Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[O:30]=[S:31]1(=[O:45])[CH2:36][CH2:35][N:34]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:41]([C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:33][CH2:32][S:31](=[O:45])(=[O:30])[CH2:36][CH2:35]4)=[CH:44][CH:43]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(N2CCS(=O)(=O)CC2)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(N5CCS(=O)(=O)CC5)cc4)nc23)CC1)Nc1nccs1
Temperature: 85 °C
Yield: 13.1 %

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (0.050 g, 0.13 mmol, 1 eq), EtOH (2.2 mL) and DMF (0.29 mL), 4-(1,1-dioxothiomorpholino)benzaldehyde (0.033 g, 0.14 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.38 mL, 0.38 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v, 92:8) and washed with DCM/MeOH (1 mL, 1/1) to give the title compound as a pale yellow solid (0.010 g, 13%); 1H-NMR (500 Mz, DMSO-d6): 2.72-2.83 (m, 4H, piperazine N(CH2)2), 3.08-3.17 (m, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CO), 3.66-3.77 (m, 4H, dithioxomorpholino SO2(CH2)2), 3.85-3.95 (m, 4H, dithioxomorpholino SO2(CH2)2), 7.17 (d, J=8.5 Hz, 2H, ArH C6H4), 7.23 (d, J=3.5 Hz, 1H) and 7.49 (d, J=3.5 Hz, 1H) (thiazole H-4, H-5), 8.08 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.12 (d, J=8.5 Hz, 1H, ArH, C6H4), 11.88 (br s, 1H, NHCO), 13.31 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.47 min—541/543 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[F:16][CH:17]([F:33])[C:18]1[N:22]2[N:23]=[C:24](N3CCNCC3)[CH:25]=[CH:26][C:21]2=[N:20][N:19]=1>>[F:33][CH:17]([F:16])[C:18]1[N:22]2[N:23]=[C:24]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]4[C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[NH:9][CH:8]=4)[CH2:3][CH2:2]3)[CH:25]=[CH:26][C:21]2=[N:20][N:19]=1
Reactant: FC(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: FC(F)c1nnc2ccc(N3CCC(c4c[nH]c5ccccc45)CC3)nn12
Yield: 85 %

