Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]=[C:7]([OH:15])[C:6]([OH:16])=[N:5]2.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:15][C:7]1[C:6]([OH:16])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:3]=2)[N:8]=1
Reactant: O=[N+]([O-])c1cc2nc(O)c(O)nc2cc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cc2nc(O)c(O)nc2cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A mixture of 500 mg (1.9 mmol) 6-bromo-2,3-dihydroxy-7-nitroquinoxaline (supra) in 10 ml dry dimethylformamide and 20 ml dry triethylamine is added to 4 mg palladium(II)acetate, 8 mg triphenylphosphine and 600 μl (4.3 mmol) trimethylsilylacetylene. The mixture is refluxed for 2.5 h under nitrogen. After cooling to room temperature, the reaction mixture is evaporated in vacuo. The residue is stirred with water, filtered and washed with water to give 500 mg of a crude product. The crude product is dissolved in ethyl acetate and purified by column chromatography (silica gel) to give 400 mg (70%) of 2,3-dihydroxy-6-trimethylsilylethynyl-7-nitroquinoxaline. NMR (DMSO-d6): δ 7.8 (1H, s), δ 7.2 (1H, s), δ 0.3 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([C:13](=[O:17])[C:14](=[O:15])[N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(c1)CCCN2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c3c(c1)C(=O)C(=O)N3CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
A solution of 6-methoxy-1,2,3,4-tetrahydroquinoline (10 g, 61.3 mmol) 600 mL CH2Cl2 was slowly added to a solution of oxalyl chloride (8.4 mL, 94.5 mmol) in 100 mL CH2Cl2 at 0° C. After addition the reaction mixture was at 0° C. for 0.5 h, aluminum chloride (24.5 g, 184 mmol) was than added to the reaction mixture, the resulting mixture was warmed up to room temperature, stirred over night. The reaction mixture was poured on ice, diluted with 1N HCl, the aqueous layer was extracted with CHCl3 (3×150 mL), the combined organic layers was washed with brine, dried over Na2SO4. The solvent was concentrated, the crude product was purified by flash chromatography (Hexane/EtOAc), obtained 10.0 g (75%) of pure title compound: 1H NMR (300 MHz, CDCl3) 2.01-2.05 (m, 2H), 2.74 (t, 2H, J=6.0 Hz), 3.73 (t, 2H, J=5.8 Hz), 3.77 (s, 3H), 6.92-6.93 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30][CH3:31])[CH:25]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:22]([CH3:21])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30][CH3:31])[CH:25]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CNCc1cccc(SC)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CSc1cccc(CN(C)C(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and N-methyl-1-(3-methylsulfanylphenyl)methanamine (17.0 mg, 0.12 mmol). The title compound was obtained as a solid (33.5 mg, 67% yield). MS m/z: 500.01, 502.00 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[Cl:19][C:20]1[C:21](F)=[N:22][CH:23]=[C:24]([O:26]CCC2OCCO2)[CH:25]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[N:22][C:21]=1[O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: Fc1ncc(OCCC2OCCO2)cc1Cl
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(O)cc4Cl)cc23)n1

Procedure:
Using 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol and 3-chloro-5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-fluoropyridine, and in the same manner as in Example 6-2) and 6-3) or according to a method similar to it or according to a combination thereof with an ordinary method, 5-chloro-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (738 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])=[CH:9][CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@H:20]2[C@@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17][C@@H:16]2[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:44])=[O:5])=[CH:12][CH:11]=2)=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C[C@H]1N[C@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)[C@@H](c2cccc(Cl)c2F)[C@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@H]1N[C@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@@H](c2cccc(Cl)c2F)[C@]1(C#N)c1ccc(Cl)cc1F

Procedure:
4-{[(2S,3R,4S,5R)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid t-butyl ester (made above, 255 mg, 0.397 mmol) was treated with 50% TFA/methylene chloride (10 mL) overnight. Removal of solvent and treating the residue with acetonitrile and water gave a white solid after filtration and dying. 239 mg.
Reaction SMILES: O[CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:12]([NH:25][C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]1=[O:45])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].N1C=CC=CC=1.S(Cl)([Cl:54])=O>O1CCCC1.O1CCOCC1>[Cl:54][CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:12]([NH:25][C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:11]1=[O:45])[C:3]([O:5][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)C(O)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1

