Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])=[O:4].C(N(CC)CC)C.[C:27]1([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[OH:39][C:33]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:38][CH2:37][N:36]([C@H:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:7])=[O:4])[CH2:35][CH2:34]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: C[C@H](OC(=O)C(Br)c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](OC(=O)[C@@H](c1ccccc1)N1CCC(O)(c2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.3 %

Procedure:
To a solution of (S)-1-phenylethyl 2-bromo-2-phenylacetate (1.50 g, 4.70 mmol) in THF (25 mL) was added triethylamine (1.31 mL, 9.42 mmol), followed by tetrabutylammonium iodide (0.347 g, 0.94 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then a solution of 4-phenyl-4-hydroxypiperidine (1.00 g, 5.64 mmol) in THF (5 mL) was added. The mixture was stirred for 16 hours and then it was diluted with ethyl acetate (100 mL), washed (H2O×2, brine), dried (MgSO4), filtered and concentrated. The residue was purified on a silica gel column (0-60% ethyl acetate-hexane) to provide an approximately 2:1 mixture of diastereomers, as judged by 1H NMR. Separation of these isomers was performed using supercritical fluid chromatography (Chiralcel OJ-H, 30×250 mm; 20% ethanol in CO2 at 35° C.), to give first the (R)-isomer of the title compound (0.534 g, 27%) as a yellow oil and then the corresponding (S)-isomer (0.271 g, 14%), also as a yellow oil. (S,R)-isomer: 1H NMR (400 MHz, CD3OD) δ 7.55-7.47 (m, 4H), 7.44-7.25 (m, 10H), 7.25-7.17 (m, 1H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s, 1H), 2.82-2.72 (m, 1H), 2.64 (dt, J=11.1, 2.5 Hz, 1H), 2.58-2.52 (m, 1H), 2.40 (dt, J=11.1, 2.5 Hz, 1H), 2.20 (dt, J=12.1, 4.6 Hz, 1H), 2.10 (dt, J=12.1, 4.6 Hz, 1H), 1.72-1.57 (m, 2H), 1.53 (d, J=6.5 Hz, 3H). LCMS: Anal. Calcd. for C27H29NO3: 415; found: 416 (M+H)+; (S,S)-isomer: H1NMR (400 MHz, CD3OD) δ 7.55-7.48 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.30 (m, 5H), 7.25-7.13 (m, 4H), 7.08-7.00 (m, 2H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s, 1H), 2.95-2.85 (m, 1H), 2.68 (dt, J=11.1, 2.5 Hz, 1H), 2.57-2.52 (m, 1H), 2.42 (dt, J=11.1, 2.5 Hz, 1H), 2.25 (dt, J=12.1, 4.6 Hz, 1H), 2.12 (dt, J=12.1, 4.6 Hz, 1H), 1.73 (dd, J=13.6, 3.0 Hz, 1H), 1.64 (dd, J=13.6, 3.0 Hz, 1H), 1.40 (d, J=6.6 Hz, 3H). LCMS: Anal. Calcd. for C27H29NO3: 415; found: 416 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]=[CH:20][NH:21][C:22](=O)[C:23]=4[N:24]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:26]1P(Cl)(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=NP=1(Cl)Cl.CCN(C(C)C)C(C)C.N>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]=[CH:20][N:21]=[C:22]([NH2:26])[C:23]=4[N:24]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Reactant: O=c1[nH]cnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)nc12
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ncnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)nc12
Temperature: 25 °C
Yield: 16.2 %

