Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH3:25])[C:4]=2[N:3]=1.[Cl:26][C:27]1[CH:28]=[C:29]([OH:38])[CH:30]=[C:31]([O:33][C:34]([F:37])([F:36])[F:35])[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[C:31]([O:33][C:34]([F:35])([F:36])[F:37])[CH:32]=1)[O:38][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH3:25])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: Oc1cc(Cl)cc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(Oc1cc(Cl)cc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of the 8-bromo-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)— dione (50 mg, 0.116 mmol, intermediate 63) in DMF (2 mL) was added 3-chloro-5-(trifluoromethoxy)phenol (29.82 mg, 0.140 mmol) followed by potassium carbonate (24.24 mg, 0.175 mmol). The reaction was stirred at 85° C. for 2 h. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product, which was purified by preparative HPLC to give 8-(3-chloro-5-(trifluoromethoxy)phenoxy)-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (35 mg, 53.5% yield) as white solid. 1H-NMR (CD3OD) δ 7.458-7.435(m,3H), 7.381-7.365(m,3H), 7.361(s,1H), 5.507(s,2H), 4.138-4.102(t,2H), 3.640-3.608(t,2H), 3.448(s,3H), 1.905-1.871(m,2H). LCMS retention time 3.325 min; LCMS MH+ 559.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)=[O:5].[C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29](O)=[O:30])=[CH:23]2)#[N:19]>C(OCC)(=O)C.Cl>[CH2:11]([C@H:3]([NH:2][C:29]([C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([C:18]#[N:19])=[CH:28][CH:27]=2)=[O:30])[C:4](=[O:5])[N:6]1[CH2:10][CH2:9][S:8][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCSC1
Reactant: N#Cc1ccc2[nH]c(C(=O)O)cc2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]c(C(=O)N[C@@H](Cc3ccccc3)C(=O)N3CCSC3)cc2c1

Procedure:
(S)-2-Amino-3-phenyl-1-thiazolidin-3-yl-propan-1-one hydrochloride (4.0 mmol) and 5-cyano-1H-indole-2-carboxylic acid (4.0 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 48 hours reaction time) with the following workup: the reaction mixture was diluted with ethyl acetate and 2 N HCl, the resulting precipitate collected by filtration, washed with 2 N HCl and 2 N NaOH. The crude product was purified by chromatography on silica gel eluted with 30, 40 and 60% ethyl acetate in hexanes. Yield 1.22 g, 75%; HPLC (60/40) 4.74 minutes (97%); PBMS 405 (MH+, 100%);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[C:16]([CH3:23])([CH3:22])[CH2:15]1.O[N:25]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N>C(=O)(O)[O-].[Na+].O1CCOCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:25])=[O:13])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:20])(=[O:21])[C:16]([CH3:23])([CH3:22])[CH2:15]1
Reactant: On1nnc2ccccc21
Reactant: CC1(C)CC(c2c[nH]c3c(C(=O)O)cc(Br)cc23)CCS1(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: N
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CCS1(=O)=O
Temperature: 10 °C
Yield: 67.9 %

Procedure:
(racemic)-5-bromo-3-(1,1-dioxido-2,2-dimethylthian-4-yl)-1H-indole-7-carboxylic acid (490 mg, 1.224 mmol), was placed in a microwave flask and dissolved with DMF (2 mL) and 1,4-Dioxane (8 mL). HOBt (1-hydroxybenzotriazole) (165 mg, 1.224 mmol) and EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) (657 mg, 3.43 mmol) was added. 0.5N NH3 in dioxane (7.34 mL, 3.67 mmol) was added. The reaction mixture was heated under microwave at 10° C. for 20 minutes. The reaction was diluted with saturated aqueous solution of sodium bicarbonate (20 mL) and extracted with ethyl acetate (2×). The organic layers were combined and washed with water, dried (MgSO4) and the solvent was removed under vacuum. The residue was dissolved in the minimum amount of EtOAc (around 2 mL, sonicating and heating when necessary), precipitated by adding hexane, and then filtering off the solid. This operation was repeated on the filtrate to increase the recovery affording a total of 332 mg of the title compound as a pale yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]([NH:17][C:18]3[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35]([NH:24][C:19]3[C:18]([NH:17][C:15]([O:14][CH2:13][CH:10]4[CH2:9][CH2:8][N:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH2:12][CH2:11]4)=[O:16])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:36])=[CH:32][CH:33]=2)[NH:28][CH:27]=1