Procedure:
1(1-Hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one (570mg) was dissolved in a 1:1 mixture of dry tetrahydrofuran and dioxan (20ml) and the solution, under nitrogen, was cooled to -10°. Pyridine (224mg) in dry dioxan (5ml) was then added, followed by the dropwise addition of thionyl chloride (0.206ml) in dry dioxan (5ml) over 2-3 minutes. After a further 15 minutes the precipitated solid was filtered off and the filtrate evaporated to dryness. Dry toluene was added and was decanted from any solid. The organic solution was evaporated to dryness and re-evaporation from dry ether gave 1-(1-Chloro-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14](C(OC)=O)[CH2:13][C@@H:12]2[CH3:21])=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]2[CH3:21])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: COC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2C#N)[C@@H](C)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1[nH]c(C(=O)N[C@@H]2CCNC[C@@H]2C)c(C#N)c1Cl
Yield: 63.7 %

Procedure:
A solution of methyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate (Intermediate 42, 3.3 g, 8.39 mmol), potassium hydroxide (3.3 g, 58.77 mmol), and hydrazine hydrate (2.97 mL, 58.77 mmol) in ethylene glycol (200 mL) was stirred for 48 h at 120° C. The reaction mixture was poured in to water (200 mL), then extracted with ethyl acetate (2×250 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to yield the crude product, which was triturated with water (100 mL) to afford 4-chloro-3-cyano-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide 1.5 g (63%) as solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].[C:22]([C:30](O)=[O:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:30](=[O:31])[C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: O=C(O)C(=O)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(C(=O)C(=O)c2ccccc2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 67 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol) and benzoylformic acid (45 mg, 0.30 mmol) were suspended in DMF (3 mL). The suspension was subjected to the same operation as in Example (138a) to obtain 86.2 mg of the title compound as a colorless amorphous solid (67%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>O1CCCC1>[CH3:31][O:32][CH2:33][C:34]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1)=[O:35]
Reactant: COCC(=O)Cl
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(N)c3)cs2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(NC(=O)COC)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A solution (4 mL) of the crude compound (290 mg, 0.88 mmol) obtained in Example 26a in tetrahydrofuran was cooled in an ice bath, triethylamine (0.16 mL, 1.14 mmol) and methoxyacetylchloride (115 mg, 1.06 mmol) were added, and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=30/70-ethyl acetate) to give the title compound (339 mg, 96% in 2 steps) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[O:8])=[CH:5][CH:4]=1>C(Cl)Cl.C1COCC1.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[O:8])=[CH:17][CH:18]=1)=[O:1]
Reactant: O=C(Nc1ccccc1O)c1ccc(CO)cc1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)Nc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
4-Hydroxymethyl-N-(2-hydroxyphenyl)-benzamide from above (0.56 g, 2.3 mmol) was dissolved in CH2Cl2 (12 mL) and THF (12 mL), treated with activated MnO2 (2.0 g, 23 mmol) and stirred at room temperature overnight. The mixture was filtered through celite, the cake washed with CH2Cl2 and the solvent from the eluent removed under reduced pressure. Purification of the crude by column chromatography on silica gel (5% MeOH/CH2Cl2) gave 4-formyl-N-(2-hydroxyphenyl)-benzamide (0.05 g, 10%). 1H NMR (CDCl3) δ 6.95 (t, 1H, J=7.8 Hz), 7.05 (d, 1H, J=7.8 Hz), 7.16 (t, 1H, J=7.8 Hz), 7.42 (d, 1H, J=7.8 Hz), 8.04 (m, 5H), 8.33 (br, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:26][C:27]#[N:28])[C:16]3[S:20][N:19]=[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)[N:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[N-:29]=[N+:30]=[N-:31].[Na+].CC(O)C.C(Cl)Cl>[Br-].[Zn+2].[Br-].C(Cl)Cl.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][N:15]([C:16]3[S:20][N:19]=[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)[N:17]=3)[CH2:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#CCN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CO
Product: c1cn(-c2nsc(N(CCCNCc3ccc4c(c3)OCO4)Cc3nnn[nH]3)n2)cn1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A solution of [{3-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetonitrile (37 mg, 91 μmol), sodium azide (12 mg, 184 μmol) and zinc (II) bromide (10 mg, 46 μmol) in 2:1H2O/iPrOH (1 mL) was heated to 150° C. for 24 h. The reaction mixture was cooled to r.t. prior to loading directly onto a SiO2 column (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 14 mg (35%) of N′-benzo[1,3]dioxol-5-ylmethyl-N-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-N-(1H-tetrazol-5-ylmethyl)-propane-1,3-diamine as a white solid. [M+H]+ 441.01; 1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 7.74 (s, 1H), 7.07 (s, 1H), 6.85-6.74 (m, 3H), 5.92 (s, 2H), 4.43 (s, 2H), 4.06 (s, 2H), 3.81 (br s, 2H), 3.31 (t, 2H), 3.06 (t, 2H), 2.17 (tt, 2H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O.Cl[C:16]1[N:21]=[C:20]([N:22]2[C:26]([CH3:27])=[CH:25][C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23]2)[CH:19]=[CH:18][CH:17]=1.C(O)CC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:27][C:26]1[N:22]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:14])([F:13])[F:1])[N:21]=2)[N:23]=[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CCOC(=O)c1cc(C)n(-c2cccc(Cl)n2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(-c3ccccc3OC(F)(F)F)n2)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 12.3 %