Procedure:
6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4 (3H)-one (100 mg, 0.28 mmol), phosphonitrilic chloride (100 mg, 0.28 mmol) and as stir bar were transferred to a vial, capped and placed under nitrogen atmosphere. Dry acetonitrile (3 mL) was transferred and allowed the contents to stir at room temperature. i-Pr2NEt was added for 2 min to the heterogeneous slurry. Upon stirring the red homogeneous slurry for 2 h, nitrogen balloon was replaced with NH3 balloon and stirred. After stirring the contents for 6 h, the reaction mixture was concentrated and the crude residue was partitioned between chloroform/water. Organic layer was removed and re-extracted the aqueous layer with chloroform. Usual workup and purification by preparative HPLC provided 6-(2-(3-Chloro-4-fluorophenyl)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (16 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([F:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]1=[O:25].CCN(C(C)C)C(C)C.[Cl:35][C:36]1[CH:41]=[N:40][C:39](Cl)=[CH:38][N:37]=1.CCOCC>CN(C=O)C.[Cl-].[Na+].O>[Cl:35][C:36]1[N:37]=[CH:38][C:39]([N:22]2[CH2:23][CH2:24][CH:19]([N:16]3[CH2:17][CH2:18][C@H:14]([NH:13][C:3]4[CH:4]=[C:5]([F:12])[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=4[F:1])[C:15]3=[O:25])[CH2:20][CH2:21]2)=[N:40][CH:41]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: CS(=O)(=O)c1cc(F)c(N[C@H]2CCN(C3CCNCC3)C2=O)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(F)c(N[C@H]2CCN(C3CCN(c4cnc(Cl)cn4)CC3)C2=O)cc1F
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 42.5 %

Procedure:
To a solution of (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Table 2, compound 1; 1.5 g, 4.02 mmol) and DIEA (3.50 mL, 20.1 mmol) in DMF (15 mL) was added 2,5-dichloropyrazine (1.20 g, 8.03 mmol). This mixture was heated to 100° C. for 3 hours under nitrogen. The mixture was poured into brine (150 mL) and extracted into ethyl acetate (3×500 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an oil. Ether (100 mL) was added and a precipitate formed overnight. The ether was decanted and the solid was triturated using ethanol (100 mL) at reflux with stirring for 5 minutes. The material was purified by column chromatography using 50% to 100% ethyl acetate/hexane. The resulting solid was dried over the weekend under high vacuum to provide the title compound (0.83 g, 39% yield). Mass spectrum (apci) m/z=486.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH2:24])[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][O:20][C:21](=[O:23])[CH3:22])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2].O.[C:27]([OH:31])(=[O:30])[CH:28]=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]([CH:5]1[CH:6]([CH2:7][O:8][CH3:9])[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][O:20][C:21](=[O:23])[CH3:22])[NH:12][C:11]=2[CH:28]([C:27]([OH:31])=[O:30])[NH:24]1)=[O:25])[CH3:2]
Reactant: O=CC(=O)O
Reactant: CCOC(=O)C(N)C(COC)c1c[nH]c2cccc(COC(C)=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1NC(C(=O)O)c2[nH]c3cccc(COC(C)=O)c3c2C1COC
Temperature: 0 °C

Procedure:
A solution of 3-(4-acetoxymethylindol-3-yl)-2-amino-4-methoxy-butyric acid ethyl ester (8.7 g) in ethyl acetate (40 ml) is slowly added drop by drop to a solution of glyoxylic acid monohydrate (2.4 g) in water (30 ml), cooled to 0° C., under argon protection and with stirring. The pH of the solution is adjusted to 4 by addition of potassium carbonate (about 1 g). Then the mixture is stirred for 2 hours, whereby it is allowed to warm to room temperature. Ethyl acetate and water phases are separated, the water phase is shaken out three times with ethyl acetate. The combined ethyl acetate extracts, for their part, are washed once with water, dried with sodium sulfate and evaporated. 9 g of the title compound remains.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C:20]([F:27])([F:26])[C:21]1([OH:25])[CH2:24][NH:23][CH2:22]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][C:21]([OH:25])([C:20]([F:27])([F:26])[F:19])[CH2:22]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: OC1(C(F)(F)F)CNC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: O=C(c1ccc(C2CC2)c(OCC2CC2)n1)N1CC(O)(C(F)(F)F)C1
Yield: 22.9 %

