Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:9]=1)=[O:7])[CH3:4].[OH-].[K+].[CH2:38]1OCCOCCOCCOCCOCCOC1.IC>C1COCC1>[CH3:38][O:1][CH2:2][C@@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
In a 10 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide (44 mg, 0.085 mmol) was dissolved in THF (0.85 ml) to give a colorless solution. The reaction was cooled in an ice bath. Crushed KOH (64 mg, 1.14 mmol), catalytic 18-crown-6, and iodomethane (9 μl, 0.147 mmol) were added successively to the cooled solution. The reaction mixture was stirred at 0° C. for 1 h after which the ice bath was removed. The reaction mixture was stirred at room temperature for 2 h then diluted with dichloromethane (10 mL) and washed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-100% EtOAc) to afford 22 mg (49%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a white solid. MS: [M+Na]+=551.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4](O)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].N1C=CC=CC=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH:4]([CH2:3][CH2:2][Cl:1])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCCCC(O)CCCl
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(O)CCCCC(Cl)CCCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2.4 g (12.3 mmoles) of (+)-8-chloro-6-hydroxy-octanoic acid (+)-(VI) and 0.05 g (0.6 mmoles) of pyridine in 30 ml toluene, 3.3 g (27.7 mmoles) of thionyl chloride were added slowly. The mixture was then refluxed for 1 hour. The reaction mixture was cooled to room temperature and added to 50 ml ice water. The organic phase was then removed, washed with 20 ml water and stirred for 4 hours with 30 ml of 2N NaOH. The aqueous phase was then removed, adjusted to a pH of 1 with 3N HCl and extracted twice with 20 ml diethylether. The combined ether extracts were dried over magnesium sulfate. After that, the solvent was evaporated under vacuum. (-)-6,8-dichloro-octanoic acid (-)-(VII) was obtained in a yield of 2.1 g (80% of the theoretical yield). [α]D20 =-30.6° (c=1; benzene).
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@H:7]([OH:20])[CH2:8][O:9][C:10]1[C:18]2[NH:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:37]3[CH2:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[OH:20][C@H:7]([CH2:8][O:9][C:10]1[C:18]2[NH:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH2:6][NH:5][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[CH:29]=[CH:30][C:31]([S:34]([N:37]3[CH2:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])(=[O:36])=[O:35])=[CH:32][CH:33]=2)[CH2:26][CH2:27]1
Reactant: O=C1CCN(c2ccc(S(=O)(=O)N3CC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1CN(S(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)C(=O)N1
Reaction time: 0.33 h
Yield: 39.5 %

Procedure:
Acetic acid (0.14 mL, 2.38 mmol) was added dropwise into a mixture of 4-{[(2S)-3-amino-2-hydroxypropyl]oxy}-1,3-dihydro-2H-benzimidazol-2-one (265 mg, 1.19 mmol), 1-[[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl]-2,4-imidazolidinedione (400 mg, 1.19 mmol) and N,N-dimethylformamide (5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (303 mg, 1.43 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 3/1) to produce a brown solid (256 mg, 40% yield): mp 230° C. (decomposed); 1H NMR (400 MHz, DMSO-d6): δ 1.52-1.63 (m, 2H), 2.04-2.15 (m, 2H), 2.48 (m, 2H), 2.9-3.0 (m, 2H), 3.13-3.15 (m, 1H), 3.2-3.4 (m, 3H), 4.0-4.1 (m, 5H), 4.42 (s, 2H), 6.6-6.63 (m, 2H), 6.8-6.85 (m, 1H), 7.03-7.05 (m, 2H), 7.78-7.8 (m, 2H), 10.6 (s, 1H), 10.7 (s, 1H); MS m/e 543 (M−H)+; Analysis for: C24H28N6O7S Calc'd: C, 45.24; H, 5.38; N, 12.88 Found: C, 45.88; H, 5.36; N, 13.88.
Reaction SMILES: [CH:1]([C:3]1[C:4]2[C:14]([CH:15]=[CH:16][CH:17]=1)=[CH:13][C:7]1[C:8](=[O:12])[O:9][CH:10]([OH:11])[C:6]=1[CH:5]=2)=[O:2].[CH3:18][C:19](OC(C)=O)=[O:20]>[Cl-].[Na+].O>[C:19]([O:11][CH:10]1[O:9][C:8](=[O:12])[C:7]2[CH:13]=[C:14]3[C:4](=[CH:5][C:6]1=2)[C:3]([CH:1]=[O:2])=[CH:17][CH:16]=[CH:15]3)(=[O:20])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cccc2cc3c(cc12)C(O)OC3=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=O)OC1OC(=O)c2cc3cccc(C=O)c3cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.6 %

