Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)C=O.[Cl:13]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[ClH:25]>C(Cl)(Cl)Cl>[ClH:13].[Cl:25][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Cc1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: ClCc1ccccn1
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A solution of 200 g (2.15 moles) of 2-methyl-pyridine and 14 g of dimethylformamide in 750 ml chloroform was heated at reflux while 300 g (1.29 mole) of trichloroisocyanuric acid (min. 90% available chlorine) were added thereto in portions without heating over 50 minutes as the reaction mixture remained under reflux by itself. The mixture was stirred for another 2 hours and was cooled and vacuum filtered. The filtrate was washed with 100 ml of 5% sodium hydroxide and the chloroform phase was dried over MgSO4, and filtered. 100 g (2.74 moles) of dry hydrogen chloride were added to the filtrate which was evaporated to dryness under vacuum. The residue was added to 250 ml of dry acetone and the mixture was stirred and vacuum filtered. The precipitate was washed with a little acetone and dried to obtain 185 g of 2-chloromethyl-pyridine hydrochloride. The acetone solution was cooled in the refrigerator to obtain another 42 g product for a total yield of 227 g (64.4%) melting at 120° to 122° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C@@H:13]3[CH2:17][NH:16][C@H:15]([C:18](O)=[O:19])[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:17][NH:16][C@H:15]([CH2:18][OH:19])[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: Nc1ncc(-c2cnn([C@@H]3CN[C@H](C(=O)O)C3)c2)cc1-c1nc2ccccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ncc(-c2cnn(C3CN[C@H](CO)C3)c2)cc1-c1nc2ccccc2s1
Temperature: 25 °C

Procedure:
A solution of (2S,4S)-4-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-pyrrolidine-2-carboxylic acid (10.0 mg, 0.0155 mmol) in THF (4 mL, 0.05 mol) was cooled to −78° C. LiAlH4 (1.0 M in THF; 0.2 mL, 0.2 mmol) was added slowly, and the mixture was allowed to warm to rt overnight. The material was concentrated in vacuo, then dissolved in DCM, transferred to a separatory funnel, and washed with sat. NaHCO3. The organic layer was loaded onto a prep TLC plate, eluting with 8% (7N NH3 in MeOH)/DCM. The band containing the product was filtered off using 1:1 MeOH/DCM. The filtrate was concentrated in vacuo to afford the title compound (mixture of diastereomers) as a yellow solid. MS (ES+): m/z=393.14 [MH+].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([Cl:7])=[CH:4][C:3]=1[C:8](Cl)=[O:9].[CH3:11][NH2:12]>C(Cl)Cl>[CH3:11][NH:12][C:8]([C:3]1[CH:4]=[C:5]([Cl:7])[S:6][C:2]=1[Cl:1])=[O:9]
Reactant: CN
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(Cl)sc1Cl
Reaction time: 8 h
Yield: 51 %

Procedure:
To a stirred solution of 2,5-dichloro-3-thenoyl chloride (commercially available from Maybridge Chemical Co. Ltd. 1.07 g, 5 mM) in CH2Cl2 (5 mL) was added 40% aqueous solution of methylamine (1 mL) at room temperature. After stirring overnight, the mixture was poured into CH2Cl2 (50 mL). The whole was washed with water (40 mL), brine (40 mL), dried over MgSO4, and concentrated in vacuo. The resulting solid was triturated with Et2O-hexane to give the subtitle compound (0.54 g, 51% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a solution of 3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (3.07 g), 4-hydroxybenzaldehyde (2 g) and triphenylphosphine (4.51 g) in tetrahydrofuran (50 ml) was added diethyl azodicarboxylate (2.7 ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=5:1) and dried under reduced pressure to give the title compound (3.2 g).
