Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].[CH2:18]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]Br)=[CH:28][CH:27]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].OS(O)(=O)=O>CN(C)C=O.O>[C:3]([NH:6][C:7]([CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:31][CH:30]=1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCc1ccc(CCBr)cc1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
60% NaH in oil (9.65 g) is added portionwise to a solution of diethyl acetamidomalonate (58.5 g) in dimethylformamide (240 ml) at such a rate to keep the temperature below 10° C. The resulting mixture is stirred for 90 min., the temperature being allowed to increase to room temperature. To this mixture is added dropwise within 15 min. a solution of 2-(4-octylphenyl)ethyl bromide (19) (40 g) in dimethylformamide (40 ml). The reaction mixture is heated to ca. 80° C. within ca. 25 min. and further stirred for ca. 3–5 hrs. After cooling to room temperature, water (280 ml) is added and the resulting mixture is further stirred until a beige precipitate is formed. The mixture is adjusted to pH 7 with 10% H2SO4. After cooling to ca. 2° C., the residue is filtered, washed with 200 ml water and then recrystallized in heptane to yield compound (8) as colorless crystals. The resulting compound (8) exhibits the same physico-chemical characteristics as indicated in Example 7.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.C(COC)OC.C(Cl)[Cl:37]>>[ClH:37].[F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:37])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: ClCCl
Solvent: COCCOC
Product: Cl
Product: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A cold solution of 25 g. of 4-[15-(trifluoromethyl)-pentadecylamino]benzoic acid in 500 ml. dimethoxyethane-methylene chloride (4:1) is prepared and dry hydrochloric acid is bubbled through the solution until no more precipitate forms. The solution is treated with 25 ml. thionyl chloride and refluxed until all of the precipitate has dissolved. The solvents are evaporated to yield 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride as an orange, semi-crystalline mass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.C(N(C(C)C)CC)(C)C.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30]>ClCCl.C(O)C>[CH3:30][CH:29]([N:32]1[CH2:37][CH2:36][N:35]([CH2:26][CH2:25][C:24]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=3)[CH2:6][CH2:7]2)=[O:27])[CH2:34][CH2:33]1)[CH3:31]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: CC(C)N1CCNCC1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CCN1CCN(C(C)C)CC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (1.0 g, 5.15 mmol) and polymer-bound diisopropyl ethylamine (4.20 g, 15.46 mmol) in dichloromethane (200 mL) was added acryloyl chloride (0.51 g, 5.67 mmol) via a dropwise addition. After stirring overnight at rt, the solids were removed by vacuum filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure and maintained under vacuum for several hours. A portion of this crude mixture (0.52 g, 2.1 mmol) was redissolved in absolute ethanol (25 mL) and to this was added isopropylpiperazine (0.81 g, 6.29 mmol). After heating at 60° C. for 3 hrs, the reaction was concentrated under reduced pressure and solids were recrystallized from ethyl acetate/hexanes to provide 1-{3-[4-(1-methylethyl)-1-piperazinyl]propanoyl}-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (0.62 g, 79%). ESIMS (M+H)+=377.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]3[C:12](=[NH:23])[NH:11][C:10](=N)[C:9]2=3)=[CH:4][CH:3]=1.Cl.[N:26]1([C:31]2[S:32][CH2:33][C:34](=[NH:36])[N:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1.N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[NH:23]=[C:12]1[C:13]2[CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:16][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[C:9]=2[C:10](=[C:33]2[S:32][C:31]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:35][C:34]2=[NH:36])[NH:11]1
Reactant: N=C1CSC(N2CCCC2)=N1
Reactant: N=C1NC(=N)C2=C1C(c1ccccc1)CCC2c1ccc(Br)cc1