Procedure:
To a solution of 5-formyl-3-hydroxynaphtho[2,3-c]furan-1(3H)-one (190 mg, 0.83 mmol) pyridine (1.66 mL) at rt was added Ac2O (126 mg, 0.117 mL, 1.25 mmol). The solution was stirred at rt for 18 hours and then poured into brine and extracted with EtOAc. The extract was dried over MgSO4 and concentrated The crude material was chromatographed on silica get (3:1 hexanes:EtOAc) to give the title compound (100 mg, 44%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[CH3:13][OH:14]>[OH-].[Na+]>[CH3:13][O:14][C:7]1[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[C:9]([CH3:11])[N:8]=1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: COc1nc(C)cc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of methyl-2-chloro-6-methylpyrimidine-4-carboxylate (5.0 g) in 2N aq. NaOH (67 mL) and methanol (67 mL) is stirred at rt for 24 h. Methanol is evaporated and the aq. phase is acidified with 25% aq. HCl at 0° C. A beige crystalline solid crushes out. It is filtered, rinsed with water and heptane and dried (3.0 g); LC-MS: tR=0.55 min, [M+H]+=169.01; 1H NMR (D6-DMSO): δ 2.50 (s, 3H), 3.94 (s, 3H), 7.52 (s, 1H), 13.7 (s br, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.[Cl-].[NH4+].[N-:10]=[N+:11]=[N-:12].[Na+]>C(O)C>[N:10]([CH2:4][CH:3]([OH:5])[C:2]([F:7])([F:6])[F:1])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 1,1,1-trifluoro-2,3-epoxypropane (2.0 g, 18 mmol) in 70% ethanol (20 mL) was added ammonium chloride (1.9 g, 36 mmol) followed by sodium azide (2.3 g, 36 mmol). The reaction mixture was stirred at room temperature. After 6 h, the reaction mixture was partitioned between water (100 mL) and diethyl ether (100 mL). The organic layer was washed with additional water (100 mL). The first aqueous layer was back-extracted with diethyl ether (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 3-azido-1,1,1-trifluoropropan-2-ol as a crude oil. 1H NMR (600 MHz, DMSO-D6) 4.14 (m, 1H); 3.58-3.49 (m, 2H); 2.58 (d, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[NH2:22][CH:23]([CH3:27])[C:24]([NH2:26])=[O:25]>CO.C(Cl)Cl>[C:24]([CH:23]([NH:22][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:27])(=[O:25])[NH2:26]
Reactant: CC(N)C(N)=O
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(NCc1ccc2[nH]c(C(N)=O)c(Sc3ccccc3)c2c1)C(N)=O