Reaction SMILES: [CH3:1][CH:2]1[C:7]2([CH3:11])[CH:8]([CH3:10])[CH2:9][CH:4]([C:5](C(OCC)=O)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6]2)[N:3]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH4+].[OH-]>C(N(CC)CC)C>[CH3:1][CH:2]1[C:7]([CH3:11])([CH2:6][CH2:5][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]([CH3:10])[CH2:9][CH2:4][N:3]1[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CC2(C)C(C)CC1N(Cc1ccccc1)C2C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC1(C)C(C)CCN(Cc2ccccc2)C1C
Temperature: 160 °C
Reaction time: 24 h
Yield: 93.1 %

Procedure:
A mixture of diethyl 3,4,8-trimethyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane-6,6-dicarboxylate (3.4 g, 8.8 mmol) formic acid (3 mL) and triethylamine (4 mL) was heated to 160° C. for 1.5 hours. The reaction mixture was cooled to room temperature and allowed to stand for 24 hours. The mixture was basified with concentrated NH4OH and the mixture was extracted with ether (3X). The organic layers were combined, dried over anhydrous MgSO4 and concentrated in vacuo to afford 2.6 g (93%) of ethyl 2,3,4-trimethyl-1-(phenylmethyl)-3-piperidinepropanoate as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7](Cl)=[O:8])[N:6]=1.[C:10]1([S:16]([N:19]2[C:27]3[CH:26]=[C:25]([Sn:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=[C:23]([NH2:32])[C:22]=3[CH:21]=[N:20]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:32][C:23]2[CH:24]=[C:25]([Sn:28]([CH3:31])([CH3:30])[CH3:29])[CH:26]=[C:27]3[C:22]=2[CH:21]=[N:20][N:19]3[S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)Cl)cs1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
2-Methyl-1,3-thiazole-4-carbonyl chloride (350 mg) in DCM (4 ml) was added dropwise to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (300 mg) in DCM (15 ml) and pyridine (0.167 ml). The reaction was stirred at room temperature overnight. Saturated sodium bicarbonate (aq) (25 ml) was added and the reaction vigorously stirred for 15 min. The DCM was passed through a hydrophobic frit then evaporated to dryness. The residue was dissolved in DCM and purified on a silica cartridge, preconditioned with cyclohexane, washing with cyclohexane followed by elution with ether. The ether was evaporated to give title compound (373 mg).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1
Reactant: COc1ccc(-c2c(NC(=O)C(F)(F)F)nc3ccc(C(=O)c4ccccc4)cn23)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(N)nc3ccc(C(=O)c4ccccc4)cn23)cc1

Procedure:
The 2-trifluoroacetamido-3-(4-methoxyphenyl)-6-benzoyl-imidazo[1,2-a]pyridine (4.89 g, 11.1 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 3.08 g. (80%). EA, MS(FD).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18])[CH3:2].[O:19]=[S:20]1(=[O:36])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=[O:29])[N:21]1[CH2:30][CH2:31][CH2:32][C:33](=O)[CH3:34].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(O)(C)C.CCO.[Ti+4].O>[O:19]=[S:20]1(=[O:36])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=[O:29])[N:21]1[CH2:30][CH2:31][CH2:32][CH:33]([N:15]1[CH2:16][CH2:17][CH:12]([N:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:3]([CH2:1][CH3:2])[C:4]2=[O:18])[CH2:13][CH2:14]1)[CH3:34]
Reactant: CC(=O)CCCN1C(=O)c2ccccc2S1(=O)=O
Reactant: CCn1c(=O)n(C2CCNCC2)c2ccccc21
Agent: [Ti+4]
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(C)O
Solvent: CCO
Solvent: O
Product: CCn1c(=O)n(C2CCN(C(C)CCCN3C(=O)c4ccccc4S3(=O)=O)CC2)c2ccccc21
