:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[O:30])[CH:25]=1
Reactant: C[C@@](CCn1cc(F)c(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: COc1ccc(B(O)O)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2F)cc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Pd Encat™ (580 mg, 0.17 mmol) was added to a mixture of potassium carbonate (723 mg, 5.2 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (318 mg, 2.1 mmol), and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, T3, (900 mg, 1.7 mmol) in 1,4-dioxane:water (5:1, 24 mL). The reaction was heated to 80° C. and allowed to stir at this temperature overnight. The reaction was filtered through a pad of celite, which was washed with methanol (250 mL). The filtrate was concentrated under reduced pressure, and the resulting crude material was purified via flash chromatography using an eluent of EtOAc in heptanes (20-100%), then 10% methanol in EtOAc to provide the title compound as a light tan residue (800 mg, 99%). MS (LCMS) m/z 495.1 (M−1).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C1COCC1>[NH2:10][CH2:9][C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:14]
Reactant: CN(C)CCOc1cccc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(CN)c1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
3-(2-Dimethylamino-ethoxy)-benzonitrile (0.8 g, 1 eq, 4.1 mmol) was dissolved in THF (80 mL) and cooled down to 0-5° C. A 1.0 M solution of lithium aluminium hydride in THF (0.47 g, 3.0 eq, 12.3 mmol) was added at 0-5° C. The reaction mixture was allowed to warm to RT and was stirred for 4 hrs. After completion of the reaction (confirmed by TLC), ethyl acetate at 0-5° C. was slowly added to quench any excess of lithium aluminium hydride in the reaction mixture, followed by addition of saturated sodium sulphate solution (2 mL). The reaction mass was filtered through hy-flow bed and the filtrate was concentrated in vacuo to obtain the crude product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=O)[CH:28]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1C
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
The aniline prepared in Example 308C (180 mg, 0.48 mmol) and 3-pyridine carboxaldehyde (55 mg, 0.51 mmol) were combined in methanol (4 mL) and sodium cyanoborohydride (48 mg, 0.77 mmol) was added followed by 100 mg of crushed molecular sieves. The reaction was adjusted to pH6 with acetic acid and stirred at 25° C. for 3 hours. The reaction was concentrated and transferred directly to a column of silica gel and purified by flash chromatography (5% methanol-ethyl acetate) to give the tide compound (182 mg, 82%) as an oil that solidified after standing. 1H NMR (300 MHz, CD3OD) δ 8.54 (d, J=2.4 Hz, 1H), 8.40 (dd, J=5.1, 1.3 Hz, 1H), 7.84 (bd, J=8.4 Hz, 1H), 7.65-7.55 (m, 1H), 7.40 (dd, J=7.8, 4.7 Hz, 1H), 7.30-7.10 (m, 4H), 6.66 (dd, J=8.8, 2.3 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 4.45 (s, 2H), 3.64 (s, 3H), 2.10-1.98 (m, 8H), 1.90-1.78 (m, 1H), 1.65-1.55 (m, 1H). MS (CI) 464 (M+H)+. HRMS FAB Calcd m/z MH+ for C26H29O3N3S 464.2008, found 464.2023.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3C(C)=NO[N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=[C:33](N2CC[C@H](OC(=O)C(F)(F)F)C2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2N=1)(C)(C)C.ClCC1N(C2CC2)N=NN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:37]([CH:35]4[CH2:33][CH2:34]4)[N:38]=[N:39][N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Agent: ClCc1nnnn1C1CC1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3nnnn3C3CC3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-1-cyclopropyl-1H-tetrazole and isolated as light yellow gum. MS (m/e): 385.3 (MH+).