Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[OH:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2oc(C)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(O)c2oc(C)cc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Ethyl 7-(Acetyloxy)-2-methyl-1-benzofuran-5-carboxylate was dissolved in absolute ethanol (200 mL). Potassium carbonate (18 g, 0.13 mol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The residue was and crystallized from ether/hexane mixture, 1:5 to give the desired product 8.5 g (38 mmol, 81%) as a cream solid. 1H NMR (DMSO-D6): δ ppm 1.35 (t, 3H), 2.40 (s, 3H), 4.20 (qt, 2H), 6.65 (s, 1H), 7.32 (s, 1H), 7.65 (s, 1H); MS (APCI, pos): 221.1.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[NH2:8][C:9]1[S:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:13]=1[C:14]([NH2:16])=[O:15]>C1(C)C=CC=CC=1>[NH2:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][C:13]=1[C:14]([NH2:16])=[O:15])=[O:7]
Reactant: NC(=O)c1cc(-c2ccccc2)sc1N
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NC(=O)Nc1sc(-c2ccccc2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Chlorosulphonylisocyanate (0.081 mL) was added to a stirred suspension at 0° C. of 2-amino-5-phenyl-3-thiophenecarboxamide (0.2 g) in toluene (10 mL). After stirring for 16 h at room temperature, the solvent was evaporated and the residue dissolved in acetonitrile (20 mL). 10% Sodium bicarbonate solution (2 mL) was added and the mixture was stirred for 1 h. After acidification with 2M hydrochloric acid, the solution was extracted three times with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent was evaporated. Chromatography on silica eluting with methanol/dichloromethane mixtures gave the title urea (0.027 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[N:40]1[CH:45]=[CH:44][CH:43]=[N:42][C:41]=1[C:46]1([NH2:49])[CH2:48][CH2:47]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:49][C:46]1([C:41]2[N:42]=[CH:43][CH:44]=[CH:45][N:40]=2)[CH2:48][CH2:47]1)[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC1(c2ncccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80.1 %

Procedure:
To a suspension of the (S)-2-tert-Butoxycarbonylamino-propionic acid (43 mg, 0.23 mmol), HATU (99 mg, 0.26 mmol), and 1-Pyrimidin-2-yl-cyclopropylamine dihydrochloride (45 mg, 0.22 mmol) in CH2Cl2 (1.5 mL) was added triethylamine (0.12 mL, 0.87 mmol). The reaction was stirred at room temperature for 22 h, diluted with CH2Cl2 (7 mL) and then washed with saturated aqueous NaHCO3 (2×6 mL) and brine (1×6 mL). The organic phase was dried with MgSO4 and concentrated to afford 54 mg of [(S)-1-(1-Pyrimidin-2-yl-cyclopropylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester as white solid, m/z 307.56 [M+1]+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[CH2:40]([CH2:43][NH2:44])[CH:41]=[CH2:42]>>[CH2:40]([CH2:43][NH:44][CH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:38][CH:39]=1)[CH:41]=[CH2:42]
Reactant: C=CCCN
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: C=CCCNCCc1ccc(CCCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 15.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and allylmethylamine (13 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (2.7 mg) was obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[C:58]1(=[O:64])[O:63][C:61](=[O:62])[CH2:60][CH2:59]1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:58](=[O:64])[CH2:59][CH2:60][C:61]([OH:63])=[O:62])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: O=C1CCC(=O)O1
