Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:17][CH2:16]2)=[C:11](C)[CH:10]=1)[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC([N+]([O-])=O)=C[C:36]=1[O:44]C>>[NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:17][CH2:16]2)=[C:11]([O:44][CH3:36])[CH:10]=1)[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1cc(N=C(N)c2cccs2)ccc1N1CCN(C(=O)NCCCCC2CCSS2)CC1
Product: COc1cc(N=C(N)c2cccs2)ccc1N1CCN(C(=O)NCCCCC2CCSS2)CC1
Yield: 25 %

Procedure:
The experimental protocol used is the same as that described for the compound of Example 6, 2-chloro-5-nitroanisole replacing 2-fluoro-5-nitrotoluene. A pale yellow solid product is obtained (yield 25%). Melting point: 185.6-186.3° C.
Reaction SMILES: [Br:1]Br.[N:3]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N:3]1([C:9]2[C:14]([Br:1])=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: BrBr
Reactant: Cc1cc(N2CCCCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCCCC2)c(Br)cn1
Reaction time: 3.5 h

Procedure:
A solution of bromine (9.3 ml) in dimethylformamide (50 ml) was added dropwise-to a stirred mixture of 4 -piperidino-2 -picoline (15 g), potassium carbonate (23.5. g) in dimethylformamide (50 ml) at 25°-30°. After 3.5 hours, the mixture was stripped and the residue taken up in water, adjusted to pH 13 with 40 % aqueous NAOH, and extracted with ether. After drying (K2CO3 ) and stripping, the residue was chromatographed (silica gel, n-hexane:ether) to give 4 -piperidino-5 -bromo-2 -picoline, 11.18 g, as an oil and 4 -piperidino-3 -bromo-2 -picoline, 3.5 g, as an oil.
Reaction SMILES: [F:1][C:2]([C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([F:5])[CH2:3]I.[N-:12]=[N+:13]=[N-:14].[Na+].CS(C)=O>O>[N:12]([CH2:3][C:2]([C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([F:5])[F:1])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(CI)c1ncccn1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCC(F)(F)c1ncccn1
Temperature: 95 °C
Reaction time: 72 h
Yield: 102.6 %

Procedure:
A mixture of 2-(1,1-difluoro-2-iodo-ethyl)-pyrimidine (841 mg, 3.11 mmol), as prepared in the previous step, NaN3 (338 mg, 5.19 mmol), and DMSO (2.35 mL) was stirred at 95° C. for 3 days. The reaction was then shaken with water (10 mL) and extracted with ether (3×8 mL). The organic layers were combined, dried (Na2SO4), and concentrated to give the intermediate 2-(2-azido-1,1-difluoro-ethyl)-pyrimidine as a clear yellow oil (591 mg) that was immediately used in the next step without further purification or characterization.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:25]=[CH:24][C:7]2[O:8][C:9]3[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=3[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:12][C:6]=2[CH:5]=1>>[F:3][C:4]1[CH:25]=[CH:24][C:7]2[O:8][C:9]3[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=3[CH:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH2:12][C:6]=2[CH:5]=1
Reactant: CN1CCN(C2=Cc3cc(F)ccc3Oc3ccccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CN1CCN(C2Cc3cc(F)ccc3Oc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.15 g. of sodium borohydride are added in small portions over a period of 15 minutes to a solution of 12.3 g. of 1-[2-fluoro-dibenzo[b,f]oxepin-10-yl-4-methyl-piperazine in 185 ml. of glacial acid with cooling in such a manner that the temperature does not exceed 25° C. The mixture is stirred for an additional 1 hour at room temperature and the acetic acid is then evaporated in vacuo. The residue is partitioned between 3-N sodium hydroxide solution and chloroform. The aqueous phase is separated and extracted again with chloroform. The chloroform extracts are washed three times with water, dried over sodium sulfate, evaporated in vacuo, and there is obtained 1-[2-fluoro-10,11-dihydro-dibenzo [b,f]-oxepin-10-yl]-4-methyl-piperazine as a crystalline residue. The dihydrochloride, prepared in ethanol, melts at 240°-241° C. (with decomposition).