Reactant: O=C(O)c1ccc2c(Br)c[nH]c2c1
Reactant: Nc1ccccc1NC(=O)OCC1CCN(c2ccncc2)CC1
Product: O=C(Nc1ccccc1NC(=O)c1ccc2c(Br)c[nH]c2c1)OCC1CCN(c2ccncc2)CC1

Procedure:
Using the procedure described in Example 23, Part C, and purifying with preparative RPHPLC method A, N2-[1-(4-Pyridyl)-piperidin-4-yl]methoxycarbonyl-1,2-benzenediamine (326 mg, 1.0 mmol) and 3-bromoindole-6-carboxylic acid (240 mg, 1.0 mmol) yielded the title compound.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[CH:7]=1.O(C1C=CC(N)=CC=1)C1C=CC=CC=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)[NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:59][CH:58]=2)C)=CC=1)C(O)=O)C>>[CH3:20][O:19][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([CH3:14])([C:16](=[O:18])[NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:59][CH:58]=2)[CH3:15])[CH:7]=1)[C:3]([OH:2])=[O:21]
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Reactant: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)O)c1)OC
Agent: Nc1ccc(Oc2ccccc2)cc1
Product: CO[C@@H](Cc1cccc(OC(C)(C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)c1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (EXAMPLE 56, step 2) and 4-phenoxy-phenyl amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C28H31NO6 [M−H]−: 476.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:13]#[N:14])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[ClH:16]>C(O)C.[Pt]=O>[ClH:16].[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:13][NH2:14])[CH3:2]
Reactant: CCOC(=O)C(C#N)=Cc1ccccc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CN)Cc1ccccc1

Procedure:
A solution of 1.01 g of 2-cyano-3-phenylpropenoic acid ethyl ester and 0.7 ml of concentrated hydrochloric acid in 20 ml of ethanol was hydrogenated over 0.1 g of platinum oxide under a hydrogen atmosphere at room temperature for 5 hours. After filtration of the catalyst, the filtrate was concentrated under reduced pressure. The residue was dissolved in water, washed with benzene, and then made alkaline by adding a 5% aqueous sodium bicarbonate solution. The alkaline solution was extracted with diethyl ether, the ethereal layer was washed with water and dried over anhydrous magnesium sulfate. Hydrogen chloride gas was passed into the ethereal solution. The ethereal solution was concentrated under reduced pressure to obtain 832 mg of 3-amino-2-benzylpropionic acid ethyl ester hydrochloride as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:25]=[C:24]([CH3:26])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:25]=[C:24]([CH3:26])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[N:14]([O-])=O.[Na+]>S(=O)(=O)(O)O>[CH3:13][C:3]1[C:2]2[NH:1][N:14]=[N:12][C:11]=2[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(N)c(N)c1C
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1ccc2nn[nH]c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
