Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([F:17])([F:16])[F:15])[C:7]2[CH2:11][O:10][B:9]([OH:12])[C:8]=2[CH:13]=1)([O-])=O.C([O-])(O)=O.[Na+].CCOC(C)=O>CO.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([F:16])([F:17])[F:15])[C:7]2[CH2:11][O:10][B:9]([OH:12])[C:8]=2[CH:13]=1
Reactant: O=[N+]([O-])c1cc2c(c(C(F)(F)F)c1)COB2O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc2c(c(C(F)(F)F)c1)COB2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-nitro-4-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXXXI) (0.95 g, 3.83 mmol) in MeOH/2M HCl mixture (1:1) (129 mL) was added Zn (dust) (2.5 g, 38.31 nmol). The reaction mixture was stirred at room temperature for 3 hours before it was slowly neutralized by a solution of saturated aq. NaHCO3/EtOAc (1:1, 100 mL/100 mL). Then the reaction mixture was filtered through Celite and washed with EtOAc. The organic layer was washed with 5% NaHCO3, brine, dried over anhydrous MgSO4, filtered and evaporated to dryness to yield 6-amino-4-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXXXII) as a slightly brown crystalline solid (700 mg, 3.22 mmol, 84% yield). ESIMS found for C8H7BF3NO2 m/z 216.4 (M−H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[C:18]([CH3:21])[N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Br)[N:24]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[C:25]([NH:1][C@H:2]([C:4]2[N:5]=[C:6]3[S:20][CH:19]=[C:18]([CH3:21])[N:7]3[C:8](=[O:17])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH3:3])[N:24]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: Cc1csc2nc([C@H](C)N)c(-c3cccc(F)c3)c(=O)n12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc([C@H](C)Nc3nc(N)nc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Temperature: 100 °C
Yield: 18.7 %

Procedure:
A solution of 7-[(1S)-1-aminoethyl]-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.33 mmol) and 2-amino-6-bromopurine (0.11 g, 0.49 mmol) in 1-butanol (0.66 mL) was treated with N,N-diisopropylethylamine (86 μL, 0.49 mmol), degassed with nitrogen for 5 min and heated at 100° C. for 18 hours. The reaction was not complete and was, therefore, heated at 115° C. for an additional 5 hours. The reaction mixture was diluted with methanol (10 mL), stirred, and filtered. The filtrate was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (27 mg, 19%) as a white solid. LCMS for C20H18FN8OS (M+H)+: m/z=437.0.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:4]1.Cl[C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)C>[CH3:15][O:14][C:12]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:3]([NH:2][C:17]1[C:18]3[C:25]([CH3:26])=[CH:24][S:23][C:19]=3[N:20]=[CH:21][N:22]=1)[CH2:4]2)=[O:13]
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: COC(=O)c1cccc2c1CC(N)C2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c1CC(Nc1ncnc3scc(C)c13)C2

Procedure:
Using 2-(tert-butoxycarbonylamino)-4-methoxycarbonylindan (45 mg, 0.15 mmol) synthesized in the above Preparation Example 7, 4N hydrochloric acid-dioxane (0.7 ml) and acetic acid (2.1 ml), a similar procedure to Example 24 was carried out to obtain 2-amino-4-methoxycarbonylindan hydrochloride. Then, using the 2-amino-4-methoxycarbonylindan hydrochloride, 4-chloro-5-methylthieno[2,3-d]pyrimidine (28 mg, 0.15 mmol), triethylamine (63 μl, 0.45 mmol), and ethanol (1 ml), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (15 mg, 0.044 mmol) having the following physical properties:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][CH2:13][CH2:14]Br)[CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:10]([O:12][CH2:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: OCc1ccc(O)cc1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1ccc(CO)cc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxybenzyl alcohol (3.00 g), 2-bromoethyl ethyl ether (4.1 ml), potassium carbonate (6.68 g) and DMF (30 ml) was stirred at 90° C. for 3 days. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:2→1:1) to obtain 4-(2-ethoxyethoxy)benzyl alcohol (2.45 g) as a light yellow, oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]=O)=[CH:15][CH:14]=1>>[CH3:7][C:5]1[N:6]=[C:2]([CH3:1])[N:3]2[CH2:8][CH2:9][NH:10][CH:21]([CH2:20][CH2:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]([F:11])([F:23])[F:24])=[CH:14][CH:15]=3)[C:4]=12
Reactant: Cc1cn(CCN)c(C)n1
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Product: Cc1nc(C)n2c1C(CCc1ccc(C(F)(F)F)cc1)NCC2

