Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1.CCO.O1CCOCC1>[C:7]1([CH2:6][NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@H](N)CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C[C@@H](CO)NCc1ccccc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of (2S)-2-amino-1-propanol (5.01 g, 66.70 mmol) in toluene (130 mL) was added benzaldehyde (7.08 mL, 70.05 mmol). The flask was fitted with a Dean-Stark trap, and the solution was heated at 150° C. for 2 h. The solution was then cooled to room temperature and concentrated in vacuo. To a 0° C. solution of the residue in EtOH (130 mL) was added NaBH4 (6.31 g, 166.8 mmol) and sufficient 4 N HCl in dioxane to adjust the pH to ca. 2. The mixture was stirred overnight and then concentrated in vacuo. The residue was partitioned between 1 N aq. HCl (200 mL) and DCM (100 mL). The aqueous phase was washed with a fresh portion of DCM (100 mL), and then adjusted to pH>13 with 6 N aq. NaOH. The aqueous phase was extracted with DCM (2×150 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to provide (2S)-2-[(phenylmethyl)amino]-1-propanol (10.52 g, 95%) as a colorless oil. LCMS: (M+H)+: 166.1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[N:34]([CH3:35])[N:33]=[C:32]([CH3:36])[C:31]=1[S:37](Cl)(=[O:39])=[O:38].Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:28])[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:37]([C:31]2[C:32]([CH3:36])=[N:33][N:34]([CH3:35])[C:30]=2[Cl:29])(=[O:38])=[O:39])=[CH:23][N:22]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)nc1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(C(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A solution of 2-(5-amino-pyridin-2-yl)-malonic acid dibenzyl ester in pyridine cooled to 0° C. was treated with 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride. The reaction mixture was allowed to slowly warm to 25° C. and was stirred at 25° C. for 24 h. At this time, the reaction mixture was cooled to 0° C. and acidified to pH=1 with 3.0M aqueous hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate. The organics were washed with a 1.0M aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 65/35 ethyl acetate/hexanes) afforded 2-[5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-malonic acid dibenzyl ester (55%) as a colorless solid; LRMS for C27H25ClN4O6S (M+H)+ at m/z=569/571.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:10][C:11]([CH3:14])=[N:12][CH:13]=1)(C)(C)C.[OH-].[Na+]>C(Cl)Cl>[CH3:6][NH:7][C:8]1[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[N:10][C:11]([CH3:14])=[N:12][CH:13]=1
Reactant: Cc1ncc(N(C)C(=O)OC(C)(C)C)c(Oc2ccccc2C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNc1cnc(C)nc1Oc1ccccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 1.90 g (5.77 mmol) methyl-(2-methyl-4-o-tolyloxy-pyrimidin-5-yl)-carbamic acid tert.-butyl ester in 25 ml CH2Cl2 2 ml trifluoracetic acid was added and the reaction mixture stirred for 2 hrs. at 40°. The reaction mixture was poured into ice-water and the pH of the solution adjusted to 10 with 1N NaOH solution. The aqueous phase was extracted three times with 80 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated to give 0.95 g (72%) methyl-(2-methyl-4-o-tolyloxy-pyrimidin-5-yl)-amine as a light yellow solid, MS (EI): 229.2 (M+).
Reaction SMILES: [C:1]([O:4][CH3:5])(=[S:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.CN(C)C=O>O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:2][C:1]([O:4][CH3:5])=[S:3])=[N:17][CH:18]=1)([O-:24])=[O:23]
Reactant: COC(C)=S
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=S)Cc1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
A mixture of methyl thioacetate (3 g), diisopropylethylamine (8.14 g), 2-chloro-5-nitropyridine (5 g) and dimethylformamide (50 ml) was heated at 80° C. for 18 hours. The reaction mixture was cooled and then poured into water (500 ml). After stirring for 1 hour at ambient temperature the mixture was filtered to give the title compound (2.03 g) as a brown solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([C:10]2([F:25])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[CH3:26][S:27]([Cl:30])(=[O:29])=[O:28].C(N(C(C)C)CC)(C)C>>[ClH:30].[F:25][C:10]1([C:6]2[CH:5]=[C:4]([NH:3][S:27]([CH3:26])(=[O:29])=[O:28])[CH:9]=[CH:8][CH:7]=2)[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:15]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(C2(F)CCN(CCOc3ccccc3)CC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cccc(C2(F)CCN(CCOc3ccccc3)CC2)c1
Yield: 64 %