Procedure:
In analogy to the procedure described in Example 127 e), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 20 mg, 85.7 μmol) was reacted with 3-(trifluoromethyl)azetidin-3-ol hydrochloride (CAN 848192-96-1, 18.3 mg, 103 μmol) to obtain the title compound (7 mg, 23%) as colorless oil, MS (EI): m/e=357.3 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([OH:13])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].C(#N)C=C>[C:7]([CH2:6][CH2:5][N:11]1[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][C:6]=2[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[N:8][CH:9]([OH:13])[C:10]1=[O:12])#[N:8]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: C=CC#N
Product: N#CCCN1C(=O)C(O)N=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1 g of Teba and 8 drops of a 40% methanolic solution of Triton B were added to a suspension of 10 g of 7-chloro-3-hydroxy-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one ("Lorazepam") in 50 ml of acrylonitrile and the mixture was stirred for 24 hours at room temperature. Then the reaction mixture was cooled to 4° C., the precipitate was filtered and recrystallized from ethyl acetate. 1-(2-Cyanoethyl)-7-chloro-3-hydroxy-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 198° to 202° C., was obtained. Without addition of Teba also the disubstituted 1-(2-cyanoethyl)-7-chloro-3-(2-cyanoethoxy)-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 210° to 213° C. (from acetonitrile), is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:11]([C:23]3[CH:24]=[CH:25][C:26]([NH:48]CC4C=CC(OC)=CC=4OC)=[C:27]([NH:29][C:30]([C@@H:32]4[CH2:36][CH2:35][CH2:34][N:33]4[C:37](=[O:47])[C@@H:38]([NH:42][C:43](=[O:46])[O:44][CH3:45])[CH:39]([CH3:41])[CH3:40])=[O:31])[CH:28]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:48][C:26]1[CH:25]=[CH:24][C:23]([CH:11]2[CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]2[C:13]2[CH:14]=[CH:15][C:16]([C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:17][CH:18]=2)=[CH:28][C:27]=1[NH:29][C:30]([C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37](=[O:47])[C@@H:38]([NH:42][C:43](=[O:46])[O:44][CH3:45])[CH:39]([CH3:41])[CH3:40])=[O:31]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cc(C2CCC(c3ccc(Br)cc3)N2c2ccc(C(C)(C)C)cc2)ccc1NCc1ccc(OC)cc1OC)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cc(C2CCC(c3ccc(Br)cc3)N2c2ccc(C(C)(C)C)cc2)ccc1N)C(C)C
Reaction time: 0.17 h

Procedure:
The product from example 191G (0.65 g, 0.748 mmole) was dissolved in CH2Cl2 (10 mL) then added concentrated trifluoroacetic acid (2 mL, 26 mmole)) and the reaction mixture was stirred 10 minutes. The solvent was removed in vacuo and the residue was re-evaporated twice from CH2Cl2 and once from toluene. The residue was dissolved in EtOAc (100 mL) washed with 10% NaHCO3, dried over anhydrous Na2SO4(s), filtered and solvent removed in vacuo leaving a brown foamy material as the title compound as a mixture of isomers (0.5 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.I[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:20][CH:19]=1.C(Cl)Cl.CO>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COC(=O)CCCc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)CCCc1ccc(-c2ccc(N)cc2)cc1
Temperature: 110 °C
Yield: 82.5 %

Procedure:
Solid 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (158 mg, 0.723 mmol) and Pd(PPh3)4 (38 mg, 0.033 mmol) were added to a solution of methyl 4-(4-iodophenyl)butanoate (200 mg, 0.657 mmol) in dimethoxyethane/2M Na2CO3 (3 mL, 2:1) at rt. The resulting mixture was degassed with argon gas then heated at 110° C. using microwave for 30 min. The reaction mixture was diluted with EtOAc (10 mL) then washed with H2O (10 mL), brine (10 mL), dried over Na2SO4, and concentrated to give crude (294 mg) as brown oil. Chromatography (9:1, CH2Cl2/MeOH) afforded the title compound (146 mg, 82%) as a light yellow solid. ES/MS calcd. for C17H20NO2+ 270.2. Found m/z=270.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[F:16][C:17]([F:37])([F:36])[C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[N:24]=[CH:23]2)=[O:19]>C1COCC1.CCOCC>[F:37][C:17]([F:16])([F:36])[C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[N:24]=[CH:23]2)([C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1)[OH:19]
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: COc1ncc(Br)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ncc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C
Reaction time: 0.5 h