Procedure:
To the solution of 2-trifluoromethoxyphenyl boronic acid (0.192 g, 0.92 mmol) and the 2-chloropyridine compound from Step 1 (0.165 g, 0.62 mmol) in toluene:n-propanol (3 mL:3 mL) were added tetrabis(triphenylphosphine)palladium (0.072 g, 0.062 mmol) and aqueous sodium bicarbonate (2.0M, 0.62 mL, 1.2 mmol). The reaction mixture was stirred at 90° C. for 16 hours. After cooling to room temperature, the mixture was filtered through a Celite pad, and washed with ethyl acetate (3 times). The filtrate was concentrated. The resulting residue was dissolved in ethyl acetate and washed with saturated sodium carbonate aqueous solution and brine, the organic layer was dried over anhydrous sodium sulfate. After concentration, the crude product was applied to column chromatography on silica gel to afford the titled compound, as yellow oil, 30 mg, 12.3% yield.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[O:15]1[C:24]2[CH:23]=[C:22]([CH:25]=O)[N:21]=[CH:20][C:19]=2[O:18][CH2:17][CH2:16]1.[BH4-].[Na+].O>CO.ClCCl>[O:15]1[C:24]2[CH:23]=[C:22]([CH2:25][NH:1][CH2:2][CH:3]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]3)[N:21]=[CH:20][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CNCc2cc3c(cn2)OCCO3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a solution of 0.28 g of tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate in a mixture of 7 mL of methanol and 20 mL of dichloromethane, 0.23 g of 2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 0.50 g of molecular sieves 3A were added, the mixture was stirred at room temperature for 3 hours, and then, the reaction mixture was charged with 79 mg of sodium borohydride and stirred at room temperature for 5 hours 30 minutes. Thereto was added water under cooling with ice, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.48 g of tert-butyl 3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)pyrrolidine-1-carboxylate as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.Cl>[OH-].[Na+]>[CH3:1][C:2]1([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)CCCCC1(C)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(CCCCC(=O)O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Yield: 83.3 %