Methyl 3,4-diamino-2-methylbenzoate (0.27 g, 1.5 mmol) was taken up in concentrated sulfuric acid (30 mL) and heated to solubilize, then cooled with an ice bath. Concurrently, sodium nitrite (0.14 g, 2.1 mmol) was solubilized in concentrated sulfuric acid (8.4 mL) using heating. This sodium nitrite solution was then cooled and added dropwise to the cooled solution of diamine. The mixture was stirred at 0° C. for 30 minutes then warmed to 60° C. for 15 minutes. The solution was then poured onto ice and extracted with 10% methanol in ethyl acetate (2×100 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to give 0.3 g of crude methyl 7-methyl-1H-benzotriazole-6-carboxylate, which was taken up in methanol (5 mL) and tetrahydrofuran (10 mL) and treated with 2M aqueous lithium hydroxide (5 mL), then heated to 70° C. for one hour. This solution was made acidic using concentrated aqueous hydrochloric acid, then extracted with 10% methanol in ethyl acetate (2×50 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to give 0.26 g of 7-methyl-1H-benzotriazole-6-carboxylic acid. 1H NMR (400 MHz, d6-DMSO): 7.94 (d, 1H), 7.72 (m, 1H), 2.95 (s, 3H). MS (EI) for C8H7N3O2: 178 (MH+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[OH-].[K+]>CO>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH:19]=[C:20]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ncccc23)CC1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine (3 g, 25 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4.2 g, 21 mmol) and potassium hydroxide (3.56 g, 63 mmol) were added in MeOH (60 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (300 mL). The mixture was extracted with 10% MeOH/CH2Cl2 (5×150 mL). The organic extracts was dried over Na2SO4 and concentrated to form a solid. The solid was washed with MeOH (150 mL), filtered and dried to give a light yellow solid 5.7 g (91%). TLC (silica, 50% EtOAc/hexanes): Rf=0.3. MS (electrospray): exact mass calculated for C17H21N3O2, 299.16; m/z found, 300.2 [M++H]. 1H NMR (CDCl3, 400 MHz) 10.97 (br s, 1H), 8.33 (dd, J=3.33 Hz, 1.37 Hz, 1H), 8.20 (dd, J=6.65 Hz, 1.37 Hz, 1H), 7.34 (br s, 1H), 7.25 (s, 1H), 7.13 (dd, J=4.89 Hz, 3.13 Hz, 1H), 4.14 (br s, 2H), 3.68 (t, J=5.28 Hz, 2H), 2.56 (br s, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[C:8]=2[N:28]=1)[CH3:2].[O:34]=[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[N:36]1[CH2:45][C:46](O)=[O:47].N1(C2C=CN=CC=2)CCCC1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[O:34]=[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[N:36]1[CH2:45][C:46]([O:33][C:30]([CH3:32])([CH3:31])[CH2:29][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([N:17]3[C:18](=[O:27])[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:25]3=[O:26])[C:8]=2[N:28]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])=[O:47]
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Reactant: CCOCc1nc2c(N3C(=O)c4ccccc4C3=O)nc3ccccc3c2n1CC(C)(C)O
Agent: CC(C)N=C=NC(C)C
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCOCc1nc2c(N3C(=O)c4ccccc4C3=O)nc3ccccc3c2n1CC(C)(C)OC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
2-(2-(Ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-yl)isoindoline-1,3-dione (1600 mg, 3.6 mmol), 1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetic acid (CAN 4702-13-0, 2.22 g, 10.8 mmol) and 4-(1-pyrrolidinyl)-pyridine (800 mg, 5.4 mmol) were combined with DCM (36 mL) to give a white suspension. N,N′-diisopropylcarbodiimide (1.68 mL, 10.8 mmol) and molecular sieves were added. The reaction mixture was heated to 50° C. and stirred for 2 hours and was, after cooling, filtered. The filtrate was diluted with DCM (150 mL) and washed with 1 N hydrochloric acid and water. Water phases were extracted with DCM, organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo. Diisopropylurea was removed after trituration with DCM/methanol by filtration, the filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give a light yellow solid. Crystallization from DMSO yielded a first crop of product (1.95 g), and the mother liquor after concentration and preparative HPLC another 0.13 g of product. In total 2.08 g (91%) of the title compound was isolated as white solid; LC-MS (UV peak area, ESI) 95.9%, 632.2157 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3F)=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][C:31]([CH2:32][NH2:33])=[C:26]2[CH:25]=[N:24]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([C:14]3[C:15]([NH:33][CH2:32][C:31]4[CH:30]=[CH:29][N:28]=[C:27]5[NH:23][N:24]=[CH:25][C:26]=45)=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:21])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: NCc1ccnc2[nH]ncc12