Procedure:
To a chilled (−78° C.) solution of 5-bromo-3-methyl-2-methoxypyridine (1.56 mmol) in 2 mL THF was added dropwise n-butyllithium (1.71 mmol from a 2.5 M solution in hexanes). The mixture was stirred for 30 minutes and then 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (1.39 mmol) in 3 mL THF was added. After 30 minutes, the mixture was diluted with ether and quenched with aqueous ammonium chloride. The organic layer was washed with brine and dried over magnesium sulfate. Removal of the volatiles in vacuo provided a residue which was purified by Combiflash chromatography using ethyl acetate-hexane. The product-rich fractions were concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12](OC)[CH2:13][Cl:14]>>[CH3:10][O:11][CH:12]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][Cl:14]
Reactant: COC(CCl)OC
Reactant: NC(=O)c1ccccc1
Product: COC(CCl)NC(=O)c1ccccc1
Temperature: 70 °C
Yield: 91 %

Procedure:
85 g of a strongly acidic ion exchanging resin having an exchange capacity of 4 meq/g was placed in a glass column having an inner diameter of 35 mm, and this was heated to a temperature of 70° C. in a hot bath. To this was supplied a solution of 1 part per weight of benzamide dissolved in 10 parts per weight of chloroacetaldehyde dimethyl acetal at a rate of 230 g per hour via a volumetric pump. 230 g of the reaction fluid discharged from the column was concentrated by distillation chloroacetaldehyde dimethyl acetal under reduced pressure so as to reach an amount of 130 g. Next, 100 ml of n-hexane was added thereto, the precipitated crystals were filtered out, and thus 33.7 g of N-(1-methoxy-2-chloroethyl)-benzamide [Compound (1)] was obtained. With respect to the expended benzamide, the yield was 91%.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.Cl.[CH3:25][O:26][CH2:27][C:28]1([NH2:31])[CH2:30][CH2:29]1>>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:31][C:28]3([CH2:27][O:26][CH3:25])[CH2:30][CH2:29]3)=[O:13])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COCC1(N)CC1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Agent: Cl
Product: COCC1(NC(=O)c2ccc(-n3ncc(-c4ccnc(OC)c4)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 1-(methoxymethyl)cyclopropanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (s, 4H) 3.28 (s, 3H) 3.48 (s, 2H) 3.90 (s, 3H) 7.49 (br. s., 1H) 7.57 (d, J=5.3 Hz, 1H) 8.08 (d, J=5.6 Hz, 1H) 8.35-8.50 (m, 2H) 8.68 (br. s., 1H) 8.90 (t, J=1.4 Hz, 1H) 8.98 (s, 1H). MS m/z 396 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:25](I)([CH3:27])[CH3:26]>CN(C=O)C.O.O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:25]([CH3:27])[CH3:26])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1
Reactant: CC(C)I
Reactant: Clc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)n1cnc2c(Nc3cccc(Cl)c3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
500 mg (1.78 mmol) of 2-chloro-6-(3-chloro-phenyl-amino)-purine are dissolved in a mixture of 29.5 ml of DMF/water (85/15) and 5 ml of dioxane by means of gentle heating. 870 mg (2.67 mmol) of caesium carbonate, followed by 1.78 ml (17.8 mmol) of isopropyl iodide are added at room temperature. The reaction mixture is stirred at room temperature for 18 hours. To bring the reaction to completion, the reaction mixture is stirred at 45° C. for a further 24 hours. When the reaction has ended, the reaction mixture is diluted with ethyl acetate, washed with water (2 times) and saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure at 35° C. and the residue is dried under an HV. The resulting crude product is purified by crystallization from diethyl ether/hexane. 2-Chloro-6-(3-chloro-phenyl-amino)-9-isopropyl-9H-purine is obtained; Rf=0.46 (ethyl acetate); m.p. 128–129° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:58][C:59]([F:69])([F:68])[CH2:60][N:61]1[CH2:66][CH2:65][CH:64]([NH2:67])[CH2:63][CH2:62]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:67][CH:64]5[CH2:65][CH2:66][N:61]([CH2:60][C:59]([F:69])([F:58])[F:68])[CH2:62][CH2:63]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(CC(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(CC(F)(F)F)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-N-(2,2,2-trifluoroethyl)piperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.44 (m, 4 H) 1.55-1.89 (m, 10 H) 2.42 (t, J=8.0 Hz, 2 H) 2.94 (br. d., 2 H) 3.17 (q, J=10.11 Hz, 2 H) 3.31 (s, 3 H) 3.78 (m, 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.39 Hz, 2 H) 7.47 (d, J=8.0 Hz, 1 H) 7.50 (s, 1 H) 7.91 (s, 1 H) 8.15 (d, J=8.02 Hz, 1 H) 8.21 (s, 1 H) 8.27 (d, J=8.34 Hz, 1 H). Melting point: 213-215° C. [M+H] calculated for C29H36F5N7O3, 626; found 626.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3](=O)[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:15]1[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:17][O:18][C:19]=1[CH3:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:20][C:19]1[O:18][N:17]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[C:7]1[NH:8][C:9]2[C:14]([C:6]=1[CH2:5][CH2:4][CH2:3][N:2]([CH3:28])[CH3:1])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCC(=O)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCCN(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.0 g (0.0054 mole) of N,N-dimethyl-2-(5-methyl-3-phenyl-4-isoxazolyl)-3-indole propionamide in 80 ml tetrahydrofuran is added to a suspension of 0.82 g (0.0216 mole) of lithium aluminum hydride in 40 ml tetrahydrofuran dropwise, maintaining the temperature between 20° and 25° C. After the addition is complete the mixture is stirred at room temperature for two hours, cooled and quenched by the addition of 2 ml of water in 20 ml tetrahydrofuran. The resulting mixture is dried over magnesium sulfate, filtered and evaporated. The solid residue is recrystallized from ethanol to give 2-(5-methyl-3-phenyl-4-isoxazolyl)-3-(3-dimethylaminopropyl)-indole m.p. 156° to 157° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11](COCC[Si](C)(C)C)[CH:10]=2)=[N:5]1.FC(F)(F)C(O)=O.N>>[OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[N:5]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccn(CCO)n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccn(CCO)n5)c34)n(-c3ccccc3)c(=O)c12
Yield: 96.1 %