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(4-trifluoromethyl-phenyl)-propionaldehyde. LC-MS: tR=0.64 min.; [M+H]+=324 g/mol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([NH:18][CH:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:17])=[CH:10][C:9]=2[O:28][CH3:29])[CH:7]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH:2]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([NH:18][CH:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:17])=[CH:10][C:9]=2[O:28][CH3:29])[CH:7]=1)=[O:1]
Reactant: COc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1cnc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cc(/C=C/C(=O)NC2CCc3ccccc32)ccc1-n1cnc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 201 %

Procedure:
To a chloroform (5 mL) solution of (E)-3-(4-(4-hydroxymethyl-1H-imidazol-1-yl)-3-methoxyphenyl)-N-indan-1-ylacrylamide (15 mg) obtained in Example 45, activated manganese dioxide (280 mg) was added, and the reaction mixture was agitated at room temperature overnight. The reaction solution was filtered through a filter paper and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:ethyl acetate), and 30 mg of the title compound was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:15]=2[N:16]=1.[O:13]1[C:14]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:15]=2[N:16]=[CH:12]1
Reactant: C#CCCc1nc2cc(C#N)ccc2o1
Reactant: Ic1ccccn1
Product: N#Cc1ccc2oc(CCC#Cc3ccccn3)nc2c1
Product: N#Cc1ccc2ocnc2c1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (89 mg, 0.43 mmol) and 2-(but-3-ynyl)benzo[d]oxazole-5-carbonitrile (100 mg, 0.51 mmol) at room temperature. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 45 mg (0.16 mmol, 37%) of 2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-5-carbonitrile as a brown solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].C([O-])([O-])=[O:15].[Na+].[Na+]>>[OH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(Br)c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1ccc(O)c(C(=O)O)c1
Yield: 82 %

