Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.[Cl:12][C:13]1[S:17][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][C:14]=1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29]>>[Cl:12][C:13]1[S:17][C:16]([S:18]([NH:1][C:2]2[S:3][C:4]([CH3:11])=[C:5]([C:7]([OH:9])=[O:8])[N:6]=2)(=[O:20])=[O:19])=[CH:15][C:14]=1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29]
Reactant: O=S(=O)(Cl)c1cc(-c2cc(F)ccc2F)c(Cl)s1
Reactant: COC(=O)c1nc(N)sc1C
Product: Cc1sc(NS(=O)(=O)c2cc(-c3cc(F)ccc3F)c(Cl)s2)nc1C(=O)O
Yield: 21 %

Procedure:
The product was prepared from methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate (25 mg, 0.15 mmol), and 5-chloro-4-(2,5-difluorophenyl)thiophene-2-sulfonyl chloride (Intermediate 20) (48 mg, 0.15 mmol) according to the General Procedure 11, described in Example 131. The crude product was purified using reversed phase chromatography (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, gradient: H20.1% TFA in water/MeCN over 6 minutes). The title compound was obtained in 21% yield (14.1 mg). 1H NMR (400 MHz, MeOH-d4) δ ppm 2.56 (s, 3 H) 7.17-7.30 (m, 3 H) 7.55 (d, J=1.76 Hz, 1 H). MS (ESI+) m/z 451 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[C:9]1[N:14]=[N:13][C:12]([NH2:15])=[CH:11][CH:10]=1.Br[C:17]1[C:22](=[O:23])[N:21]([CH3:24])[N:20]=[C:19]([C:25]2[CH:35]=[CH:34][CH:33]=[C:32]([N:36]3[N:45]=[CH:44][C:43]4[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=4)[C:37]3=[O:51])[C:26]=2[CH2:27][O:28][C:29](=[O:31])[CH3:30])[CH:18]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:46]([C:41]1[CH:42]=[C:43]2[C:38](=[C:39]([F:50])[CH:40]=1)[C:37](=[O:51])[N:36]([C:32]1[CH:33]=[CH:34][CH:35]=[C:25]([C:19]3[CH:18]=[C:17]([NH:15][C:12]4[N:13]=[N:14][C:9]([N:5]5[CH2:4][C@@H:3]6[CH2:8][C@H:6]5[CH2:7][N:2]6[CH3:1])=[CH:10][CH:11]=4)[C:22](=[O:23])[N:21]([CH3:24])[N:20]=3)[C:26]=1[CH2:27][O:28][C:29](=[O:31])[CH3:30])[N:45]=[CH:44]2)([CH3:47])([CH3:48])[CH3:49]
Reactant: CN1C[C@@H]2C[C@H]1CN2c1ccc(N)nn1
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H]5C[C@H]4CN5C)nn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C

Procedure:
6-((1S,4S)-5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridazin-3-ylamine (100 mg, 0.487 mmol, Eq: 1.00), acetic acid 2-(5-bromo-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzyl ester (284 mg, 0.512 mmol, Eq: 1.05), xantphos (42.3 mg, 0.073 mmol, Eq: 0.15), tris(dibenzylideneacetone)-dipalladium (0) (33.5 mg, 0.036 mmol, Eq: 0.075) and cesium carbonate (476 mg, 1.46 mmol, Eq: 3.00) were added to a microwave vial. The vial was capped and purged. Degassed dioxane (about 5 ml) was added through a syringe and the vial was purged again and back filled with nitrogen. The reaction was heated at 100° C. overnight in a sand bath. The reaction was filtered through celite and concentrated. The crude product was purified by chromatography using a gradient of 0% to 25% methanol in DCM. LCMS and NMR showed major impurities. Took on to next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:17]=[CH:16][S:15][CH:14]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Brc1ccsc1
Product: Clc1cc(-c2ccsc2)nc2ccccc12