Procedure:
A mixture of 3-(piperidin-4-yl)-1H-indole and 3-(difluoromethyl)-6-(piperazin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 216 to give 3-(difluoromethyl)-6-[4-(1H-indol-3-yl)piperidin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 85% yield.
Reaction SMILES: [NH:1]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C@H:2]([C:13]([NH:15][C@H:16]([C:32]([N:34]1[CH2:48][CH2:47][CH2:46][C@H:35]1[C:36]([O:38]CC1C=CC=CC=1)=[O:37])=[O:33])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl.C(OCC)C>C1COCC1.C(OCC)(=O)C>[NH:1]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[C@H:2]([C:13]([NH:15][C@H:16]([C:32]([N:34]1[CH2:48][CH2:47][CH2:46][C@H:35]1[C:36]([OH:38])=[O:37])=[O:33])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][CH:19]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
BOC-Thr(Bzl)-Tyr(Bzl)-Pro-OBzl (14.2 g.) was dissolved in THF (30 ml.), and 1 N NaOH solution (23 ml.) was added dropwise for 15 minutes at -5° C. After stirring for 4 hours at room temperature, the pH was adjusted to 7 with 1 N HCl addition, then the mixture was concentrated in vacuo to remove THF. Water was added to the aqueous layer and after washing with ethyl ether, the pH of the water layer was adjusted to pH 2 by adding 1 N HCl, then extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and dried by anhydrous magnesium sulfate and concentrated in vacuo. The residue was crystallized from ethyl ether - n-hexane to obtain crude material (12 g.). This crude material was dissolved in ethyl acetate, ethyl ether added thereto and the solution was set aside to crystallize by gradual addition of n-hexane to give BOC-Thr(Bzl)-Tyr(Bzl)-Pro-OH (10.5 g., Yield: 84%, m.p.: 136° - 138° C.). TLC: one spot, Rf1 = 0.68, Rf5 = 0.63.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.[S:26]1[C:30]2[CH2:31][NH:32][CH:33]([CH2:35][OH:36])[CH2:34][C:29]=2[CH:28]=[CH:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:36][CH2:35][CH:33]1[N:32]([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[CH:18]=2)=[O:25])[CH2:31][C:30]2[S:26][CH:27]=[CH:28][C:29]=2[CH2:34]1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: OCC1Cc2ccsc2CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1Cc2sccc2CC1CO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
85 mg (0.25 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 50 mg (0.32 mmol) (4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-5-yl)-methanol in 50 μL (0.36 mmol) TEA and 0.90 mL DMF were combined with 80 mg (0.25 mmol) TBTU and the mixture was stirred for 5 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[OH:35][C:29]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([F:37])([F:21])[F:36])[CH2:34][CH2:33][N:32]([C:14]([C@@:11]2([CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]2)=[O:16])[CH2:31][CH2:30]1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: OC1(c2ccccc2C(F)(F)F)CCNCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3C(F)(F)F)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 2.5 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (150 mg, 0.55 mmol), 4-[2-(trifluoromethyl)phenyl]piperidin-4-ol hydrochloride (170 mg, 0.60 mmol), and triethylamine (0.17 g, 1.6 mmol) in methylene chloride (3 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.31 g, 0.60 mmol). After being stirred for 2.5 h, the reaction was quenched by addition of a saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. The crude product was carried on to the next step without purification. MS calculated for C26H37F3N2O4: (M+H) 499; found 499.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([N+:21]([O-])=O)[CH:12]=2)[CH2:3][CH2:2]1>CCOC(C)=O.CO.[Pd]>[NH2:21][C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=1)[C:10]([NH:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:24]
Reactant: O=C(NCCN1CCOCC1)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)NCCN2CCOCC2)cc(C(F)(F)F)c1

Procedure:
A mixture of N-(2-morpholinoethyl)-3-nitro-5-(trifluoromethyl)benzamide (300 mg, 0.865 mmol, 1.0 equiv) and 10% Pd/C (20 mg) in EtOAc (25 ml) and MeOH (2 mL) was exposed to an atmosphere of H2 (balloon). Upon completion of the reduction, the reaction mixture was filtered through celite and concentrated in vacuo to afford 3-amino-N-(2-morpholinoethyl)-5-(trifluoromethyl)benzamide, which was advanced without further purification. MS m/z: 318 (M+H+); Calculated for C14H18F3N3O2: 317.1
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:27][NH2:28]>>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Reactant: NCc1ccc(F)c(F)c1
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc(F)c(F)c2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3,4-difluorobenzylamine (72 mg, 0.5 mmol). The title product was obtained as an off-white solid (32.7 mg, 80% yield). 1HNMR (500 MHz, CDCl3) δ: 12.18 (1H, s), 7.83 (1H, br s), 7.53–7.47 (1H, m), 7.15–7.02 (5H, m), 4.53 (2H, d, J=6.41 Hz), 3.41 (3H, s). HRMS (ESI) calcd for C19H14F4N3O3 (M+H): 408.0971; found: 408.0969.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:22])=O)[CH:16]=3)[O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[C:27]=1[OH:33])=[O:25]>>[C:24]([C:26]1[C:27]([OH:33])=[C:28]([NH:32][C:20]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[O:11][CH:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:19][CH2:18]3)=[O:22])[CH:29]=[CH:30][CH:31]=1)(=[O:25])[CH3:23]
Reactant: O=C(O)c1ccc2c(c1)CCC(CCCc1ccccc1)O2
Reactant: CC(=O)c1cccc(N)c1O
Product: CC(=O)c1cccc(NC(=O)c2ccc3c(c2)CCC(CCCc2ccccc2)O3)c1O
Yield: 45 %