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)CCC(=O)O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of the FR-900506 substance (248 mg) in pyridine (7 ml) were added succinic anhydride (145 mg) and 4-(N,N-dimethylamino)pyridine (7 mg), and the resulting mixture was stirred at room temperature for 18 hours. The react on mixture was concentrated under reduced pressure and the residue was subjected to chromatography on silica gel (20 g) with ethyl acetate to give 17-allyl-12-[2-[4-(3-carboxypropionyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (90 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:19])[S:9](=[O:18])(=[O:17])[N:10]([CH2:11][CH:12]3[CH2:14][C:13]3([F:16])[F:15])[C:5]2=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:13]1([F:16])[CH2:14][CH:12]1[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][C:21]=3[CH3:20])[C:25]([O:27][CH3:28])=[O:26])=[CH:3][CH:4]=2)[N:8]([CH3:19])[S:9]1(=[O:18])=[O:17]
Reactant: CN1c2nc(Cl)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(-c2ccc3c(n2)N(C)S(=O)(=O)N3CC2CC2(F)F)c1
Temperature: 75 °C

Procedure:
5-chloro-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (29-1) (6.6 g, 21.3 mmol, 1.0 eq), methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (8.8 g, 32.0 mmol, 1.5 eq), tripotassium phosphate (9.0 g, 42.6 mmol, 2.0 eq), S-Phos (875 mg, 2.1 mmol, 0.1 eq), and palladium(II) acetate (239 mg, 1.1 mmol, 0.05 eq) were combined in THF (90 mL) and water (15 mL). The resulting mixture was heated at 75° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (300 mL), washed with water (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (330 g SiO2, 0-60% EtOAc in hexanes) to afford methyl 3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylbenzoate (38-1) as a yellow solid. HRMS m/z (M+H) 424.1135 found, 424.1137 required.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\[C:32]([C:34]2[CH:35]=[CH:36][C:37]3[CH:41]=CS[C:38]=3[CH:42]=2)=[O:33])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(C1C=CC(C(O)=O)=CC=1)#[N:44]>>[C:41]([C:37]1[CH:38]=[CH:42][C:34]([C:32](/[N:31]=[C:14]2/[N:13]([C@H:10]3[CH2:9][CH2:8][C@@H:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:2])[CH3:3])[CH2:12][CH2:11]3)[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)[N:18]=[CH:17][C:16]=3[NH:15]/2)=[O:33])=[CH:35][CH:36]=1)#[N:44]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(C#N)cc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 34.6 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 4-cyanobenzoic acid. After preparative HPLC purification, the TFA salt was free-based using an SCX-ion exchange column to obtain (E)-4-cyano-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide as a light yellow solid (34.6% yield). MS m/z=558.2 [M+H], calc 557.69 for C31H39N7O3.
Reaction SMILES: [CH2:1]([S:4]([NH:7][C@@H:8]([C:13]([NH:15][C@H:16]([C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)=[O:28])[CH2:17][N:18](C(OC(C)(C)C)=O)[CH3:19])=[O:14])[C@@H:9]([CH2:11][CH3:12])[CH3:10])(=[O:6])=[O:5])[CH2:2][CH3:3]>FC(F)(F)C(O)=O>[CH2:1]([S:4]([NH:7][C@@H:8]([C:13]([NH:15][C@H:16]([C:27]([NH:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=1)=[O:28])[CH2:17][NH:18][CH3:19])=[O:14])[C@@H:9]([CH2:11][CH3:12])[CH3:10])(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)N[C@@H](C(=O)N[C@@H](CN(C)C(=O)OC(C)(C)C)C(=O)NCc1ccc(C#N)cc1)[C@H](C)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)N[C@@H](C(=O)N[C@@H](CNC)C(=O)NCc1ccc(C#N)cc1)[C@H](C)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To N-(propylsulfonyl)-D-isoleucyl-3-[(t-butoxycarbonyl)(methyl)amino]-N1-(4-cyanobenzyl)-L-alaninamide (1.6 g, 3 mmol), trifluoroacetic acid (10 ml) was added and stirred at room temperature under a nitrogen stream. After 1 hour, the reaction mixture was concentrated under reduced pressure and the residue was applied to column chromatography (Fuji Silysia NH-DM-1020; mobile phase: dichloromethane:methanol=1:0, 4:1) to give N-(propylsulfonyl)-D-isoleucyl-3-(methylamino)-N1-(4-cyanobenzyl)-L-alaninamide (1.3 g, 2.9 mmol; yield 96%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:6][CH:5]=[C:4]([Cl:13])[N:3]=1.C1(=O)O[CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:13][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH:10]=[CH:11][N:12]=3)[CH2:17][CH2:16][O:15][C:2]=2[N:3]=1