Procedure:
The title compound, MS: m/e=245 (M+), was prepared from 4-chloro-quinoline and 3-bromothiophene.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[F:10].[C:11]([Cu])#[N:12].C(OCC)(=O)C>CCCCCC>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:11]#[N:12])=[C:3]([F:10])[C:4]=1[CH3:9]
Reactant: Cc1c(N)ccc(Br)c1F
Reactant: N#C[Cu]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(N)ccc(C#N)c1F
Temperature: 140 °C
Yield: 67.3 %

Procedure:
A mixture of 4-bromo-3-fluoro-2-methylaniline (23 g, 113 mmol) and cyanocopper (20.19 g, 225 mmol) N,N-dimethylformamide (200 mL) was heated to 140° C. for 7 h. After the mixture was cooled to room temperature filtered and poured into a separatory funnel containing water and ethyl acetate (1:1). Layers were separated and the organic layer was concentrated under reduced pressure. Flash chromatography (0-50% ethyl acetate in hexane) gave the desired product (11.4 g, 76 mmol, 67% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.22 (t, 1H), 6.45 (d, J=8.59 Hz, 1H), 4.23 (br. s., 2H), 2.07 (s, 3H); MS (ESI) m/z 151.1[M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.B([C:18]1[CH:19]=[C:20]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:26]1[CH:25]=[C:24]3[C:37]([CH3:45])([CH3:44])[C:38]4[C:43]([C:23]3=[CH:22][C:21]2=1)=[CH:42][CH:41]=[CH:40][CH:39]=4)(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:4]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[C:2]([C:18]2[CH:19]=[C:20]3[C:28](=[CH:29][CH:30]=2)[N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26]2[CH:25]=[C:24]4[C:37]([CH3:45])([CH3:44])[C:38]5[C:43]([C:23]4=[CH:22][C:21]3=2)=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:3]=1
Reactant: CC1(C)c2ccccc2-c2cc3c4cc(B(O)O)ccc4n(-c4ccccc4)c3cc21
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)c2ccccc2-c2cc3c4cc(-c5ccc6[nH]c7ccccc7c6c5)ccc4n(-c4ccccc4)c3cc21

Procedure:
14.07 g (57.18 mmol) of 3-bromo-9H-carbazole 22, 25.37 g (62.90 mmol) of compound 13 and 6.75 g of sodium carbonate are suspended in 1800 ml of dioxane, 1800 ml of toluene and 750 ml of water. 3.38 g (2.93 mmol) of Pd(PPh3)4 are added to this suspension. The reaction mixture is heated under reflux for 5 h. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is extracted with hot toluene and recrystallised from toluene. The yield is 19.5 g (65%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([C@@](C(O)=O)(CC(N(CCCl)CCCl)(C1C=CC=C(C)C=1)C(=O)N)NC(OC1C=CC=CC=1)=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]1([CH3:23])[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[CH2:24]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1cccc(C(C[C@](Cc2ccccc2)(NC(=O)Oc2ccccc2)C(=O)O)(C(N)=O)N(CCCl)CCCl)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cccc(CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-amino-phenylacetic acid benzyl ester p-toluene sulphonic acid was prepared by adding 3-aminophenylacetic acid (10 g) and p-toluene sulphonic acid monohydrate (13.2 g) to benzyl alcohol (27.2 ml) in toluene (30 ml). The mixture was heated under reflux and the water formed collected in a Dean-Stark receiver. When all the water had been distilled off the mixture was allowed to cool to 25° C. before diluting with diethyl ether and placing in an ice-bath for 1 hr. The crystalline p-toluene sulphonate was filtered off and dried in a dissicator (23.5 g) NMR δ 2.31(s)3H, 3.82(s)2H, 5.11(s)2H, 7.11(d)2H, 7.25-7.45(m)8H, 7.52(d)2H.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:30]2>COC(O)CC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:26][C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[CH2:32][N:31]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:30]5)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)CN1Cc2ccc(N)cc2C1
Reactant: COc1ccc(-c2ccc3cnc(OS(=O)(=O)C(F)(F)F)nn23)cn1
Agent: CCC(O)OC
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5c(c4)CN(CC(N)=O)C5)nn23)cn1