Procedure:
Following the process described in example 1 (point K), starting from 2-(3-phenylpropyl)-6-chromanecarboxylic acid and 3-amino-2-hydroxyacetophenone, the title compound was prepared (45% yield).
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:15]([CH3:22])[C@@H:16]([O:20][CH3:21])/[CH:17]=[CH:18]/[CH3:19])[C@@H:4]([CH3:14])[CH2:5][O:6]CC1C=CC=CC=1>C1COCC1>[CH3:1][O:2][C@H:3]([C@@H:15]([CH3:22])[C@@H:16]([O:20][CH3:21])/[CH:17]=[CH:18]/[CH3:19])[C@@H:4]([CH3:14])[CH2:5][OH:6]
Reactant: C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)COCc1ccccc1
Solvent: C1CCOC1
Product: C/C=C/[C@H](OC)[C@H](C)[C@@H](OC)[C@@H](C)CO
Temperature: 25 °C

Procedure:
To ((E)-(2S,3S,4S,5S)-3,5-Dimethoxy-2,4-dimethyl-oct-6-enyloxymethyl)-benzene (5.5 g, 18.0 mmol) in anhydrous THF (180 ml) at −78° C. and under an atmosphere of nitrogen, was slowly added LiDBB until a dark green colour persisted. The temperature was maintained below −70° C. during the addition. The reaction was quenched with saturated ammonium chloride, allowed to warm to room temperature and extracted with diethyl ether (2×). The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by flash chromatography (SiO2, iHex/EtOAc, 50:1 then 1:1) to afford 3.6 g (93%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 5.66 (dq, J=15.2 Hz, 6.4 Hz, 1H), 5.19 (dd, J=15.2 Hz, 8.8 Hz, 1H), 3.75-3.52 (m, 3H), 3.49 (s, 3H), 3.31 (t, J=9.1 Hz, 1H), 3.24 (s, 3H), 2.82 (dd, J=8.2 Hz, 2.9 Hz, 1H), 1.91 (m, 1H), 1.77 (d, J=6.4 Hz, 3H), 1.68 (m, 1H), 0.84 (d, J=6.9 Hz, 3H), 0.79 (d, J=7.1 Hz, 3H).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-:3].[Cl-:4].[F:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[CH:8][C:7]=1[C:15](F)(F)F>C(Cl)Cl>[F:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[CH:8][C:7]=1[C:15]([Cl:4])([Cl:3])[Cl:1]
Reactant: Fc1cc(C(F)(F)F)c(F)c(F)c1F
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCl
Product: Fc1cc(C(Cl)(Cl)Cl)c(F)c(F)c1F
Temperature: 0 °C