Reaction SMILES: [C:1]([N:9]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C@H:10]1[C:22]1[N:23]([CH3:42])[C:24](=[O:41])[C:25]([O:32]C(=O)C2C=CC=CC=2)=[C:26]([C:28]([O:30]C)=O)[N:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1>CO>[C:1]([N:9]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C@H:10]1[C:22]1[N:23]([CH3:42])[C:24](=[O:41])[C:25]([OH:32])=[C:26]([C:28]([NH:49][CH2:48][C:47]2[CH:50]=[CH:51][C:44]([F:43])=[CH:45][CH:46]=2)=[O:30])[N:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc([C@@H]2C[C@@H](OCc3ccccc3)CN2C(=O)c2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: Cn1c([C@@H]2C[C@@H](OCc3ccccc3)CN2C(=O)c2ccccc2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
The compound of Step 1 was dissolved in methanol and 4-fluorobenzylamine (5 eq.) was added. The mixture was refluxed overnight. After cooling, the reaction mixture was filtered and washed with ethyl ether to obtain the title product as a white solid.
Reaction SMILES: C1COCC1.[CH:6]1([C:9]2[C:10]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:11][C:12]([O:20][CH2:21][CH3:22])=[C:13]([CH:19]=2)[C:14](OCC)=[O:15])[CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH:6]1([C:9]2[C:10]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:11][C:12]([O:20][CH2:21][CH3:22])=[C:13]([CH:19]=2)[CH:14]=[O:15])[CH2:8][CH2:7]1
Reactant: CCOC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2)nc1OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1nc(-c2ccc(F)cc2)c(C2CC2)cc1C=O
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
A THF (20 mL) solution of ethyl 5-cyclopropyl-2-ethoxy-6-(4-fluorophenyl)nicotinate (2.06 g) was added to a THF (20 mL) suspension of lithium aluminum hydride (237 mg) under ice cooling in a nitrogen atmosphere. After stirring at the same temperature as above for 30 minutes, water (0.20 mL) and a 15% aqueous sodium hydroxide solution (0.20 mL) were added thereto, and the mixture was stirred for 5 minutes. Then, water (0.60 mL) was further added thereto. The reaction mixture was stirred for 1 hour and then filtered. The filtrate was concentrated under reduced pressure. Manganese dioxide (5.43 g) was added to a toluene (10 mL) solution of the obtained residue, and the mixture was stirred at 60° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.47 g).
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[N:16][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][CH2:18][C@H:19]1[O:23][C@@H:22](N2C=CC(=O)NC2=O)[C@H:21]([OH:32])[C@@H:20]1[OH:33]>>[NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([C@@H:22]3[O:23][C@H:19]([CH2:18][Cl:17])[C@@H:20]([OH:33])[C@H:21]3[OH:32])[CH:15]=[N:16][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CCl)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: c1ccc(Nc2ccnc3[nH]cnc23)cc1
Product: O[C@@H]1[C@H](O)[C@@H](CCl)O[C@H]1n1cnc2c(Nc3ccccc3)ccnc21
Temperature: 35 °C

Procedure:
7-Anilino-3H-imidazo[4,5-b]pyridine (0.8 g, 3.7 mmol) and 5'-chloro-5'-deoxyuridine (15 g, 5.7 mmol) were combined in 10 mL of 10 mM KxHxPO4, pH 7.4. Uridine phosphorylase (315 units) and purine nucleoside phosphorylase (1800 units) previously purified from E. coli, were added and the reaction stirred at 35° C. After 4 days an additional 84 units of uridine phosphorylase and 100 mL phosphate buffer were added. Twenty-one days later the particulates were collected by filtration and recrystallized from boiling ethanol yielding 0.982 g of 72% of 7-anilino-3-(5-chloro-5-deoxy-β-D-ribofuranosyl)-3H-imidazo[4,5-b]pyridine, m.p. 195° C. (dec.):
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(OCC)C.ClCCl>[Cl:15][CH2:16][C:17]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: CC1CCNCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(C(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-Methyl-piperidine (5.00 g, 50.42 mmol) and triethylamine (7.65 g, 75.63 mmol) in ethyl ether (25 ml) was added dropwise a solution of chloroacetyl chloride (6.83 g, 60.50 mmol) in ethyl ether (30 mL). The mixture was warmed to room temperature and stirred overnight. Then the mixture was diluted with dichloromethane, washed with water, dried and concentrated in vacuo to afford the crude titled compound (crude yield 100%), which was used directly in the subsequent step reaction.