Procedure:
Trifluoro-methanesulfonic acid 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.112 g, 0.298 mmol) and 2-(5-Amino-1,3-dihydro-isoindol-2-yl)-acetamide (0.077 g, 0.40 mmol) were reacted in an analogous manner to Example 908D at 50° C. for 16 h in methoxypropanol. Yellow solid precipitated out which was filtered off and washed with water (47 mg, 38%). Found to be pure desired product. LCMS=415.9 (M+H), HPLC rt=2.039 min, purity=96%. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.51 (s, 1H), 9.02 (s, 1H), 8.98 (s, 1H), 8.42 (dd, J=8.7 Hz, 2.3 Hz, 1H), 7.89 (s, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.34 (s, 1H), 7.18-7.10 (m, 3H), 6.99-6.95 (m, 2H), 4.01 (s, 2H), 3.94 (s, 5H), 3.29 (s, 2H).
Reaction SMILES: Cl.[F:2][C:3]([F:8])([F:7])[CH2:4][NH:5][CH3:6].Cl[C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=2)[C:13]([C:28]#[N:29])=[C:12]([S:30][CH2:31][C:32]2[N:33]=[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)[S:35][CH:36]=2)[N:11]=1>CN(C=O)C.O.C1COCC1>[Cl:43][C:40]1[CH:39]=[CH:38][C:37]([C:34]2[S:35][CH:36]=[C:32]([CH2:31][S:30][C:12]3[C:13]([C:28]#[N:29])=[C:14]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][OH:27])=[CH:22][CH:23]=4)[C:15]([C:16]#[N:17])=[C:10]([N:5]([CH3:6])[CH2:4][C:3]([F:8])([F:7])[F:2])[N:11]=3)[N:33]=2)=[CH:42][CH:41]=1
Reactant: CNCC(F)(F)F
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CN(CC(F)(F)F)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
41 mg (0.27 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were dissolved in 2 ml of DMF, 40 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to 100 mg (0.14 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), and the solution was stirred at RT overnight. In a separate flask, another 82 mg (0.54 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were then dissolved in 0.5 ml of DMF, 80 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to the first solution. The reaction mixture obtained was stirred at RT overnight. The mixture was then warmed to 60° C., and the reaction mixture was stirred at this temperature overnight, after which it was heated to 100° C. After stirring at 100° C. overnight, the mixture was diluted with a little water/THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 64 mg (74% of theory) of the target compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[CH3:18])O1.Cl[C:21]1[N:22]=[C:23]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[C:24]2[N:30]=[C:29]([CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([C:38]([OH:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]3)[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:18][C:10]1[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:9]=1[C:21]1[N:22]=[C:23]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[C:24]2[N:30]=[C:29]([CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([C:38]([OH:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]3)[CH:28]=[CH:27][C:25]=2[N:26]=1
Reactant: Cc1oc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: Cc1oc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
Following General Procedure A, 4,4,5,5-tetramethyl-2-(2-methylbenzofuran-3-yl)-1,3,2-dioxaborolane and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 were reacted to give 103. LCMS (MH+)=502.3. 1H-NMR (DMSO-d6): δ 8.55 (m, 1H), 8.19 (d, 1H), 7.86 (d, 1H), 7.56 (m, 1H), 7.32 (m, 2H), 4.48 (s, 4H), 4.01 (s, 1H), 3.85 (m, 4H), 3.72 (s, 2H), 2.96 (s, 3H), 2.93 (m, 2H), 2.01 (m, 2H), 1.66 (m, 2H), 1.29 (m, 2H), 1.25 (m, 1H), 1.04 (s, 6H)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=O.[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[O:21]=[C:16]1[NH:17][C:18](=[O:20])[C:19](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])[S:15]1
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)c1cc(C=O)ccc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)c1cc(C=C2SC(=O)NC2=O)ccc1OC
Yield: 85.7 %