Procedure:
85 g (0.64 mol) of aluminum chloride (anhydrous) are initially introduced into 500 ml of methylene chloride, and 109 g (0.5 mol) of 2,3,4,5-tetrafluoro-benzotrifluoride are added dropwise at room temperature; while stirring. The mixture is then subsequently stirred at 40° C. for 1 hour, allowed to cool and poured onto 600 g of ice, the organic phase is separated off, the aqueous phase is extracted with ether and the combined phases are washed with water and dried over anhydrous magnesium sulphate. After concentration, the residue is distilled. 108.3 g (81% of theory) of product are obtained; boiling point: 89-90° C./22 mbar.
Reaction SMILES: C([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])C.[OH:15][CH:16]([CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)CC#N>>[OH:15][CH:16]([CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:14][C:13]1[NH:3][C:4](=[O:12])[C:5]2[C:6]([CH:11]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CCN(CC)C(=O)c1ccccc1C
Reactant: N#CCC(O)CN1CCCC1
Product: O=c1[nH]c(CC(O)CN2CCCC2)cc2ccccc12
Yield: 3.3 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2-methylbenzamide (1.91 g) and 3-hydroxy-4-(pyrrolidin-1-yl)butyronitrile (1.54 g), 3-[2-hydroxy-3-(pyrrolidin-1-yl)propyl]-2H-isoquinolin-1-one (0.089 g) was obtained.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])[C:8](=[O:19])[CH2:7][CH2:6]2.BrBr>C(OCC)(=O)C>[Br:1][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:11]([S:12](=[O:17])(=[O:18])[NH:13][CH2:14][CH2:15][CH3:16])=[C:3]([Cl:2])[CH:4]=2)[C:8]1=[O:19]
Reactant: CCCNS(=O)(=O)c1cc2c(cc1Cl)CCC2=O
Reactant: Br
Agent: BrBr
Solvent: CCOC(C)=O
Product: CCCNS(=O)(=O)c1cc2c(cc1Cl)CC(Br)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.5 L Milliliter of 48% aqueous HBr is added to a solution of 5.76 g (20 mmoles) of 5-chloro-6-n-propylsulfamoyl-1-indanone in 50 ml of ethyl acetate. Thereafter a solution of 3.20 g (20 mmoles) of bromine in 20 ml of ethyl acetate is added dropwise. The mixture is stirred for 1 hour at room temperature, then the solution is concentrated to dryness, and 50 ml of water are added to the residue. The crystalline precipitate is filtered off with suction and washed with water. 2-Bromo-5-chloro-6-n-propylsulfamoyl-1-indanone is obtained which has a melting point of from 150° to 154° C.
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1.C(O)C>O>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:1]3[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=C(O)C1=CCC=CC1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)C1=CCC=CC1
Temperature: 4 °C
Yield: 33 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 1,4-cyclohexadiene-1-carboxylic acid (6.2 g), N,N'-carbonyldiimidazole (8 g) and 2-amino-7-chloro-1,8-naphthyridine (8 g). The product produced by precipitation in water (11 g; m.p. 205° C.) is dissolved in boiling ethanol (250 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (3×15 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7Chloro-1,8-naphthyridin-2-yl)-1,4-cyclohexadiene-1-carboxamide (4.2 g) is produced, m.p. 210° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([F:14])[CH:6]=1)=[O:4].[CH3:15][CH2:16][N:17](C(C)C)[CH:18](C)C.CNCCO>ClCCl.O>[F:14][C:7]1[CH:6]=[C:5]([CH:3]2[O:4][CH2:15][CH2:16][N:17]([CH3:18])[CH2:2]2)[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])c(F)c1
Agent: CNCCO
Solvent: ClCCl
Solvent: O
Product: CN1CCOC(c2ccc([N+](=O)[O-])c(F)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-bromo-1-(3-fluoro-4-nitrophenyl)ethan-1-one E-1.17′″ (2.00 g; 7.63 mmol) is dissolved in dichloromethane (20 ml). DIPEA (1.4 ml; 8.00 mmol) and N-methyl ethanolamine (0.60 ml; 7.63 mmol) are added. The reaction mixture is stirred at 25° C. overnight. The reaction mixture is diluted with dichloromethane and water is added. The organic layer is separated and is dried with sodium sulfate and the solvent is removed under reduced pressure. The crude intermediate is dissolved in TFA (20 ml) and triethyl silane (8 mL) is added at 25° C. and then the reaction mixture is refluxed for 16 h. The reaction mixture is diluted with dichloromethane and the mixture is basified with saturated sodium hydrogencarbonate solution. The organic layer is separated and is dried with sodium sulfate and the solvent is removed under reduced pressure. The crude product is purified using normal phase chromatography (dichloromethane/methanol: 99:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH:19][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(F)cc1)C(C)(C)O2
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(F)cc2)C(C)(C)O3)cc1
Yield: 79 %

Procedure:
By using 3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 79%. Melting point: 191-194° C. (Ethyl acetate-hexane)
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].[Na].[F:8][C:9]1[C:18]([CH2:19]Br)=[CH:17][C:16]2[C:15]([CH3:22])([CH3:21])[CH2:14][CH2:13][C:12]([CH3:24])([CH3:23])[C:11]=2[CH:10]=1>C(O)C>[F:8][C:9]1[C:18]([CH:19]=[O:2])=[CH:17][C:16]2[C:15]([CH3:22])([CH3:21])[CH2:14][CH2:13][C:12]([CH3:24])([CH3:23])[C:11]=2[CH:10]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)c(F)cc21
Agent: [Na]
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C=O)c(F)cc21
Yield: 58 %