Procedure:
The same procedure as described in Example 24 was performed but using 2.45 g (10.0 mmol) of 4-bromoisophthalic acid as the substrate and 2.70 g (25.5 mmol) of Na2CO3 instead of Ca(OH)2. A total of 1.49 g (8.2 mmol, 82% yield) of 4-hydroxyisophthalic acid was collected. The purity was determined by 1H NMR to be 88%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:8][C:5]2[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ncc(Br)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Bromo-3-nitropyridin-2-ol (30.00 g, 0.137 mmol) and p-toluenesulfonyl chloride (30.03 g, 0.158 mmol) were suspended in CH2Cl2 under N2 and treated dropwise with triethylamine (38.2 mL, 0.274 mmol) prior to the addition of DMAP (3.35 g, 0.027 mmol). After stirring at rt for 16 h the mixture was diluted with CH2Cl2 (500 mL) then washed with 1M HCl(aq) (2×500 mL) and brine (500 mL). The aqueous layer was back-extracted with CH2Cl2 (200 mL) and the combined organic layers dried over Na2SO4, and concentrated in vacuo. The crude material thus isolated was chromatographed over silica gel eluting with 50% EtOAc/hexane to give, on evaporation, a solid which was crystallized from 50% EtOAc/hexane to afford 5-bromo-3-nitropyridin-2-yl 4-methylbenzenesulfonate. 1H NMR (400 MHz, CDCl3) δ 2.51 (s, 3H), 7.43 (dd, 2H, J=8.4, 0.4 Hz), 7.99 (dt, 2H, J=6.8, 2.0 Hz), 8.52 (d, 1H, J=2.4 Hz), 8.60 (d, 1H, J=2.4 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][C:11]1[N:12](CC2C=CC=CC=2)[N:13]=[N:14][CH:15]=1.[H][H]>CO.CCOC(C)=O.[Pd].Br[Zn]Br>[NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][C:11]1[CH:15]=[N:14][NH:13][N:12]=1.[ClH:9]
Reactant: NCc1cc(Cl)ccc1Nc1cnnn1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Br[Zn]Br
Solvent: CCOC(C)=O
Solvent: CO
Product: Cl
Product: NCc1cc(Cl)ccc1Nc1cn[nH]n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-[2-(aminomethyl)-4-chloro-phenyl]-3-benzyl-triazol-4-amine 7b (439 mg, 1.40 mmol) in dry MeOH (18 mL) and EtOAc (18 mL) was treated with dibromozinc (126.0 mg, 0.56 mmol). The degassed mixture was then treated with 10% palladium on carbon (297.8 mg, 0.28 mmol) before affixing a hydrogen balloon. The mixture was stirred at room temperature for 2 h before filtering through celite and concentrating. The material was purified on an ISCO (0-100% MeOH in DCM) and the freebase was stirred in 4N HCl in dioxane for 30 min before evaporating to afford the title compound I-34 (mono hydrochloride salt) as a solid (291 mg, 80%). 1H NMR (500 MHz, DMSO-d6) δ 8.52 (1H, s) 8.47 (3H, m), 7.63 (1H, d), 7.53 (s, 1H), 7.48 (1H, d), 7.31 (1H, d) 4.12 (2H, q). MS m/z: 224.1 (M+H)+.
Reaction SMILES: C(OC(N1CCC([CH2:14][NH:15][C:16]2[N:21]3[N:22]=[CH:23][C:24]([Br:25])=[C:20]3[N:19]=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[CH:17]=2)CC1)=O)(C)(C)C.S(=O)(=O)(O)O.O1[CH2:43][CH2:42]OCC1>CO>[Br:25][C:24]1[CH:23]=[N:22][N:21]2[C:16]([N:15]([CH:43]3[CH2:42][CH2:14][NH:15][CH2:16][CH2:17]3)[CH3:14])=[CH:17][C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[N:19][C:20]=12
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(-c3ccccc3Cl)nc3c(Br)cnn23)CC1
Reactant: C1COCCO1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CN(c1cc(-c2ccccc2Cl)nc2c(Br)cnn12)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
4-{[3-Bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester (441 mg, 0.847 mmoles) (prepared as described in Example 460, Step A above) was dissolved in methanol (4.5 mL) and 10% (v/v) conc. sulfuric acid in 1,4-dioxane (11.46 mL) was added. The mixture was stirred at 25° C. for 0.5 h. The product was worked up as described in Preparative Example 241, step B and chromatographed on a silica gel column (15×5 cm) using 8% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give [3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl]piperidin-4-yl methylamine (314.4 mg, 88%): FABMS: m/z 420.0 (MH+); HRFABMS: m/z 420.0585 (MH+). Calcd. for C18H20N5BrCl: m/z 420.0591; δH (CDCl3) 1.34 (2H, m, CH2), 1.86 (2H, m, CH2), 1.91 (1H, m, CH), 2.10 (1H, bm, piperidine-NH), 2.67 (2H, m, CH2), 3.18 (2H, m, CH2), 3.38 (2H, m, CH2), 6.37 (1H, s, H6), 6.53 (1H, m, NH), 7.42 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.06 ppm (1H, s Ar—H); δC (CDCl3) CH2: 31.2, 31.2, 46.2, 46.2, 48.4; CH: 36.4, 89.5, 127.1, 130.1, 130.5, 131.6, 143.8; C: 83.2, 132.1, 138.9, 145.6, 146.4, 158.1.
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.C(Cl)CCl.[C:15]([O:19][C:20](=[O:50])[CH2:21][CH:22]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:35]=[C:36]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)[CH:37]=[CH:38][CH:39]=2)=[CH:28][CH:27]=1)[C:23](O)=[O:24])([CH3:18])([CH3:17])[CH3:16].[OH-].[NH4+]>ClCCl>[C:15]([O:19][C:20](=[O:50])[CH2:21][CH:22]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:35]=[C:36]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)[CH:37]=[CH:38][CH:39]=2)=[CH:28][CH:27]=1)[C:23]([NH2:2])=[O:24])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)CC(C(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CC(C(N)=O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Yield: 96.1 %