Temperature: 55 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidine (319 mg, 1.0 mmol) and 1,1-dioxido-2-(4-oxo-pentyl)-1,2-benzisothiazol-3-(2H)-one (267 mg, 1.0 mmol) in isopropanol (0.4 mL) containing titanium (IV) isoproproxide (0.4 mL, 1.3 mmol) was heated at 55° C. under an argon atmosphere for one hour to give a yellow solution. This solution was cooled to room temperature and diluted with absolute EtOH (4 mL). Sodium cyanoborohydride (70 mg, 1.1 mmol) was added and the reaction mixture stirred for 20 hours. Upon dilution of the reaction with water and addition of aq. NaHCO3, the product was extracted into EtOAc, the extract dried (Na2SO4) and evaporated. The crude residue was chromotographed on a column of silica gel and eluted with a gradient of 0.25-1.25% methanol/chloroform to give (±)1,1-dioxido-2-(4-(4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidin-1-yl)pentyl)-1,2-benzisothiazol-3(2H)-one (referred to herein as Compound L) as a viscous oil. 1H NMR (400 mHz, CDCl3): d 8.07 (dd, J=5.5 Hz, J=1.4 Hz, 1H), 7.93 (dd, J=6.5 Hz, J=1.1 Hz, 1H), 7.85 (quintet, 2H), 7.35-7.37 (m, 1H), 7.05 (quintet, 2H), 6.98-7.02 (m, 1H), 4.33-4.38 (m, 1H), 3.93 (q, J=7.1 Hz, 2H), 3.85 (dt, J=7.3 Hz, J=3.6 Hz, 2H), 2.86-2.90 (m, 2H), 2.73 (quartet, J=6.8, 1H), 2.57 (broad t, J =10 Hz, 1H), 2.26-2.49 (overlapping quintets, 3H), 1.97 (quintet, 2H), 1.80 (broad d, J=10 Hz, 2H), 1.61-1.69 (m, 1H), 1.41-1.48 (m, 1H), 1.33 (t, J=7.1 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H). The residual oil was converted to its hydrochloride salt and crystallized from isopropanol to give a white crystalline solid, melting point 176° C. (Compound L). Analysis calculated for C26H32N4O4S.HCl0.3 H2O: C, 57.99; H, 6.29; N, 10.41; found: C, 58.03; H, 6.19; N, 10.38.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].[CH3:17][C:18]1[C:19]([NH2:23])=[N:20][O:21][N:22]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:17][C:18]1[C:19]([NH:23][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[N:20][O:21][N:22]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: Cc1nonc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nonc1NC(=O)c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 30 h

Procedure:
495 mg (2.02 mmol) of 2-nitro-4-methylsulfonylbenzoic acid and 200 mg (2.02 mmol) of 4-methyl-1,2,5-oxadiazol-3-ylamine are dissolved at room temperature (RT) in 5 ml of CH2Cl2 and treated with 0.28 ml (2.02 mmol) of triethylamine, 49 mg (0.40 mmol) of 4-dimethylaminopyridine (DMAP) and 1.93 g (3.03 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF). The reaction mixture is stirred for 30 h at RT and subsequently washed twice with in each case 5 ml of water. The organic phase is dried over Na2SO4 and evaporated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield 350 mg (53%).
Reaction SMILES: CC1C=CC(S(O[C@H:12]([CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[CH3:13])(=O)=O)=CC=1.[CH2:21]([O:23][C:24](=[O:40])[CH2:25][N:26]=[C:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:22].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[C:28]1([C:27](=[N:26][CH:25]([C@H:12]([CH3:13])[CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH:18]=[CH2:19])[C:24]([O:23][CH2:21][CH3:22])=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C=CCCC(C)C[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCCC(C)C[C@@H](C)C(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: 110 °C
Yield: 105.2 %

Procedure:
To a solution of (2S)-4-methyloct-7-en-2-yl 4-methylbenzenesulfonate (54 g, 0.182 moles) and N-(diphenylmethylene)glycinate ethyl ester (48.7 g, 0.182 moles) in toluene (500 mL) was added LiHMDS (36.5 g, 0.218 moles, 1 M solution in THF) at 0° C. The reaction mass was allowed to come to room temperature and was then heated at 110° C. for 2 h. The reaction mass was cooled to room temperature, quenched with water and extracted with ethyl acetate (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get crude compound (3R)-ethyl 2-((diphenylmethylene)amino)-3,5-dimethylnon-8-enoate (75 g). The crude compound was taken to the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:26]3[C:22](=[O:32])[C:23]4[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:25]3=[O:27])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 50 °C

Procedure:
4′-Bromomethylbiphenyl-2-carboxylic acid t-butyl ester (4.0 g, 11.5 mmol) and potassium phthalimide were combined and dissolved in DMF (30 mL), and the mixture was heated at 50° C. for two days. The mixture was then cooled to room temperature and the reaction quenched with water (30 mL). The mixture was then extracted with EtOAc, and washed with a 10% aqueous lithium chloride solution. The organic layer was dried over MgSO4, filtered and concentrated to obtain intermediate (22a) (4.8 g). MS m/z: [M+H+] calcd for C26H23NO4, 414.5. found 414.3.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[C:27]([CH:31]=1)[C:28](O)=[O:29]>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:32]2[N:33]=[CH:34][CH:35]=[CH:36][N:37]=2)=[C:27]([C:28]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:29])[CH:31]=1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Reactant: CN(C)c1nc(N2CC3CNCC3C2)cc(C(F)(F)F)n1
Product: CN(C)c1nc(N2CC3CN(C(=O)c4cc(F)ccc4-c4ncccn4)CC3C2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 36 and Intermediate 13. MS (ESI): mass calculated for C24H23F4N7O, 501.49; m/z found 502.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.70 (d, J=4.9, 2H), 8.38-8.31 (m, 1H), 7.24-7.17 (m, 1H), 7.14-7.02 (m, 2H), 5.86 (br s, 1H), 4.06-2.78 (m, 16H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:21][C:22]1[S:31][C:25]2[N:26]=[CH:27][N:28]=[C:29](Cl)[C:24]=2[CH:23]=1.C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[Br:21][C:22]1[S:31][C:25]2[N:26]=[CH:27][N:28]=[C:29]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])[C:24]=2[CH:23]=1
Reactant: Clc1ncnc2sc(Br)cc12
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4sc(Br)cc34)n(-c3ccccc3)c(=O)c12
Yield: 42.7 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (219 mg, 0.72 mmol) was treated with 6-bromo-4-chlorothieno[2,3-d]pyrimidine (179 mg, 0.72 mmol), N,N-diisopropylethylamine (751 μl, 4.31 mmol) and tert-butanol as a solvent according to the method described in Example 17. The crude was purified using SP1® Purification (0% to 30%, hexane-ethyl acetate) to give 148 mg (42% yield) of the title compound as a white solid. Purity 97%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:22][CH2:21][N:20]([C@:23]4([CH3:35])[CH2:27][CH2:26][N:25]([C:28](OC(C)(C)C)=[O:29])[CH2:24]4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)=[CH:4][N:3]=1.Cl.O1CCOCC1.C[CH2:44][N:45](C(C)C)C(C)C.CN=C=O.C([O-])(O)=O.[Na+]>CO.C1(C)C=CC=CC=1.CS(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]3[CH2:22][CH2:21][N:20]([C@:23]4([CH3:35])[CH2:27][CH2:26][N:25]([C:28]([NH:45][CH3:44])=[O:29])[CH2:24]4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:13]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@](C)(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CN=C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CO
Product: CNC(=O)N1CC[C@@](C)(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
To a solution of tert-butyl(3R)-3-[4-(2-aminopyrimidin-5-yl)-2-(morpholin-4-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate (150 mg, 0.311 mmol) in MeOH (1.5 mL) was added 4 N HCl in dioxane (1.5 mL, 6 mmol), and the mixture was stirred at room temperature for 45 min. The mixture was diluted with toluene and concentrated under reduced pressure. The residue was triturated again with toluene to give a yellow foam. To a solution of this residue in DMSO (3 mL) was added DIPEA (0.25 mL, 1.43 mmol) and methyl isocyanate (0.021 mL, 0.342 mmol), and the mixture was stirred for 45 min. Another portion of methylisocyanate (0.005 mL) was added and the mixture was stirred at room temperature for 18 h. The mixture was dropped into 50% saturated NaHCO3 (30 mL) and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-10% (MeOH with 10% NH4OH)/(EtOAC/DCM, 1:1) as eluent. The desired fractions were concentrated to a minimum volume and the residue was taken up in MeOH/water and lyophilized to give 93 mg (68%) of the title compound as a white solid. 1H NMR (600 MHz, 80° C., DMSO-d6) δ 8.72 (s, 2 H), 6.59 (br s, 2 H), 5.72 (br d, J=3.7 Hz, 1 H), 3.75 (d, J=10.6 Hz, 1 H), 3.71-3.50 (m, 11 H), 3.41-3.24 (m, 2 H), 3.08 (t, J=8.2 Hz, 2H), 2.60 (d, J=4.5 Hz, 3 H), 2.48-2.43 (m, 1H, partially overlapped with DMSO), 2.14-2.05 (m, 1 H), 1.34 (s, 3 H). m/z (APCI+) for C21H29N9O2 440.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])=[O:3].O.C(=O)([O-])[O-].[Na+:19].[Na+].OS(O)(=O)=O.C(O)(=O)C1C(=CC=CC=1)O>O>[C:2]([O:4][C:5]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]([O-:13])=[O:12])(=[O:3])[CH3:1].[Na+:19]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: O=C(O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