Reactant: CC1(C)CCNc2cc(NC(=O)c3cccnc3F)ccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCNc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ncc34)ccc21
Temperature: 120 °C

Procedure:
N-(4,4-Dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoro-nicotinamide (60 mg, 0.201 mmol) was dissolved in NMP (0.5 mL), then C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine (36 mg, 0.243 mmol) and DIEA (70 μL, 0.401 mmol) were added. The mixture was heated at 120° C. overnight. Additional C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine (14 mg, 0.094 mmol) and DIEA (35 μL, 0.200 mmol) were added and the mixture was heated at 120° C. overnight. The mixture was partitioned between water and EtOAc. The mixture was diluted with EtOAc then washed with water and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification was achieved by preparative TLC (10% MeOH/CH2Cl2) to give N-(4,4-dimethyl-1,2,3,4-tetrahydro-7-quinolinyl)-2-((1H-pyrazolo[3,4-b]pyridin-4-ylmethyl)amino)-3-pyridinecarboxamide as a yellow solid. MS m/e 428.2(M+H)+. Calc'd for C24H25N7O—427.51.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S=C1NC(CCC2NC3=NC=C(C4C=CC([S:50]([NH:53][C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=5[CH3:60])(=[O:52])=[O:51])=CC=4)C=C3N=2)CCCC1.N>CO>[NH2:25][C:23]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][C:14]2[NH:13][C:10]3=[N:11][CH:12]=[C:7]([C:1]4[CH:2]=[CH:3][C:4]([S:50]([NH:53][C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=5[CH3:60])(=[O:51])=[O:52])=[CH:5][CH:6]=4)[CH:8]=[C:9]3[N:15]=2)[N:24]=1
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Agent: N
Solvent: CO
Product: Cc1ccccc1NS(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(N)=N4)nc3c2)cc1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 71 mg of 4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-o-tolyl-benzenesulfonamide (compound A9) and 3.2 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 66 hours. Subsequently, the solution is concentrated in vacuo to yield 60 mg of the pure title compound as an amorphous, colorless solid of m.p. 215° C. ESI-MS: 503.4 (MH+), TLC: Rf=0.25 (HPTLC RP-C18; acetonitrile/water 2:1 parts by volume).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][C@H:6]([NH:22][C:23](=O)[O:24]C(C)(C)C)[C@H:7]([OH:21])[CH2:8][NH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([I:20])[CH:18]=2)[O:13][CH2:12][CH2:11]1.[CH3:34]CN(CC)CC.C(C1NC=CN=1)(=O)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][C@H:6]([NH:22][C:23](=[O:24])[CH3:34])[C@H:7]([OH:21])[CH2:8][NH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([I:20])[CH:18]=2)[O:13][CH2:12][CH2:11]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1CCOc2ccc(I)cc21
Agent: CC(=O)c1ncc[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1CCOc2ccc(I)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
Tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-3,4-dihydro-2H-chromen-4-yl)amino]propylcarbamate (3.0 g, 5.2 mmol) was dissolved in 30 mL of 25% TFA/CH2Cl2 and stirred at room temperature for 30 min. The mixture was diluted with CH2Cl2 50 mL and washed with NaHCO3 (2×30 mL). The organic layer was washed with brine (1×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the resulting residue dissolved in 52 mL of CH2Cl2. The mixture was chilled to 0° C. followed by the addition of Et3N (1. mL, 11.9 mmol) and acetyl imidazole (0.68 g, 6.2 mmol). The mixture was warm spontaneously over night. The CH2Cl2 was removed in vacuo and the residue dissolved in EtOAc (100 mL) and washed with 1N HCl (2×30 mL), NaHCO3 (1×30 mL), brine, dried over Na2SO4, and conc. in vacuo to yield 2.5 g (92%) of the title compound as a light yellow solid. MS (ESI+) for C21H23F2IN2O3 m/z 517.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:49][CH3:50])[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:16]=[C:17]([C:34]2[CH:35]=[C:36]([CH:44]=[C:45]([F:48])[C:46]=2[CH3:47])[C:37]([O:39]C(C)(C)C)=[O:38])[C:18]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:19]=2[N:20]=1)[CH3:9].ClCCl.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:49]([N:10]([CH2:8][CH3:9])[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[N:16]=[C:17]([C:34]2[CH:35]=[C:36]([CH:44]=[C:45]([F:48])[C:46]=2[CH3:47])[C:37]([OH:39])=[O:38])[C:18]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([C:26]3[C:27]([F:33])=[CH:28][CH:29]=[CH:30][C:31]=3[F:32])[C:19]=2[N:20]=1)[CH3:50]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)OC(C)(C)C)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To the crude compound 1,1-dimethylethyl 3-[2-{[3-(diethylamino)-propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoate trifluoroacetate in dichloromethane (1.5 mL, 23.3 mmol) were added TFA (0.703 mL, 9.5 mmol) and triethylsilane (0.281 mL, 1.82 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA afforded the title compound (301 mg, 40%, 2 steps yield). LC-MS m/z 540 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:7])[CH3:2].[Na].[K]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:7])[CH3:2]
Reactant: CCOC(=O)C[C@H](N)c1ccccc1
Agent: [K]
Agent: [Na]
Product: CCOC(=O)C[C@@H](N)c1ccccc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
In a 25 ml flask, 13.0 g of D-β-phenylalanine ethyl ester was charged under nitrogen, and sodium-potassium alloy (Na : K = 56 : 44 by weight) (0.1 g) was added thereto. The mixture was stirred at 20°C for 3 hours. The reaction mixture was treated as in Example 11 to give 12.1 g of racemic β-phenylalanine ethyl ester. B.P. 95° to 96°C/0.6 mmHg. [α]D25 -0.1° (neat).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=2)=[CH:11][C:10]([C:22](OCC)=[O:23])=[N:9]1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=2)=[CH:11][C:10]([CH:22]=[O:23])=[N:9]1
Reactant: CCOC(=O)c1cc(Sc2cccc(OC)n2)n(-c2ccccc2Cl)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cccc(Sc2cc(C=O)nn2-c2ccccc2Cl)n1
Temperature: -30 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of ethyl 1-(2-chlorophenyl)-5-[(6-methoxypyridin-2-yl)thio]-1H-pyrazole-3-carboxylate (594 mg) in tetrahydrofuran (6 mL) was added a solution (3 mL) of 1.5 mol/L diisobutylaluminum hydride in toluene at −78° C., and the mixture was stirred at the same temperature for 30 min and at −30° C. for 1 hr. 1 mol/L Aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in toluene (8 mL) was added manganese dioxide (1.79 g) and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a yellow oil (yield 406 mg, yield 77%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=3[CH3:29])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[N:19]1[CH2:18][CH2:17][N:16]([C:14]([C:11]2[CH:10]=[CH:9][C:8]([N:1]3[CH2:5][CH2:4][CH2:3][C:2]3=[O:6])=[N:13][CH:12]=2)=[O:15])[CH2:21][CH2:20]1
Reactant: O=C1CCCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4=O)nc3)CC2)c(C)c1
Yield: 56.6 %

Procedure:
Using pyrrolidin-2-one (89 mg) and (6-bromopyridin-3-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (374 mg) described in Preparation Example 115 and by the reaction and treatment in the same manner as in Example 1, the title compound (214 mg) was obtained.