Procedure:
The title compound was prepared from the reaction of 4-(3-aminophenyl)-1-(2-phenoxyethyl) 4-fluoropiperidine dihydrochloride with methanesulfonyl chloride in the presence of excess diisopropylethylamine as described in Example 17. The desired material was obtained in 64% yield as an off-white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.[ClH:12].[CH2:13]=O>O>[ClH:12].[Cl:12][CH2:13][C:6]1[CH:7]=[CH:8][C:9]([OH:11])=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: Oc1cccc2cccnc12
Reactant: C=O
Agent: Cl
Solvent: O
Product: Oc1ccc(CCl)c2cccnc12
Reaction time: 2 h

Procedure:
A mixture of 14.6 g (0.1 mol) of 8-quinolinol, 16 mL of 32% HCl in water, and 16 mL (0.1 mL) of 37% formaldehyde in water at 0° C. was treated with hydrogen chloride gas for 6 h. The solution was allowed to stand at room temperature for 2 h without stirring. The yellow solid obtained was collected on a filter, washed with 90% alcohol and dried under vacuum to give 5-chloromethyl-8-quinolinol hydrochloride A (19.0 g, 98%): 1H NMR (250 MHz, CDCl3, δ) 5.32 (s, 2H), 7.53 (m, 1H), 7.85 (m, 2H), 8.12 (m, 1H), 9.12 (m, 1H), 9.28 (m, 1H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].Br[C:44]1[CH:45]=[N:46][C:47]([N:50]2[CH2:53][CH:52]([OH:54])[CH2:51]2)=[N:48][CH:49]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:44]3[CH:45]=[N:46][C:47]([N:50]4[CH2:53][CH:52]([OH:54])[CH2:51]4)=[N:48][CH:49]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: OC1CN(c2ncc(Br)cn2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2cnc(N3CC(O)C3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 110 °C

Procedure:
A heavy-walled glass vial was charged with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (13 mg), 1-(5-bromopyrimidin-2-yl)azetidin-3-ol trifluoroacetic acid salt (18 mg), Cs2CO3 (18 mg), water (0.1 mL), and 1,4-dioxane (1 mL). The mixture was sparged with N2 for 10 min before PdCl2[1,1′-bis(diphenylphosphino)ferrocene] (2 mg) was added. The mixture was sparged with N2 for 10 min and then heated in a microwave oven at 110° C. for 30 min. After cooling to room temperature, the reaction mixture was purified by preparative HPLC to afford the title compound as its trifluoroacetic acid salt as an oil. Yield: 12.1 mg (89% of theory); LC (method 5): tR=1.3 min; Mass spectrum (ESI+): m/z=503 [M+H]+; 1H NMR (CD3OD) δ 0.95 (s, 3H), 1.26 (s, 3H), 1.56 (d, 3H), 2.16 (s, 2H), 2.23 (m, 1H), 2.47 (m, 2H), 3.05 (m, 1H), 4.07 (m, 2H), 4.49 (m, 2H), 4.73 (m, 1H), 5.57 (q, 1H), 7.09 (d, 2H), 7.25-7.40 (7H), 8.63 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:13][CH2:12]1)=[O:5].[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40]>O1CCCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:22]2[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=[C:18]2[CH2:17][CH:14]2[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:38][CH:37]=[CH:36][CH:35]=4)[NH:1][C:39]3=[O:40])[CH2:16][CH2:15]2)=[CH:29][CH:28]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1C(=O)NCCCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2c(=O)n1CCCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 35.5 %