Procedure:
A mixture of methyl 5-formyl-2-methoxybenzoate (490 mg), thiazolidine-2,4-dione (358 mg), ammonium acetate (401 mg), acetic acid (0.8 ml) and benzene (10 ml) was submitted to Dean-Stalk dewatering apparatus to reflux for 4 hours under heat. After cooling, the crystals deposited were collected by filtration, washed with benzene and with 20% aqueous solution of acetone, and then dried to obtain 634 mg (86%) of aimed compound as crystals.
Reaction SMILES: [O:1]1CC[CH2:3][CH2:2]1.[NH2:6][C:7]1[C:8]([Cl:25])=[CH:9][C:10]([F:24])=[C:11]([N:13]2[C:21](=[O:22])[C:16]3=[CH:17][CH2:18][CH2:19][CH2:20][N:15]3[C:14]2=[O:23])[CH:12]=1.C(OC(=O)C)(=O)C.Cl>N1C=CC=CC=1.C(OCC)(=O)C>[C:2]([NH:6][C:7]1[C:8]([Cl:25])=[CH:9][C:10]([F:24])=[C:11]([N:13]2[C:21](=[O:22])[C:16]3=[CH:17][CH2:18][CH2:19][CH2:20][N:15]3[C:14]2=[O:23])[CH:12]=1)(=[O:1])[CH3:3]
Reactant: Nc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Reactant: C1CCOC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To an tetrahydrofuran (5 mL) solution of 2-(5-amino-4-chloro-2-fluorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.50 g, 1.69 mmol) were dropwise added acetic anhydride (0.18 mL, 1.86 mmol) and pyridine (8 drops) with stirring at room temperature. The reaction mixture was stirred for 8 hours at room temperature and further stirred for 13 hours at 80° C. 1N Hydrochloric acid (20 mL) and ethyl acetate (20 mL) were added to the resulting mixture, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL×2 times). The organic layer combined was washed with saturated sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane =1/1) to obtain a white solid of 2-(5-acetylamino-4-chloro-2-fluorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.34 g, yield:59.6%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.[OH:14][C:15]([CH3:20])([CH3:19])[C:16](=[O:18])[CH3:17]>ClCCl>[CH3:10][O:11][CH2:12][O:14][C:15]([CH3:20])([CH3:19])[C:16](=[O:18])[CH3:17]
Reactant: COCCl
Reactant: CC(=O)C(C)(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(C)(C)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N,N-diisopropylethylamine (131 ml) and chloromethyl methyl ether (57 ml) in dichloromethane (50 ml) was added under ice-cooling to a solution of 3-hydroxy-3-methyl-2-butanone (52.6 ml) in dichloromethane (450 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with an aqueous solution (250 ml×2) of 10% citric acid, a saturated aqueous solution (200 ml) of NaHCO3 and saturated brine (200 ml), and dried over MgSO4. The solvent was distilled away under reduced pressure. The residue was distilled under atmospheric pressure to give 53.6 g of the title compound (bp=155°-165° C.) as a colorless liquid (see Table 5).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[NH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:21]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[CH:24][CH:23]=1)#[N:20]
Reactant: COC(C(=O)O)c1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Oc2ccccc2)cc1