Procedure:
(S)-2-(1-((5-(1-(2-Hydroxyethyl)-1H-pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (30 mg, 0.05 mmol) was treated with trifluoroacetic acid (1 ml, 13 mmol) and a solution of ammonia (7N in methanol, 2 ml, 14 mmol) according to the method described in Example 27 to give 23.8 mg (100% yield) of the title compound. Purity 98%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[CH:13]OCC)[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=O)[CH3:2].[N+:18]([CH2:21][C:22]([NH2:24])=[O:23])([O-:20])=[O:19].C([O-])(=O)C.[Na+].Cl>C(O)C>[N+:18]([C:21]1[C:22](=[O:23])[NH:24][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH:13]=1)([O-:20])=[O:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)OCC
Reactant: NC(=O)C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc([N+](=O)[O-])c(=O)[nH]c1C(=O)OCC
Temperature: 0 °C
Reaction time: 15 h
Yield: 79.3 %

Procedure:
Diethyl(ethoxymethylene)oxalacetate (5.63 g, 0.023 mol,) is dissolved under N2 atmosphere in 20 mL of absolute ethanol and cooled to 0° C. Nitroacetamide (2.00 g, 0.019 mol,) (S. K. Brownstein, J. Org. Chem 23, 113 (1958)) and sodium acetate (1.56 g, 0.019 mol,) are added and the mixture is stirred at room temperature for 15 hours. The suspension is diluted with 15 mL of absolute ethanol and acidified to pH 2 with concentrated HCl. The inorganics are removed by filtration and the filtrate is concentrated to an oily solid which is gravity chromatographed, first with methylene chloride and then 2% methanol in methylene chloride. The fractions are combined and stripped to give 4.28 g of the title product as a yellow solid, 78.4% yield, melting point 144°-145° C.