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: N=C1N=C(N2CCCC2)SC1=C1NC(=N)C2=C1C(c1ccc(Br)cc1)CCC2c1ccccc1

Procedure:
When equivalent amounts of 4-(p-bromophenyl)-7-phenyl-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-pyrrolidino-4-imino-2-thiazoline hydrochloride are substituted for the 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride respectively, in the procedure described in Example 10, part A above, there is obtained as the product 1-imino-4-(p-bromophenyl)-7-phenyl-4,5,6,7-tetrahydro-3-(2-pyrrolidino-4-imino-2-thiazolin-5-ylidene)isoindoline.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1C#N>ClCCl>[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: N#Cc1cnccn1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: c1ccc2c(c1)nc1snc(-c3cnccn3)n12
Temperature: 25 °C
Reaction time: 36 h
Yield: 91.1 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-α]benzimidazole-3(2H)-one (300 mg, 1.213 mmol) and pyrazinecarbonitrile (319 mg, 3.03 mmol) in 8 mL of dicloromethane was stirred at room temperature for 36 hr. The precipitate was filtered and washed with dichloromethane to give 0.28 g (91%) of 3-(2-pyrazinyl)-1,2,4-thiadiazolo[4,5-α]benzimidazole as a white solid; 1H NMR (CDCl3) δ 7.32 (t, 1H, ArH), 7.50 (t, 1H, ArH), 7.83 (d, 1H, ArH), 8.67 (d, 1H, ArH), 8.87 (br.d, 2H, py-H), 9.59 (s, 1H, py-H); mp 255-256.5° C.
Reaction SMILES: [NH3:1].C(O[C:5]([CH:7]1[CH:11]([C:12]([O:14]CC)=O)[CH2:10][N:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8]1)=O)C.[Cl-].[NH4+].C1[CH2:30][O:29]CC1>>[CH2:17]([N:9]1[CH2:8][CH:7]2[CH:11]([C:12](=[O:14])[NH:1][C:30](=[O:29])[CH2:5]2)[CH2:10]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1C(=O)OCC
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Product: O=C1CC2CN(Cc3ccccc3)CC2C(=O)N1
Temperature: -40 °C

Procedure:
A solution of 9.00 mmol of Na in liquid NH3 was prepared at -78° C. To this was added 15 mg of FeCl3, and the reaction mixture was warmed to -40° C. To this solution, stirred under N2, a cooled (-40° C.) solution of the compound (957 mg) from step 457a in THF was added over a 10 minute period, and the reaction mixture was stirred at -33° C. for 3 hours. Ammonium chloride (1.5 g) was added with stirring, then the mixture was warmed to room temperature and the excess ammonia was evaporated. To this was added 60 mL of water, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried and concentrated. The residue was chromatographed on silica gel to give 425 mg of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[C:19]([NH2:27])(=[S:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:27]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:26][CH:15]=2)[CH:9]=1
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Product: O=C(O)COc1ccc(Br)cc1-c1csc(-c2ccccc2)n1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and thiobenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.69 min, m/z 390 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[C:4]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:3]1[CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH:9]=2)[C:4]([C:12](=[O:20])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[C:3]1[CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(O)cc2n1C
Reactant: BrCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 180 mg of the phenol from Step E in 5 mL of DMF were added 124 mg of milled K2CO3 followed by 150 mg of 2-(bromomethyl) quinoline. The mixture was stirred at R.T. for 18 h, poured onto 25% aq. NH4OAc and extracted with ethyl acetate. The extract was dried over Na2SO4 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to give the title compound as a foam,
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][C:18]([N:20]1[C:28]2[C:23](=[C:24]([F:39])[C:25]([C:29]3[C:33]4[C:34]([NH2:38])=[N:35][CH:36]=[CH:37][C:32]=4[O:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19].O>CN(C=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][C:18]([N:20]1[C:28]2[C:23](=[C:24]([F:39])[C:25]([C:29]3[C:33]4[C:34]([NH2:38])=[N:35][CH:36]=[C:37]([I:8])[C:32]=4[O:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: Nc1nccc2occ(-c3ccc4c(c3F)CCN4C(=O)Cc3cc(F)ccc3F)c12