Procedure:
1-hydroxybenzotriazole (225 mg, 1.65 mmol) and EDC (315 mg, 1.65 mmol) were added sequentially to compound 50.3 (750 mg, 1.5 mmol) in dichloromethane (25 mL). The resulting mixture was stirred for 1 h before ammonium hydroxide (25% in water, 630 mg, 4.5 mmol) was added dropwise. The reaction was quenched after 30 min. with water (10 mL). The reaction mixture was extracted with dichloromethane (10 mL×3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pleasure. The product was purified via flash chromatography (50% ethyl acetate in hexanes) to yield 51.1 (720 mg) as a white solid. MS ESI (pos.) m/e: 500 (M+H). 1H NMR (400 MHz) (CDCl3) δ 7.72 (4H, s); 7.68 (1H, s); 7.57-7.48 (3H, m); 7.29-7.25 (2H, m); 7.0-6.97 (2H, d, J=6,8 Hz); 5.14 (2H, s); 3.91-3.88 (1H, m); 3.19-3.13 (1H, m); 2.60-2.55 (1H, m); 1.4 (9H, s).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].NC1CCC2C=CC=CC=2N(CC(OC(C)(C)C)=O)C1=O.C(=O)C1C=CC=CC=1>C(O)C>[C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Solvent: CCO
Solvent: O=Cc1ccccc1
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 186.6 %

Procedure:
A solution of 12.65 g of L-(+)-tartaric acid in 54 ml of ethanol which had been heated to 650° C. was added to a solution, which had been heated to 65° C., of 24.5 g of the racemic tert-butyl 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation, see Example II). The reaction mixture was stirred at room temperature for one hour. A solution of 1.72 ml of benzaldehyde in 1.3 ml of ethanol was then added dropwise. The resulting suspension was boiled under reflux at 800° C. for 14 hours and then cooled down to room temperature. The resulting crystalline precipitate was filtered out with suction and taken up in 80 ml of ethanol; this solution was boiled under reflux for a further 8 hours. It was then cooled down to room temperature and the crystals were filtered out with suction and dried at 50° C. under reduced pressure. 23.6 g of tartaric acid salt were obtained with a melting point of from 195° to 196° C. and an optical rotation value [α]20D of -152° C. (c=0.5 in methanol). In order to liberate the base, 23.6 g of the tartaric acid salt in a mixture consisting of 250 ml of water and 108 ml of dichloromethane were cooled down to 0° C., while being stirred, and adjusted to pH 9.6 by adding aqueous ammonium solution. The organic phase was separated, and the aqueous phase was extracted with a further 30 ml of dichloromethane; the organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The remaining residue was crystallized from methyl tert-butyl ether and dried under reduced pressure. 12.2 g of tert-butyl (3S) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate were obtained with a melting point of from 113° to 115° C. and an optical rotation value [α]20D of -276.2° (c=0.5 in methanol).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.S(Cl)(Cl)=O.[CH2:23](O)[CH3:24]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:23][CH3:24])=[O:5]
Reactant: CCO
Reactant: COc1c(F)ccc(C(=O)O)c1F
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(F)c(OC)c1F
Temperature: 60 °C
Reaction time: 7 h