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]>>[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][N:31]([CH2:15][C:14]3[CH:17]=[CH:18][C:11]([C:10]([F:20])([F:19])[F:9])=[CH:12][CH:13]=3)[C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: BrCc1ccccc1
Product: CC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Yield: 74 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-(trifluoromethyl)benzyl bromide to react with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one, the title compound was obtained in 74% yield: mp 141-142° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 4.54 (s, 2H), 4.13-4.07 (m, 2H), 3.50-3.41 (m, 2H), 2.66 (s, 3H), 225 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.6, 159.6, 155.9, 155.4, 139.6, 130.2, 128.5, 126.0, 124.8, 122.1, 47.6, 42.0, 41.8, 30.5, 18.2; MS (ES+) m/z 384.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[F:37])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Oc1ccccc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1CC(Oc2ccccc2F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
(2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS Reg. No. 74844-91-0) (300 mg, 1.22 mmol) was dissolved in THF (10 ml), and triphenylphosphine (385 mg, 1.47 mmol) and 2-fluorophenol (164.5 mg, 1.47 mmol) were added. The reaction was cooled in ice, DIAD (0.23 ml, 1.2 mmol) added dropwise and the reaction stirred at room temperature overnight. The mixture was concentrated in vacuo, CH2Cl2 (20 ml) added and the solution washed with 2N NaOH (10 ml). The phases were separated and the organic phase washed with saturated brine (10 ml), dried over MgSO4 and evaporated. The residue was dissolved in a minimum of diethylether and pentane added until solution just maintained. After seeding with triphenylphosphine oxide, the solution was cooled in ice and the resultant precipitate filtered. The filtrate was evaporated and the residue purified by flash chromatography on silica (50 g) eluting initially with pentane:diethylether (2:1 by volume), then pentane:diethylether (1:1 by volume) to give the title product (388 mg, 58%) as an impure oil containing diisopropylbicarbamate as an impurity.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=2)[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:17]>CO.[Pt](=O)=O>[ClH:17].[CH:1]1([CH:7]2[CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][CH2:15][NH:16]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccnc(-c2ccccc2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(C2CCCCC2)C1
Reaction time: 5 h
Yield: 89.6 %

Procedure:
Methyl 2-phenylisonicotinate (3.182 g, 14.92 mmol) (from reference compound 34, step 1) was dissolved in MeOH (30 mL) and hydrogen chloride (1.25 M in MeOH, 14.33 mL, 17.91 mmol) was added. The solvents were evaporated to give a slightly yellow solid. The residue was dissolved in MeOH (60 mL) and platinum(IV) oxide (0.102 g, 0.45 mmol) was added. The resulting mixture was then hydrogenated in a Büchi hydrogenator at 8 bar for 5 h. More platinum(IV) oxide (121 mg) was added and the hydrogenation continued overnight at 8 bar (15 h). Platinum(IV) oxide (120 mg) was added and the hydrogenation continued at 60 C for 5 hours. Platinum(IV) oxide (120 mg) was added and the hydrogenation was continued at 60 C overnight (15 h). The reaction mixture was filtered through diatomic earth containing filter carton and washed with methanol. The solvents were evaporated and the residue dried in vacuum to give a white solid. The residue was redissolved in MeOH (60 mL). Platinum(IV) oxide (340 mg) was added and the hydrogenation continued at 8 bar, 60 C overnight (22 h). The reaction mixture was filtered through diatomic earth containing filter carton and washed with methanol. The solvents were evaporated and the residue dried in vacuum to give methyl 2-cyclohexylpiperidine-4-carboxylate hydrochloride (3.50 g, 89%) as a white solid. MS m/z 226 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH3:38][NH:39][CH3:40]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:31])[CH3:32])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:39]([CH3:40])[CH3:38])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CNC