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2occ(-c3ccc4c(c3F)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A solution of NIS (130 mg, 0.578 mmol) in DMF (2 mL) was added dropwise to a solution of 3-{1-[(2,5-difluorophenyl)acetyl]-4-fluoro-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (190 mg, 0.449 mmol) in DMF (2.5 mL) at −40° C., and the mixture was stirred and allowed to slowly warm to room temperature. It was stirred for 25 hours then poured into water (25 mL) and stirred for a few minutes. The precipitate was collected by vacuum filtration. The damp solid was then rinsed into another filter flask using DCM (50 mL), and the filtrate was dried (Na2SO4), filtered, and concentrated in vacuo to give 3-{1[(2,5-difluorophenyl)acetyl]-4-fluoro-2,3-dihydro-1H-indol-5-yl}-7-iodofuro[3,2-c]pyridin-4-amine (252 mg) as a dark solid. LC/MS (ES) m/z=550 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][C:9]([CH3:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:7]2[N:22]=[CH:23][C:24]([C:25]#[N:26])=[C:6]12)=[O:4].[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[ClH:1].[CH3:11][C:9]1[CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:36]2[CH2:35][CH2:34][N:33]([CH2:32][C:31]3[CH:39]=[CH:40][CH:41]=[C:29]([C:28]([F:42])([F:43])[F:27])[CH:30]=3)[CH2:38][CH2:37]2)[C:6]2[N:7]([N:22]=[CH:23][C:24]=2[C:25]#[N:26])[C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1
Reactant: CC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CCl)C1
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CN2CCN(Cc3cccc(C(F)(F)F)c3)CC2)C1
Product: Cl

Procedure:
A mixture of 1.83 g of 4-(chloroacetyl)-7-[3(trifluoromethyl)phenyl]-4,5-dihydro-6-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile, 1.5 g of 3(trifluoromethyl)benzylpiperazine, 2 g of potassium carbonate and 60 ml of toluene was reacted as described in Example 16, giving the base form of the product, which was converted to the hydrochloride salt by the procedure of Example 97, giving 1.78 g, mp 195°-198°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].Cl[CH2:11][CH2:12][C:13](Cl)=[O:14].[Al+3].[Cl-].[Cl-].[Cl-].S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:11][CH2:12][C:13]2=[O:14])=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: O=C(Cl)CCCl
Reactant: COc1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)C(=O)CC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-2-methoxybenzene (12.8 mL, 100 mmol) and 3-chloropropanoyl chloride (10.5 mL, 110 mmol) in CH2Cl2 (100 mL) at 0° C. was added AlCl3 (14.6 g, 110 mmol) portionwise during about 1 minute. After 30 minutes, sulfuric acid (300 mL) was poured slowly into the reaction mixture during about 3 minutes. The CH2Cl2 was removed by rotary evaporation under reduced pressure and the viscous residue was stirred at 100 ° C. for 2 hours. After cooling to ˜50° C., the viscous reaction mixture was poured cautiously onto 1.5 L of ice and allowed to stand overnight. The mixture was filtered and the cake of crude product was washed with water. The crude product was dissolved in 500 mL of 2% MeOH in CH2Cl2, dried over a mixture of Na2CO3 (˜10 g) and Na2SO4 (˜20 g), filtered and concentrated under vacuum to give 6-chloro-5-methoxyindan-1-one as an off-white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:15]3[N:43]=[CH:42][S:41][C:16]=3[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:38]=[CH:39][CH:40]=3)[CH2:23][NH:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[N:19]=2)[CH:10]=[CH:11][CH:12]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:15]3[N:43]=[CH:42][S:41][C:16]=3[N:17]=[C:18]([C:20]3[CH:40]=[CH:39][CH:38]=[C:22]([CH2:23][NH:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:21]=3)[N:19]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: C[C@H]1CCCN1c1cccc(Nc2nc(-c3cccc(CNC4CCN(C(=O)OC(C)(C)C)CC4)c3)nc3scnc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CCCN1c1cccc(Nc2nc(-c3cccc(CNC4CCNCC4)c3)nc3scnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a stirred solution of (S)-tert-butyl 4-(3-(7-(3-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzylamino)piperidine-1-carboxylate (110 mg, 0.184 mmol) in 2 mL of DCM was added 2 mL of 2,2,2-trifluoroacetic acid. The solution was stirred at room temperature overnight. The mixture was washed with NaHCO3(aq.), the organic layer was concentrated. The residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% TFA V/V) initially, and then proceed to 55% acetonitrile/45% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give (S)—N-(3-(2-methylpyrrolidin-1-yl)phenyl)-5-(3-((piperidin-4-ylamino)methyl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine 2,2,2-trifluoroacetate (40 mg, 43%) as an oil. 1H NMR (300 MHz, DMSO): δ 9.18 (s, 1H), 8.60 (s, 1H), 8.51 (dd, 1H, J1=7.5 Hz, J2=1.2 Hz), 7.92 (s, 1H), 7.84 (brs, 1H), 7.68-7.52 (m, 3H), 7.15 (brs, 1H), 4.40 (s, 2H), 4.08-4.01 (m, 2H), 3.87-3.85 (m, 1H), 3.64-3.55 (m, 4H), 3.17-3.08 (m, 2H), 2.48-2.21 (m, 5H), 2.03-1.87 (m, 3 h), 1.34 (d, 3H, J=6.3 Hz). LC-MS: 250 [M/2+H]+, 500 [M+H]+, tR=1.20 min. HPLC: 100% at 214 nm, 100% at 254 nm, tR=4.59 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:42][C:43]([F:60])([F:59])[C:44]1[CH:49]=[CH:48][C:47]([S:50]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)(=[O:52])=[O:51])=[CH:46][CH:45]=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:56]2[CH2:55][CH2:54][N:53]([S:50]([C:47]3[CH:46]=[CH:45][C:44]([C:43]([F:59])([F:60])[F:42])=[CH:49][CH:48]=3)(=[O:51])=[O:52])[CH2:58][CH2:57]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Cl)nc1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
To a suspension of 6-chloro nicotinic acid (1.76 g, 11.2 mmol) in DCM (50 ml) at 0° C. was added EDC.HCl (2.93 g, 15.3 mmol), HOBt (2.34 g, 15.3 mmol) and DIPEA (7.52 ml, 40.8 mmol) and the mixture stirred for 20 min. 1-{[4-(Trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 1) (3.00 g, 10.2 mmol) was added and the solution allowed to warm to room temperature, then stirred overnight. The mixture was diluted with DCM (20 ml), washed with water (5×20 ml), then the organic layers dried (Na2SO4) and concentrated under vacuum to leave the crude compound. Flash chromatography (silica; 60% EtOAc in pet. ether) gave the title compound as a white solid (2.20 g).
Reaction SMILES: N[C@H:2]([C:5](O)=[O:6])C[SeH].[C:8]([CH2:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([OH:10])=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1.C(OCC)C>[C:5]([CH:11]1[C:12]2[C:13](=[CH:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=2)[C:14](=[O:15])[O:16][C:8]1=[O:10])(=[O:6])[CH3:2]
Reactant: N[C@@H](C[SeH])C(=O)O
Reactant: COc1ccc(C(=O)O)c(CC(=O)O)c1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(C(C)=O)C(=O)OC2=O
Reaction time: 3 h

Procedure:
Following a literature procedure (Ind. J. Chem. Sec. B, 1986, 25B, 640-643), 2-carboxymethyl-4-methoxybenzoic acid (1.0 g; 4.8 mmol) was dissolved in a mixture of pyridine (1.4 mL) and acetic anhydride (8.6 mL; 9.3 g; 91 mmol) then stirred for 3 hours, during which time a solid had formed. The suspension was diluted with diethyl ether, filtered and the filter cake washed with diethyl ether. Yield: 905 mg (81%) of 4-acetyl-6-methoxyisochroman-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[C:10]([CH2:12][NH2:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:20][CH:21]([CH3:25])[C:22](O)=[O:23].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][C:22](=[O:23])[CH:21]([CH3:25])[CH3:20])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)C(=O)O
Reactant: NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(=O)NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reaction time: 8 h

Procedure:
(2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanamine from Example 145 (0.1 g) was added to a pre-stirred (15 minutes) solution of 2-methylpropanoic acid (1.2 eq), 1-hydroxybenzotriazole (1.1), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.1), triethylamine (2 eq) in N,N-dimethylformamide (2.77 mL). The reaction was stirred overnight then extracted with Ethyl Acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to give quantitative yield of N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)isobutyramide.