Procedure:
2,4-Difluoro-3-methoxybenzoic acid (18.8 g) was placed in a reaction vessel and was suspended in 100 ml of toluene added thereto at room temperature. After dropwise addition of 0.5 mL of N,N-dimethylformamide, 14.6 mL of thionyl chloride was added dropwise, and the resulting mixture was heated to 60° C. with stirring. After 7 hours, 50 mL of ethanol was added and an insoluble matter was filtered out. The filtrate was washed with water and saturated brine, and dried with anhydrous sodium sulfate. The solvent was distilled away to give the title compound (21.4 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:44])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[N:28][C:29]([NH2:43])=[C:30](OS(C3C=CC(C)=CC=3)(=O)=O)[CH:31]=2)=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O.O>[CH3:17][O:18][C:19](=[O:44])[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[N:28][C:29]([NH2:43])=[C:30]([O:10][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=3[C:11]([F:12])([F:13])[F:14])[CH3:9])[CH:31]=2)=[CH:24][CH:25]=1
Reactant: CC(O)c1cccc(F)c1C(F)(F)F
Reactant: COC(=O)c1ccc(-c2cnc(N)c(OS(=O)(=O)c3ccc(C)cc3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cnc(N)c(OC(C)c3cccc(F)c3C(F)(F)F)c2)cc1
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
To a stirred solution of 1-(3-fluoro-2-trifluoromethyl-phenyl)-ethanol (2.0 g, 9.6 mmol) in anhydrous DMF (500 mL) at 0° C. under a N2 atmosphere was added NaH (0.38 g, 9.6 mmol). The reaction was allowed to stir for 0.5 hr. A solution of 4-[6-Amino-5-(toluene-4-sulfonyloxy)-pyridin-3-yl]-benzoic acid methyl ester (3.8 g, 9.6 mmol) in anhydrous DMF (30 mL) was added to the reaction mixture which was allowed to come to ambient temperature slowly and stirred for 21 hr at this temperature. The reaction was diluted with EtOAc (500 mL) and H2O (100 mL). The organic layer was separated off and the aqueous was further extracted with EtOAc (1×200 mL). The organic layers were combined and washed with brine (1×100 mL), dried with Na2SO4 and concentrated to dryness under vacuum. The crude mixture was purified by column chromatography (silica gel, 40:60 to 70:30 EtOAc:hexanes) and the fractions containing product were combined and concentrated in vacuo to yield 4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid methyl ester (1.4 g, 3.2 mmol, 34%). 1H NMR (CDCl3, 300 MHz) δ 1.73 (d, 3H, J, 6.2 Hz), 3.91 (s, 3H), 4.87-4.64 (brs, 2H), 5.81 (q, 1H, J, 6.1; 6.3 Hz), 6.92 (d, 1H, J, 1.8 Hz), 7.38 (d, 2H, J, 8.5 Hz), 7.46-7.66 (m, 3H), 7.93 (d, 1H, J, 1.8 Hz), 8.02 (d, 2H, J, 8.5 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:34][CH2:35][CH2:36][CH:37]1[O:41][CH2:40][CH2:39][O:38]1>>[C:1]([O:5][C:6]([NH:8][CH:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:21][CH2:34][CH2:35][CH2:36][CH:37]2[O:41][CH2:40][CH2:39][O:38]2)=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1
Reactant: ClCCCC1OCCO1
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)OCCCC3OCCO3)cc2)c1

Procedure:
The title compound was prepared from 4-((3-(((tert-butoxycarbonyl)amino)-(phenyl)methyl)phenoxy)methyl)benzoic acid and 2-(3-chloropropyl)-1,3-dioxolane according to the method of Chiral Example 5 Step 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.Cl.[C:13]([Cl:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.Cl>>[ClH:21].[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:10]=2)[CH:7]=1
Reactant: Nc1nc2ccc(Br)cn2n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A5), 5.0 g; 23.5 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (5.01 g; 28.2 mmol; 1.2 eq.) as a light yellow solid (6.30 g; 84%). HPLC, Rt: 1.32 min. (purity 99.6%). LC/MS, M+(ESI): 317.9. CHN analysis: [C12H8N5OBr.1.0 HCl.1.0 H20] Corrected: C, 38.68%; H, 2.98%; N 18.80%. Found: C, 38.76%; H, 3.11%; N, 18.66%.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[NH:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1.CN1CCOCC1>CN(C=O)C>[CH3:1][CH:2]([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([N:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1)=[O:6]
Reactant: CC(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Reactant: N#CC1CNC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)N1CC(C#N)C1)N1Cc2ccnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
(R)-3-Methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (80 mg, 0.29 mmol), HOBt (54 mg, 0.35 mmol) and EDC (84 mg, 0.44 mmol) were combined in DMF (2 mL). Azetidine-3-carbonitrile HCl salt (52 mg, 0.44 mmol) and N-methylmorpholine (130 μL, 1.17 mmol) were added, and the solution was stirred at room temperature for 2 h. Purification by preparative HPLC (10-45% AcCN/water with 0.035% TFA) followed by purification by silica gel chromatography (8% MeOH/DCM) gave the title compound as a white solid (28 mg, 28%). 1H NMR (500 MHz, DMSO-d6) δ 0.90 (dd, J=6.5, 2.0 Hz, 3H), 1.06 (dd, J=6.5, 2.0 Hz, 3H), 2.42-2.51 (m, 1H), 3.61-3.75 (m, 1H), 4.15-4.68 (m, 4H), 4.95-5.21 (m, 3H), 7.09 (t, J=5.0 Hz, 1H), 7.81 (d, J=12.5 Hz, 1H), 8.27 (t, J=5.0 Hz, 1H). [M+H] calc'd for C18H19N5O2, 338; found, 338.