Procedure:
A solution of 0.52 g of ethyl 5-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-10-yl)valerate in 3 ml of 1N sodium hydroxide is stirred overnight at a temperature in the region of 20° C. The mixture is then treated with 3 ml of 1N hydrochloric acid and the precipitate formed is filtered off. The solid obtained is washed with distilled water (2×10 ml) and with ethyl ether (3×10 ml), and dried at 60° C. under vacuum (1 mmHg; 0.13 kPa). 0.4 g of 5-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)valeric acid is obtained in the form of an ochre solid melting above 260° C. (Analysis, % calculated C: 67.64, H: 5.68, N: 12.45, O: 14.23, % found C: 67.6, H: 5.8, N: 12.5).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:27][CH2:28][O:29]C)[CH:4]=[CH:5]2.O.[C:32](O)(=O)C>>[C:28]([O:27][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH:11]=[CH:10][C@@H:9]35)(=[O:29])[CH3:32]
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](Oc4ccccn4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@@H](Oc4ccccn4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinan-7-ene (0.54 g, 1.33 mmol) is mixed with H2O (20 ml) and glacial acetic acid (20 ml) and stirred for 2.5 hours at 100° C. The mixture is then concentrated by rotary evaporation in a Rotavapor at 40° C. and the residu e obtained is purified by flash chromatography (90 g silica gel; CH2Cl2 /MeOH=9/1). The product is dissolved in H2O (7 ml) and glacial acetic acid (0.7 ml) and lyophilised. Yield: 0.436 g (1.03 mmol, 77.6%)
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[C:3]=1[O:35][CH3:36].[OH-].[Na+]>CCO>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:22]=[N:21][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]3)=[N:19][CH:18]=2)[C:3]=1[O:35][CH3:36]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)c(OC)c(Br)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)c(OC)c(Br)c2s1
Temperature: 60 °C

Procedure:
Ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-6-methoxy-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (47 mg, 0.081 mmol) was dissolved in EtOH (3 mL) and NaOH solution (1 mL, 1 M, aq) was added to give a pale yellow solution. The mixture was heated to 60° C. overnight then cooled to rt, the EtOH removed under reduced pressure and the residue acidified with HCl solution (1 M, aq) to pH 3. The mixture was extracted into EtOAc (3×15 mL) and the combined organic layer washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure. The mixture was purified by chromatography, Biotage SP4, 4 g Si cartridge, 50-100% EtOAc in heptane. The relevant fractions were combined to give Compound 208 as an off white solid, 8 mg (18%). 1H NMR (CDCl3): δ 1.31 (3H, t, J=7.2 Hz), 1.42 (3H, s), 1.61 (2H, m), 2.27 (2H, m), 3.47 (2H, m), 3.64 (3H, s), 3.84 (2H, m), 4.15 (2H, q, J=7.2 Hz), 4.2-7.2 (3H, br s), 7.48 (1H, s), 8.62 (2H, s). MS: 549.07/551.06 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([OH:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][C:38]1[C:43]([F:44])=[CH:42][CH:41]=[CH:40][N:39]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([O:22][CH2:37][C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cccnc1CBr
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(O)cc(C)cc12)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3ncccc3F)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
A solution of 49 mg (0.12 mmol) of rac-[1-{[7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carbonyl)amino]}-1-methylbutyl)carbamic acid tert-butyl ester (Example 141A) in 2.1 ml of DMF was admixed with 78 mg (0.24 mmol) of caesium carbonate and 69 mg (0.360 mmol) of 2-bromomethyl-3-fluoropyridine (Example 143A). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated off under reduced pressure and the residue was partitioned between dichloromethane and water. The organic phase was removed and concentrated under reduced pressure. The residue was purified by preparative HPLC chromatography (Method 21), which gave 21 mg (33% yield, 96% pure) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH2:14](O)[CH3:15]>>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH2:14][CH3:15])=[O:8]
Reactant: Cc1ccsc1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1sccc1C
Temperature: 25 °C
Yield: 86 %

Procedure:
To a stirred solution of 3-methylthiophene-2-carboxylic acid (1.84 g, 12.9 mmol) in ethanol (20 mL) was added thionyl chloride (0.94 mL, 12.9 mmol). The resulting reaction mixture was stirred at reflux for 20 h, and then allowed to cool to ambient temperature and concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl 3-methylthiophene-2-carboxylate as light yellow liquid (1.89 g, 86%): 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=5.0 Hz, 1H), 6.90 (d, J=5.0 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.37 (t, J=7.1 Hz, 3H).