Procedure:
(RS)-Methoxy-(4-phenoxy-phenyl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-(4-phenoxy-phenyl)-acetamide. Colorless solid. MS 373.3 ([M+H]+)
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[C:8]([CH2:19][CH3:20])[NH:7][N:6]=1)[CH3:4].[CH3:21]I>CN(C)C=O>[CH2:3]([C:5]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[C:8]([CH2:19][CH3:20])[N:7]([CH3:21])[N:6]=1)[CH3:4]
Reactant: CI
Reactant: CCc1n[nH]c(CC)c1Oc1cccc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(C)c(CC)c1Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 22 mg, 0.53 mmol) was added to a solution of the pyrazole from Example 60 (100 mg, 0.41 mmol) and methyl iodide (34 μl, 0.53 mmol) in dimethylformamide (1.5 ml) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature and was stirred for 4 hours. The reaction was quenched with water and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (20 ml) and water (10 ml) and the organic phase was washed with water (2×10 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluting with a solvent gradient of 100% pentane changing to 100% ethyl acetate and finally ethyl acetate:methanol (10:1, by volume) to provide the title compound (65 mg) as a colourless oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][C:11]=1[CH3:18].[CH3:19][C:20]1(C)[O:25]C(=O)CC(=O)[O:21]1.Cl>C(=O)([O-])[O-].[K+].[K+].O.C(O)=O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:19][C:20]([OH:25])=[O:21])=[CH:12][C:11]=1[CH3:18]
Reactant: COc1ccc(C=O)cc1C
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1C
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
Formic acid, 40.3 grams (0.88 mole), was stirred and cooled to below 5° C., to which was added 36.9 grams (0.37 mole) of triethylamine at a rate to maintain the reaction mixture temperature below 20° C. Upon completion of addition, 22.0 grams (0.15 mole) of (4-methoxy-3-methylphenyl)formaldehyde was added to the reaction mixture, followed by 22.2 grams (0.15 mole) of 2,2-dimethyl-1,3-dioxane-4,6-dione. Upon completion of addition, the reaction mixture was warmed to 60° C. where it stirred for about 15 minutes. The source of heat was removed, during a period when an exothermic reaction with evolution of gas took place within the reaction vessel. The heat source was returned once the exothermic reaction subsided, and heating of the reaction mixture was resumed for about two hours at 75° C. to 95° C. After this time the reaction mixture was cooled in an ice and water bath, and 200 mL of water, followed by 100 mL of aqueous 4N hydrochloric acid were added. The mixture was then extracted with two portions of diethyl ether. The combined extracts were washed with two portions of an aqueous dilute sodium chloride solution, with one portion of an aqueous saturated sodium chloride solution, and then dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding a residual solid. The solid was dissolved in an aqueous solution of 1N potassium carbonate and washed with two portions of diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid, and then it was extracted with two portions of diethyl ether. The combined ether extracts were washed with one portion of an aqueous dilute sodium chloride solution, and then dried with sodium sulfate. The mixture was filtered and concentrated under reduced pressure, yielding 26.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[CH3:31][O:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>CN(C=O)C>[CH3:31][O:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:36]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccccc1OC

Procedure:
1-(2-Methoxybenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 2-methoxybenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:8]=2[C:9](=[O:12])[NH:10][CH:11]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:13]([N:10]1[C:9](=[O:12])[C:8]2[N:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:2]([Br:1])=[CH:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(Br)c2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c2ncccc2c(Br)cn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a suspension of 5-bromo-1,7-naphthyridin-8(7H)-one (0.50 g, 2.22 mmol) in anhydrous DMF (60 mL) was added benzyl bromide (0.34 mL, 2.88 mmol) and Cs2CO3 (0.94 g, 2.88 mmol). The reaction was stirred at rt for 16 h. After that time the reaction was concentrated under reduced pressure, diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with water then brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 98:2 dichloromethane/methanol) to give 7-benzyl-5-bromo-1,7-naphthyridin-8(7H)-one (0.584 g, 83%) as a brown solid: 1H NMR (400 MHz, CDCl3) δ 8.93 (dd, J=4.4, 1.5 Hz, 1H), 8.16 (dd, J=8.2, 1.5 Hz, 1H), 7.66 (dd, J=8.2, 4.4 Hz, 1H), 7.42 (s, 1H), 7.28-7.41 (m, 5H), 5.28 (s, 2H); ESI MS m/z 314.9 [M+H]+ and 316.9 [M+H]+.