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 2-aminopropionamide (62.3 mg, 0.50 mmol) as described in General Procedure X to afford Iaf (39 mg, 62.9%) as an ivory colored solid, tlc Rf=0.5 (10% MeOH/CH2Cl2-0.2% Et3N), m/z obs=369 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[O:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([NH:29][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:18])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: NOc1ccccc1
Reactant: O=C(O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Product: O=C(NOc1ccccc1)c1cc2ncn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 3-(4-fluoro-benzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-phenoxyamine hydrochloride under the same conditions as those in step (c) of example 1. 1H NMR (300 MHz, MeOH-d4) δ; 8.82 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.24 (d, 2H, J=7.9 Hz), 7.38–7.33 (m, 2H), 7.07–7.01 (m, 2H), 6.88–6.74 (m, 3H), 5.57 (s, 2H). LCMS (API-ES, M+H+): 363.1. HRMS calcd for C20H16FN4O2 (M+H) 363.1257. found 363.1256. HPLC: >85% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[C:19](I)[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].[C:25]([C:27]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29][CH2:28]1)#[CH:26]>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][C:25]([C:27]5([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29][CH2:28]5)=[CH:26][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Reactant: CCCOc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Temperature: 45 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of the product of Step C (0.1 g; 0.22 mmol) and tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (0.056 g; 0.22 mmol) in a mixture of DMF and DIPEA (3 ml: 0.3 ml) was degassed with N2 and Cl2Pd(PPh3)4 (0.025 g) was added, followed by catalytic amount of CuI. The mixture was stirred overnight at 45° C. under N2, diluted to 20 ml with saturated NH4Cl and extracted with EtOAc (40 ml). The organic layer was separated, dried over MgSO4 and filtered. The filtrate was distilled off and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.11 g, 78%), as pale paste. 1H-NMR (CDCl3) 8.34 (d, 1H, J=1.29 Hz); 8.24 (d, 1H, J=2.13 Hz); 8.08 (t, 1H, J=1.56 Hz); 8.05 (t, 1H, J=1.56 Hz); 7.53 (d, 1H, J=8.67 Hz); 7.03 (d, 1H, J=8.67 Hz); 6.75 (s, 1H); 4.26-4.19 (m, 4H); 4.06 (t, 2H, J=5.49 Hz); 1.94-1.87 (m, 2H); 1.41 (s, 9H); 1.36 (s, 6H); 1.1 (t, 3H, J=7.44 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[C-]#N.[CH3:18][N:19](C=O)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1COCC1>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:18]#[N:19])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Agent: [Fe+2]
Agent: [C-]#N
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Temperature: 110 °C
Reaction time: 21 h
Yield: 84 %

Procedure:
Under an inert atmosphere a flask is charged with [2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Example 3) (1.0 g, 3.74 mmol), zink cyanide (0.235 g, 2 mmol), Pd2(dba)3xCHCl3 (0.194 mg, 5 mol %), dppf (bis-diphenylphosphino ferrrocene) (0.207 g, 0.374 mmol, 10 mol %), and DMF (12 mL). The orange slurry is heated to 110° C. and stirred for 21 hours. To the black suspension which has formed, THF (100 mL) is added, and this is extracted with 1 N NaOH (100 mL). The organic layer is washed with water twice (50 mL each), dried and removal of the solvent gives the title product (0.67 g, 84%) as brown solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].Cl.[CH2:32]([O:34][C:35]([C:37]1([NH2:40])[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:40][C:37]3([C:35]([O:34][CH2:32][CH3:33])=[O:36])[CH2:39][CH2:38]3)=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: COCc1cc(-c2nc(-c3cccc(C(=O)Cl)c3)no2)ccc1-c1ccccc1C
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Product: CCOC(=O)C1(NC(=O)c2cccc(-c3noc(-c4ccc(-c5ccccc5C)c(COC)c4)n3)c2)CC1