An aqueous solution of sodium acetylsalicylate was prepared using 100.0 g. of aspirin, 34.6 g. of sodium carbonate hydrate and 1,425 ml. water at room temperature (25° C.). After solution of all solids had occurred, 30.0 g. of instant tea was added while stirring at room temperature. To the aqueous solution was added with rapid stirring in less than 30 seconds 280 ml. of 2N H2SO4 and stirring was continued for 15 minutes at room temperature. The pH of the reaction after acidification was 3.3. The aqueous slurry was immediately thereafter spray dired in a Nichols portable spray drier (Minor Type 53) using a Nitro atomizer having a rotational speed of 31,000 r.p.m. The operating temperatures were about 165° C. on the inlet side and less 80° C. on the exhaust side. Weight of the spray dried product was 158.5 g. Analysis of the spray dried product containing the coprecipitate showed it contained 55% aspirin, 0.64% salicylic acid and 2.7% water. Tea content of the spray dried product is approximately 18.8%.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[O:26])[C:12]3[CH:17]=[CH:16][N:15]([CH2:18][O:19]CC[Si](C)(C)C)[C:13]=3[N:14]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:19][CH2:18][N:15]1[C:13]2[N:14]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:28])[F:1])=[CH:8][CH:7]=3)[NH:10][C:11](=[O:26])[C:12]=2[CH:17]=[CH:16]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)nc2c1ccn2CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
A solution of 2-(4-(trifluoromethyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (47.7 mg, 116 μmol) in anhydrous methylene chloride (6.0 mL) was cooled, under nitrogen, to 0° C. The solution was then treated portion-wise with trifluoroacetic acid (1.5 mL). The reaction was stirred under nitrogen at 0° C. for 30 min. At this time, the reaction was warmed to room temperature where it continued to stir for an additional 3 h. At this time, the reaction was diluted with methylene chloride and was concentrated in vacuo onto Celite® while maintaining a water bath temperature less than or equal to 30° C. Flash chromatography (12 g silica gel column, 40-70% ethyl acetate/hexanes) afforded 7-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as an off-white solid (20.9 mg, 58.0%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.55 (d, J=7.91 Hz, 2H) 6.56 (d, J=3.39 Hz, 1H) 6.63 (t, J=7.35 Hz, 1H) 7.27 (d, J=3.39 Hz, 1H) 7.91 (d, J=8.48 Hz, 2H) 8.37 (d, J=8.10 Hz, 2H) 12.38 (s, 1H). LC-MS calcd. for C14H11F3N3O2 [(M+H)+] 310, obsd. 310.0.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[O:28][CH2:27][CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:29]N1C(C(O)=O)=CC(C2C=CC=CC=2)=N1>>[ClH:2].[CH3:29][N:11]1[C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23]3[O:28][CH2:27][CH2:26][NH:25][CH2:24]3)=[CH:19][CH:18]=2)=[O:15])=[CH:13][C:9]([C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[N:10]1
Reactant: Cn1nc(-c2ccccc2)cc1C(=O)O
Reactant: O=C(Nc1ccc([C@@H]2CNCCO2)cc1)c1cc(-c2ccc(Cl)cc2)n[nH]1
Agent: Cl
Product: Cn1nc(-c2ccccc2)cc1C(=O)Nc1ccc([C@@H]2CNCCO2)cc1

Procedure:
The title compound was prepared in analogy to Example 1 using (R)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (prepared in Example 12) instead of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate and 1-Methyl-3-phenyl-1H-pyrazole-5-carboxylic acid (CAS-10250-64-3) instead of 3-phenyl-1H-pyrazole-5-carboxylic acid. White solid. MS (ISP): 363.3 ([M+H]+).