Procedure:
A mixture of 10.3 parts of 2-amino-N-[4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]-butyl]benzamide, 3.2 parts of 1,1'-carbonylbis[1H-imidazole] and 180 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using first a mixture of trichloromethane and methanol saturated with ammonia (97:3 by volume) and then a mixture of trichloromethane and methanol saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone, yielding 3.8 parts (35.5%) of 3-[4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]butyl]-2,4(1H,3H)-quinazolinedione; mp. 187.3° C. (489).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CC(C)([O-])C.[K+].COCCOC>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.O>[N:22]1([C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(N3CCCC3)nc2)CC1

Procedure:
A stirred solution of 1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (0.71 g, 2.0 mmol), pyrrolidine (2.0 g, 20 mmol), potassium tert-butoxide (0.45 g, 4.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) and 1.2-dimethoxyethane was stirred at reflux overnight. Water (40 ml) was added and the mixture was extracted twice with ethyl acetate (20 ml) Chromatography on silica gel with a mixture of petroleum:ethyl acetate (1:1) gave the title compound as free base. Yield 0.21 g, 30%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(4-chlorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])C1C=CC=CC=1.CN(C)C=O.S(Cl)([Cl:29])=O>>[Cl:29][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1O
Reaction time: 3 h
Yield: 100 %

Procedure:
7-Benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (10.1 g) was suspended in thionyl chloride (200 ml) then dimethylformamide (0.5 ml) added and the resultant mixture heated to 80° C. and stirred for 3 hours. The reaction mixture was evaporated and azeotroped with toluene to yield 4-chloro-7-hydroxy-6-methoxyquinazoline as a solid (12.1 g, 100%); NMR: 4.88 (s, 3H), 5.25 (s, 2H), 7.44 (s, 1H), 7.49 (s, 1H), 7.32-7.52 (m, 5H), 8.83 (s, 1H); m/s: M+H+ 283.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH:20]3[CH2:22][CH2:21]3)[CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][C:7]=1Br.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]3)O1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH:20]3[CH2:22][CH2:21]3)[CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][C:7]=1[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]2
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Reactant: CN(C1CC1)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Product: CN(C1CC1)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)n2)cc1
Yield: 85 %

Procedure:
General method C was applied to 4-(5-amino-6-bromopyrazin-2-yl)-N-cyclopropyl-N-methylbenzenesulfonamide (383 mg, 1.00 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (300 mg, 1.1 mmol) to provide 4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)-N-cyclopropyl-N-methylbenzenesulfonamide (382 mg, 85% yield) after purification by preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (s, 1H), 8.26 (d, J=8.5 Hz, 2H), 8.03 (br. s., 1H), 7.97 (d, J=8.0 Hz, 1H), 7.84 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 3.42 (t, J=5.3 Hz, 2H), 2.99 (t, J=6.4 Hz, 2H), 2.67 (s, 3H), 1.77-1.86 (m, 1H), 0.61-0.81 (m, 4 H); MS (EI) m/z=450.5 [M+1]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.P(=O)(O)(O)O.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=1
Reactant: COC(=O)CC(C)(C)C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P(O)(O)O
Agent: [OH-]
Solvent: CO
Product: COC(=O)CC(C)(C)Cc1ccc(O)cc1

Procedure:
A solution of the product of STEP 3 in methanol and phosphoric acid (catalytic amount) was shaken in Parr hydrogenation apparatus with 20% Pd(OH)2/C under 60 psi hydrogen pressure for 9 hours. The solution was filtered and filtrate concentrated in vacuo. An ether solution of the residue was treated with excess diazomethane in ether at 0° C. The resulting solution was concentrated in vacuo and the residue was purified by chromatography over silica gel using 10% ethyl acetate in hexane as eluant to provide the above compound as a colorless thick liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Cl[C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: OCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Temperature: 120 °C
Yield: 87 %