Procedure:
5.26 g (59.0 mmol) of 2-nitropropane was added to a solution prepared by dissolving 1.04 g (45.4 mmol) of sodium in 60 mL of ethanol. The resulting solution was added to a solution of 16.9 g (45.4 mmol) of crude 2-fluoro-3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 60 mL of ethanol. After 5 hours the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1M aqueous sodium hydroxide, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by flash chromatography on silica gel (1% ethyl acetate/hexane) to afford 6.17 g (58%) of 3-fluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p.=119.4-120.0° C.).
Reaction SMILES: [Li].[N:2]([N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][O:7][CH2:6][C:5]1([CH3:13])[CH3:12])=O>O1CCCC1.C(OCCCC)CCC>[NH2:2][N:4]1[C:5]([CH3:13])([CH3:12])[CH2:6][O:7][CH2:8][C:9]1([CH3:11])[CH3:10]
Reactant: CC1(C)COCC(C)(C)N1N=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: CC1(C)COCC(C)(C)N1N
Temperature: 99 °C

Procedure:
About 20% of a solution of 5 g of lithium alanate in 50 ml of tetrahydrofuran is added dropwise to a heated solution of 17.2 g of 4-nitroso-3,3,5,5-tetramethylmorpholine in 50 ml of tetrahydrofuran and 100 ml of dibutyl ether. The tetrahydrofuran is distilled off and the internal temperature is increased to 99° C. The remainder of the lithium alanate solution is then added dropwise and the mixture is kept at 70° C. for a further hour. After the mixture has been cooled in an ice-bath, 10 ml of water and 10 ml of 15% strength sodium hydroxide solution are carefully added. After filtration with suction, the filtrate is extracted by shaking first with water and then with 100 ml of 1N hydrochloric acid. The aqueous HCl phase is then extracted by shaking once more with diethyl ether and used in the next stage.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([O:18]C)[N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:20])[N:3]=1.[CH3:21][CH:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[NH2:20][C:4]1[N:3]=[C:2]([NH:25][CH2:24][CH2:23][CH:22]([CH3:26])[CH3:21])[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:18])[N:8]2[CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1nc2c(N)nc(Cl)nc2n1CC1CCOCC1
Reactant: CC(C)CCN
Product: CC(C)CCNc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 170 °C

Procedure:
A mixture of 2-chloro-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (45 mg) in 3-methyl-1-butylamine (0.234 mL) was heated in a microwave at 170° C. for 10 mins. The mixture was concentrated in vacuo to give a green oily residue. This was purified by C18 reverse phase chromatography (ISCO) using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) to give the title compound as a white solid (10 mg).
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:22]([O:24]CC)=[O:23])=[C:18]([CH2:20][CH3:21])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>O1CCOCC1.ClCCl>[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:22]([OH:24])=[O:23])=[C:18]([CH2:20][CH3:21])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)c1c(CC)nc2c(OCC3CCCCC3)cccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.8 ml of 2N aqueous sodium hydroxide solution was added to a solution of 26 mg (0.082 mmol) of ethyl 8-(cyclohexylmethoxy)-2-ethylimidazo[1,2-a]pyridine-3-carboxylate in 1.15 ml of dioxane, and the mixture was stirred at room temperature overnight. The mixture was then acidified with 1.5 ml of 6N aqueous hydrochloric acid, diluted with 5 ml of dichloromethane and filtered over an Extrelut® cartridge. The cartridge was washed with 30 ml of dichloromethane, the filtrate was concentrated and the residue formed was dried under high vacuum. This gave 24 mg (97% of theory) of 8-(cyclohexylmethoxy)-2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid as a crude product which was used as such for the next reaction.