Reactant: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN(C)C)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 101) (226 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in DMF according to the method described in Example 45. Obtained as a light brown solid (134 mg, 56%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[CH:13][N:12]=1.Cl>C(O)C>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2ccc(OCCOCCOCCO)nc2)cc1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(/C=C/c2ccc(OCCOCCOCCO)nc2)cc1
Temperature: 0 °C
Yield: 75.3 %

Procedure:
Stannous chloride (202.8 mg, 1.07 mmol) was added to a solution of compound 7 (100 mg 0.27 mmol) in ethanol (10 ml) followed by the addition of concentrated HCl (0.5 ml). The reaction mixture was refluxed for 1.5 h and then cooled to 0° C. Yellow precipitate was collected by filtration and then suspended in ethyl acetate. Saturated NaHCO3 was added to adjust pH to 9. Organic layer was separated, dried over anhydrous sodium sulfate and evaporated. The residue was purified by PTLC (5% MeOH in DCM as developing solvent) to give product 8 (70 mg, Yield: 76%): 1H NMR (200 MHz, CDCl3): δ 8.12 (1H, d, J=2.4 Hz), 7.73 (1H, d, d, J1=8.6 Hz, J2=2.4 Hz), 7.29 (2H, d, J=8.5 Hz), 6.84 (2H, m), 6.75 (1H, d, J=8.6 Hz), 6.69 (2H, d, J=8.5 Hz), 4.48 (2H, t, J=4.8 Hz), 3.86 (2H, t, J=4.8 Hz), 3.71 (6H, m), 3.60 (2H, m), 3.32 (3H, b), HRMS (EI) m/z calcd. for [C19H24N2O4]+ 344.1736.
Reaction SMILES: CC(C)=O.C(=O)=O.[Br:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[CH:10]=1.Cl[CH:19]([F:21])[F:20]>C(O)(C)C.[OH-].[Na+]>[Br:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([O:16][CH:19]([F:21])[F:20])=[C:11]([CH3:17])[CH:10]=1
Reactant: Cc1cc(Br)nc(C)c1O
Reactant: FC(F)Cl
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: Cc1cc(Br)nc(C)c1OC(F)F
Temperature: 25 °C
Yield: 60 %

Procedure:
A three-necked round bottom flask (500 mL) equipped with dry ice condenser (−78° C., acetone/dry ice) was charged with a solution of 6-bromo-2,4-dimethyl-3-hydroxypyridine (7.2 g, 35.6 mmol) in i-propanol (100 mL) and aqueous sodium hydroxide solution (20%, 100 mL) was added. The reaction mixture was stirred vigorously at 40° C. for 5 hours while chlorodifluoromethane was bubbled continuously into the solution at a moderate rate. The reaction mixture was then cooled to room temperature and extracted with Et2O (3×100 mL). The combined extracts were washed with water (2×50 mL), dried over magnesium sulfate and concentrated in vacuo. Purification of the crude mixture by flash column chromatography using 5% ethyl acetate in hexane afforded the title compound (5.4 g, 60%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][CH2:26][OH:27]>C1(C)C=CC=CC=1>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([C:2]2([CH3:1])[O:27][CH2:26][CH2:25][CH2:24][O:3]2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: OCCCO
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCCO1
Temperature: 25 °C

Procedure:
A mixture of 4-nitroacetophenone (1.65 g, 10.0 mmol), p-toluenesulfonic acid (172 mg, 1.00 mmol) and 1,3-propanediol (2.3 mL, 30 mmol) in dry toluene (20 mL) was heated at reflux with a Dean-Stark apparatus under nitrogen for 24 h. The mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was taken up in ether (20 mL) and the solution was washed with saturated sodium bicarbonate solution (2×10 mL) and brine (1×10 mL), then dried (Na2SO4) and concentrated under reduced pressure. Recrystallisation from ether and hexane afforded 2-(4-nitrophenyl)-2-methyl-1,3-dioxane (26) as a pale yellow crystals (1.60 g, 72%; yield based from the first crop of crystals). 1H nmr (300 MHz, CDCl3) 1.52 (s, 3H, CH3), 2.08-2.22 (m, 2H, OCH2CH2CH2O), 3.65-3.80 (m, 2H, OCH2), 3.88-4.00 (m, 2H, OCH2), 7.63 (d, J=8.9 Hz, 2H, 2×ArH), 8.26 (d, J=8.9 Hz, 2H, 2×ArH).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13](=O)[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: O=C(CCCN1CCNCC1)c1c[nH]c2ccc(F)cc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Fc1ccc2[nH]cc(CCCCN3CCNCC3)c2c1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
The obtained 1-(5-fluoro-1H-indol-3-yl)-4-(piperazin-1-yl)butan-1-one dihydrochloride (3.20 g) was dissolved in tetrahydrofuran (50 ml) and cooled to 0° C. A solution of LiAlH4 in tetrahydrofuran (60 ml; 1M, ˜53 mmol LiAlH4) was slowly added. Subsequently, the mixture was heated at 80° C. for 20 hours. The excess LiAlH4 was cautiously hydrolyzed and after extractive work-up, 5-fluoro-3-[4-(piperazin-1-yl)butyl]-1H-indole (2.39 g, 98% yield) was obtained. 1H-NMR (400 MHz, DMSO-d6) δ 1.40-1.50 (m, 2H), 1.61 (quintet, J=7, 2H), 2.12-2.35 (m, 7H), 2.60-2.70 (m, 6H), 6.85-6.92 (m, 1H), 7.17 (d, J˜2, 1H), 7.23 (dd, J˜9 and 2, 1H), 7.30 (dd, J˜9 and 4, 1H), 10.85 (br s, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]4[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=4)[NH2:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]4[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=4)[NH:19][C:23](=[O:25])[CH3:24])=[N:14][N:15]=3)[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2nnc3ccc(N4CCCCC4)nn23)c1
Product: CC(=O)Nc1cccc(-c2nnc3ccc(N4CCCCC4)nn23)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 3-[6-(piperidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine-3-yl]aniline (180 mg) and acetic anhydride (3 ml) was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the resultant crude crystals were washed with diethyl ether to obtain 3′-[6-(piperidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]acetoanilide (190 mg) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[N:13][C:12]([N:15]([CH2:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([CH3:26])[CH3:25])C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)=[N:7][CH:8]=1)#[N:2].OO.C(=O)([O-])[O-:37].[K+].[K+].Cl.O1CCOCC1>O.C(OCC)(=O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]([CH3:25])([CH3:26])[CH2:23][NH:15][C:12]2[N:13]=[N:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:37])=[CH:8][N:7]=3)=[CH:10][CH:11]=2)=[CH:32][CH:31]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(-c2ccc(C#N)cn2)nn1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CNc1ccc(-c2ccc(C(N)=O)cn2)nn1)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a 20 dram vial was added crude tert-butyl 6-(5-cyanopyridin-2-yl)pyridazin-3-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate, hydrogen peroxide (2 mL), and potassium carbonate (150 mg). The reaction was stirred for 30 min and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was subsequently treated with 4N HCl/dioxane (1 mL). The reaction was stirred for 1 h at room temperature, concentrated, quenched with aqueous sodium bicarbonate, and extracted with ethyl acetate (20 mL). The organic layer was then dried (Na2SO4), filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to afford 10 mg of 6-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)nicotinamide, m/z=366.1 [M+H].
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:38]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A166) and methoxy-acetyl chloride the title compound is obtained as colorless solid.