Procedure:
The title compound was prepared following procedure described in Example 121 starting from 3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride, prepared as in example 130, and 1-aminocyclopropane-1-carboxylic acid ethyl ester hydrochloride. The title compound was obtained as a white foam (120 mg, 98%). 1H NMR: (DMSO-d6, 300 MHz) δ 9.35 (m, 1H), 8.60 (m, 1H), 8.35 (m, 1H), 8.29 (m, 1H), 8.19 (m, 1H), 8.09 (m, 1H), 7.77 (t, J=7.8 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.39-7.26 (m, 3H), 7.15 (m, 1H), 4.23 (d, J=12.9 Hz, 1H), 4.17 (d, J=12.9 Hz, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.25 (s, 3H), 2.04 (s, 3H), 1.47 (m, 2H), 1.21 (m, 1H), 1.15 (t, J=7.1 Hz, 3H). LC/MS (Method B): 512.2 (M+H)+ 510.3 (M−H)−. HPLC (Method A) Rt: 5.27 min (purity: 99%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>FC(F)(F)S(O)(=O)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[I:1]
Reactant: O=C1CCC(=O)N1I
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=S(=O)(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(Cl)c(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
N-Iodosuccinimide (1.71 g, 7.60 mmol) was added to a solution of 1-chloro-4-nitrobenzene (1.17 g, 7.42 mmol) in trifluoromethanesulfonic acid (10 ml) at 0° C., then stirred 1 hour at room temperature. The reaction was quenched with ice-water and extracted with MeCl2 (3×50 ml). Organics were combined washed with 10% sodium bisulfite (20 ml) then dried over Na2SO4, filtered and evaporated solvent yielding the title compound as a white solid (1.3 g, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6](=[O:29])/[CH:7]=[CH:8]/[C:9]1[C:10]([CH:26]2[CH2:28][CH2:27]2)=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:2].C(O)=O.CCN(CC)CC.C([O-])(O)=O.[Na+]>CN(C=O)C.CC(OC)(C)C.CCCCCC.CC(OC)(C)C>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH:6]([OH:29])/[CH:7]=[CH:8]/[C:9]1[C:10]([CH:26]2[CH2:28][CH2:27]2)=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:2]
Reactant: CCOC(=O)CC(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1

Procedure:
A solution of (E)-5-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-oxo-pent-4-enoic-acid-ethylester (1.6 g, 3.97 mmol), Ru[(1R,2R)-p-TsNCH(C6H5)CH(C6H5)NH2]Cl(η6-p-cymene) (12.6 mg, 0.02 mmol) and a mixture of HCOOH (1.095 g, 23.8 mmol)/NEt3 (0.963 g, 9.52 mmol) is heated in DMF (6.0 ml) at 50° C. for 20 h. After that the solution is diluted with MTBE (5 ml) and neutralised with NaHCO3 (4 ml). Standard aquous work-up with NaCl solution and extraction with MTBE and removel of the solvent give the crude product. Chromatography on silica gel using a 4:1 hexane-MTBE mixture as eluent to afford of (E)-5-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-pent-4-enoic-acid-ethylester.
Reaction SMILES: [CH2:1]([C:3]([C:7]1[CH:8]=[CH:9][C:10](=O)[NH:11][N:12]=1)([CH3:6])[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:10]1[N:11]=[N:12][C:7]([C:3]([CH2:4][CH3:5])([CH3:6])[CH2:1][CH3:2])=[CH:8][CH:9]=1
Reactant: CCC(C)(CC)c1ccc(=O)[nH]n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCC(C)(CC)c1ccc(Cl)nn1

Procedure:
To 34 g. of 6-(1-ethyl-1-methylpropyl)pyridazin-3-one was added 175 ml. of phosphorus oxychloride, and the mixture was stirred under reflux for 30 minutes. It was then cooled, excess phosphorus oxychloride was removed under vacuum, and the residual oil was poured into ice water. The residue was made basic to pH 9 with ammonia, and triturated. The aqueous mixture so prepared was extracted with two one-liter portions of diethyl ether, and the combined organics were dried and evaporated under vacuum to obtain 35 g. of the desired product, identified by mass spectroscopy, which showed a molecular ion having a weight of 198.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>ClCCl>[Br:17][C:10]1[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][N:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[N:5][C:6]=12
Reactant: Clc1ccnc2cc(-c3ccccc3)nn12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Clc1ccnc2c(Br)c(-c3ccccc3)nn12
Reaction time: 0.5 h
Yield: 81 %