Reaction SMILES: [CH3:1][Si:2]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])OCC.[CH3:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N([C:21]1C=CC(O)=CC=1)=O>C(OCC)C>[CH:13]([C:14]1[CH:21]=[CH:18][C:17]([Si:2]([CH3:1])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])=[CH:16][CH:15]=1)=[CH2:12]
Reactant: CCO[Si](C)(OCC)OCC
Reactant: O=Nc1ccc(O)cc1
Reactant: CCCCCCC
Solvent: CCOCC
Product: C=Cc1ccc([Si](C)(OCC)OCC)cc1
Temperature: 2 °C
Yield: 70.3 %

Procedure:
A, is slowly added dropwise in order to achieve a permanent exothermal reaction. The solvent is stirred under reflux at ambient pressure. After termination of said exothermal reaction, the reaction mixture is cooled down to 2° C., and subsequently, 155.5 g (872 mmol) methyl triethoxysilane in 160 ml dry diethyl ether is added; the temperature should not substantially exceed 15° C. After termination of the substitution reaction, stirring is continued over night at ambient temperature. Subsequently, about 200 ml n-heptane is added to obtain a precipitation of the magnesium salts. The magnesium salts are separated by filtration, 5.4 g (0.44 mmol) 4-nitrosophenol is added to the filtrate, the solvent is removed in a rotary evaporator, and the residue is subjected to a fractionating distillation under vacuum. 72.5 g (307 mmol) of the product was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23]([OH:25])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.Cl.[CH3:55][NH:56][O:57][CH3:58]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23](=[O:25])[N:56]([O:57][CH3:58])[CH3:55])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNOC
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)OC)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.7 %

Procedure:
30 g (81.6 mmol) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 800 ml CH2Cl2 were treated with 62.8 ml (571.2, 7 eq) NMM, 2.19 g (16.24 mmol, 0.2 eq) hydroxybenzotriazole, 37.5 g (195.84 mmol, 2.4 eq) EDCI and 17.5 g (179.52 mmol, 2.2 eq) N,O-dimethylhydroxylamine-hydrochloride. The solution was stirred for 3 h at RT, concentrated and dissolved in 500 ml 1M KHSO4 solution and 500 ml EtOAc were added. The organic layer was separated and washed with brine, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography on silica gel with EtOAc:hexane 1:1 as eluent yielding 3.6 g (62.4%) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as light yellow oil, MS: 411 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1([C:15]([O:17]CC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:4].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[O:17]=[C:15]1[N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:2][C:3](=[O:4])[N:5]2[CH2:9][CH2:8][CH2:7][C:6]12[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1C(=O)CBr
Solvent: CC#N
Product: CCOC(=O)C12CCCN1C(=O)CN(Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of diethyl 1-(bromoacetyl)-2,2-pyrrolidinedicarboxylate (D64, 950 mg) in acetonitrile (10 mL) at r.t, benzylamine (340 microL) was added. The resulting mixture was stirred at r.t. for 3.5 hours: the formation of a white solid was observed. The suspension was then filtered over a Gooch funnel. The organic filtrate was diluted with ethyl acetate (15 mL) and washed with water (2×10 mL). The organic phase was dried and concentrated in vacuo to a residue which was purified by flash chromatography (Cycl/EtOAc from 50/50 to 35:65) to give the desired compound (200 mg) as colourless oil.