Procedure:
A mixture of 3-flouro-benzyl alcohol (1.0 g, 7.92 mmol), 2-chloro-5-nitro-benzamide (1.59 g, 7.92 mmol) and K2CO3 (1.31 g, 9.51 mmol) in DMA (5 ml) was heated at 120° C. for 7 h. The mixture was cooled to rt, diluted with EtOAc(40 ml), filtered and concentrated in vacuo to give 14A (2.0 g, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([C@@H:7]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH:9]=O)[CH:6]=1.O1CCCC1.[OH-].[NH4+:22].II>O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C@@H:7]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][C:9]#[N:22])[CH:6]=1
Reactant: O=CC[C@H](C1CCCC1)n1cc(Br)cn1
Reactant: [NH4+]
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#CC[C@H](C1CCCC1)n1cc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a stirred solution of (3R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropanal ((R)-40, 230.5 mg, 0.85 mmol) in tetrahydrofuran (THF, 2.4 mL, 29 mmol) at room temperature was added a solution of 14.3 M of ammonium hydroxide (NH4OH) in water (2.4 mL), followed by iodine (I2, 237 mg, 0.935 mmol, 1.1 equiv). The resulting reaction mixture was stirred at room temperature for 30 min. When LCMS showed that the reaction was complete, the reaction mixture was quenched with 10% aqueous Na2S2O3 solution (15 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2) with 0-30% EtOAc/hexane gradient elution to give (3R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile ((R)-41, 180.7 mg, 227.9 mg theoretical, 79.3% yield) as a colorless viscous oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[CH3:12][O:13][CH2:14][C:15](Cl)=[O:16]>CN(C)C(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:15](=[O:16])[CH2:14][O:13][CH3:12])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: COCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: COCC(=O)Nc1cn2nc(I)ccc2n1
Yield: 79 %

Procedure:
Using 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g, 3.85 mmol), N,N-dimethylacetamide (10 mL) and methoxyacetyl chloride (0.46 g, 4.23 mmol) as starting materials and in the same manner as in Reference Example 5, the title compound (1.01 g, 79%) was obtained as a dark brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[NH:10][C:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>C(O)(=O)C.C(Cl)(Cl)Cl.C(Cl)Cl>[Br:29][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:11]2[NH:10][C:9](=[O:21])[CH:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: COc1ccc2c(c1)NC(=O)C(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CCC(C(=O)OC(C)(C)C)C(=O)N2

Procedure:
A suspension of 3-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (1.00 g, 3.43 mmol) and NBS (0.672 g, 3.78 mmol) in acetic acid (0.8 mL) and chloroform (8 mL) was heated at reflux for 3 hrs. Then, the reaction mixture was diluted with DCM (30 mL), washed with water, dried over Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography on silica column using gradient elution with EtOAc/DCM (from 5% ethyl acetate in DCM to 10% ethyl acetate in DCM). The title compound was obtained as a white powder (0.689 g, 54%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][NH:27][CH3:28])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:30][O:31][C:32](Cl)=[O:33].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:28])[C:32](=[O:33])[O:31][CH3:30])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)Cl
Reactant: CNCc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)N(C)Cc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To a cold (5° C.) solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one (0.20 g, 0.4 mmol) in DMF (2.0 ml), was added methylchloroformate (0.049 g, 0.52 mmol), followed by the addition of triethylamine (0.072 g, 0.71 mmol). The mixture was stirred at 5° C. for 30 min and at room temperature for an additional 30 min and concentrated in vacuo. The residue was partitioned between water (5.0 mL) and EtOAc (10.0 mL). The organic extract was washed with water, dried (Na2SO4), and concentrated to dryness. The resulting material was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z=523 M+H) were combined and freeze dried to give a white powder. This was partitioned between 5% NaHCO3 (10 mL) and EtOAc (15 mL). The organic layer was washed with water, dried (Na2SO4), and concentrated to dryness to afford the title compound (0.12 g, 53%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.59 (s, 1H), 8.41 (m, 1H), 7.60 (m, 1H), 7.05 (m, 2H), 6.52 (s, 1H), 5.45 (s, 2H), 5.29 (s, 2H), 4.58 (s, 2H), 3.69 and 3.64 (s, 3H), 2.97 (s, 3H), 2.85 (s, 3H), and 2.55 (s, 3H); 19F NMR(CD3OD/400 MHz) −111.69 (m) and −116.09 (m); ES-HRMS m/z 523.0775(M+H calcd for C22H22BrF2N4O4 requires 523.0787).