Procedure:
7-Chloro-2-phenylpyrazolo[1,5-α]pyrimidine (0.1 g, 0.44 mmol, prepared as described in J. Med. Chem. 1981, 24, 610) was dissolved in dichloromethane (5 mL) and to this solution was added N-bromosuccinimide (108 mg, 0.61 mmol). The resulting reaction mixture was stirred for 30 minutes. Additional dichloromethane was added and the mixture was extracted with sodium hydroxide (1N), water and a saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting solid was purified by silica gel chromatography (ethyl acetate:hexane 1:2) to give 110 mg (82%) of 3-bromo-7-chloro-2-phenylpyrazolo[1,5-α]pyrimidine as a yellow solid.
Reaction SMILES: [C:1](=[O:25])([O:3][CH:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH:15]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[O:16][C:10]3=[CH:9][C:8]=2[NH:7][CH:6]([CH3:24])[CH2:5]1)[NH2:2].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33].Cl>ClCCl>[C:1](=[O:25])([O:3][CH:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH:15]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[O:16][C:10]3=[CH:9][C:8]=2[N:7]([C:32](=[O:34])[CH3:33])[CH:6]([CH3:24])[CH2:5]1)[NH2:2]
Reactant: CC1CC(OC(N)=O)c2cc3c(cc2N1)OC(Cc1ccccc1)O3
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2cc3c(cc2C(OC(N)=O)CC1C)OC(Cc1ccccc1)O3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
[Step 3] 675 mg (approx. 1.98 mmol) of the benzyl-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]quinolin-8-yl carbamate were dissolved in 15 mL of dichloromethane followed by adding 313 mg (4.0 mmol) of pyridine. 234 mg (3.0 mmol) of acetyl chloride were further added followed by stirring for 30 minutes at room temperature. Following completion of the reaction, aqueous hydrochloric acid (1 mol/L) was added followed by extraction with chloroform. The organic phase was washed with water and then dehydrated with anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate 2:1) to obtain 367 mg of benzyl-5-acetyl-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]quinolin-8-yl carbamate in the form of a pale brown oil (56%, 2 steps).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([O:11][C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Oc1cccc2c1CCCC2
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Oc2cccc3c2CCCC3)ccn1
Yield: 97.6 %

Procedure:
Using the method of Example 3, Step A, 5,6,7,8-tetrahydronaphthalen-1-ol (935 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(5,6,7,8-tetrahydronaphthalen-1-yloxy)pyridine (1.60 g, 98% yield) as an oil. 1H NMR (CDCl3) δ 8.19 (d, 1H), 7.15 (t, 1H), 7.03 (d, 1H), 6.82 (d, 1H), 6.71-6.75 (m, 2H), 2.82 (t, 2H), 2.52 (t, 2H), 1.71-1.81 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C(=O)N([Br:16])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:16])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cncc(Br)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: BrCc1cncc(Br)n1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
To a solution of 2-bromo-6-methyl-pyrazine (3.0 g, 17.31 mmol) in CCl4 (25 mL) was added NBS (4.60 g, 26.01 mmol) and AIBN (0.248 g, 1.734 mmol) at RT. The mixture was stirred at 55° C. for 48 h. H2O was added followed by extraction with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified over silica eluting with 5% EtOAc:Hexane to obtain i (1.40 g, 32%). 1H NMR (CDCl3, 400 MHz): δ 8.64 (s, 1H), 8.62 (s, 1H) and 4.50 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[CH:35]=[CH:34]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH3:32])[CH:34]=[CH:35]3)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(ccn2C)c1
Yield: 68.7 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.058 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.321 g; 1.25 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.142 g (69%) of the title compound.