Reactant: Clc1ccc(-c2ncc[nH]2)c(Cl)n1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(n1)OCCn1ccnc1-2

Procedure:
A mixture of 0.856 g (4.00 mmol) of 2,6-dichloro-3-(1H-imidazol-2-yl)pyridine, 704 mg (8.00 mmol) of ethylene carbonate and 2930 mg (9.00 mmol) of cesium carbonate was heated in 25.0 ml of N,N-dimethylformamide for 13 hours at 90° C. The mixture was filtered, the filtrate concentrated in high vacuum, the residue purified on 10 g of silica column eluting with 80% of ethyl acetate in heptane to give 9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine. Yield 0.359 g (41%). M/z 222.0, calc. 221.04. 1H NMR (500 MHz, CDCl3) δ 8.84 (d, J=8.2, 1H), 7.18 (s, 1H), 7.15 (d, J=8.2, 1H), 7.02 (s, 1H), 4.63-4.57 (m, 2H), 4.47-4.41 (m, 2H)
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1.[Cl:13]C(Cl)(Cl)[C:15]([C:17]1[NH:18][CH:19]=[CH:20][CH:21]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>>[ClH:13].[NH2:12][C:9]1[NH:10][CH:11]=[C:7]([CH2:6][CH2:5][CH2:4][NH:3][C:15]([C:17]2[NH:18][CH:19]=[CH:20][CH:21]=2)=[O:16])[N:8]=1
Reactant: NCCCc1c[nH]c(N)n1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1nc(CCCNC(=O)c2ccc[nH]2)c[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-amino-propyl)-1H-imidazol-2-ylamine dihydrochloride 16 (0.100 g, 0.458 mmol), 2-trichloroacetyl pyrrole 6 (0.103 g, 0.488 mmol), and anhydrous sodium carbonate (0.172 g, 1.63 mmol), were dissolved in anhydrous N-dimethylformamide (5 mL). The reaction was stirred at ambient temperature for 16 h. Evaporation of the reaction under reduced pressure and purification of the residue by column chromatography (CH2Cl2/MeOH sat. NH3 85:15) afforded the desired compound in its free base form. Addition of a single drop of concentrated hydrochloric acid to a methanol solution (8 mL) and evaporation under reduced pressure yielded 0.078 g (63%) of the title compound 17 as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 11.59 (s, 1H), 11.45 (s, 1H), 8.14 (t, 1H, J=5.1 Hz), 7.30 (s, 2H), 6.81 (m, 2H), 6.74 (s, 1H), 6.59 (s, 1H), 6.04 (s, 1H), 3.19 (dt, 2H, J=6.6, 12.6 Hz), 2.42 (t, 2H, J=6.9 Hz), (tt, 2H, J=6.6, 13.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 160.74, 146.76, 126.43, 126.40, 121.13, 110.28, 108.65, 108.50, 37.59, 28.14, 21.60; HRMS (ESI) calcd for C11H16N5O (MH+) 234.1349. found 234.1354.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.Cl[CH2:11][C:12](=O)[CH3:13]>C(O)C>[NH2:9][C:6]1[CH:5]=[CH:4][N:3]2[CH:11]=[C:12]([CH3:13])[N:1]=[C:2]2[C:7]=1[Br:8]
Reactant: CC(=O)CCl
Reactant: Nc1ccnc(N)c1Br
Solvent: CCO
Product: Cc1cn2ccc(N)c(Br)c2n1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 2,4-diamino-3-bromopyridine (17) (in Rauckman, B. S, and al. J. Med. Chem. 1980, 23, 384-391) (2.00 g, 10.6 mmol) in ethanol (40 mL) was added chloracetone (3.93 g, 42.5 mmol). The solution was stirred under reflux for 24 h. After cooling to room temperature, the solution was evaporated to dryness. The residue was diluted with water (40 mL) and the resulting solution made basic by the addition of Na2CO3. The solution was extracted with CH2Cl2 and the combinated extracts were dried (Na2SO4), filtered and evaporated under reduced pressure. The crude product was purified by chromatography using CH2Cl2/EtOAc (4/1, v/v) as eluent to afford compound 18 (yield: 90%); mp 158-160° C.; 1H NMR (200 MHz, DMSO-d6) δ 2.19 (s, 3H), 5.78 (brs, 2H), 6.41 (d, 1H, J=7 Hz), 7.36 (s, 1H), 8.07 (d, 1H, J=7 Hz); 13C NMR (100 MHz, DMSO-d6) δ 14.1, 86.2, 104.6, 109.1, 125.5, 140.8, 143.1, 144.0. Anal.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)[C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:11][N:12]([CH:16]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17]1)[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)N(C)C1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C)C1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 2 h

Procedure:
4-Fluoronitrobenzene (25.0 g) was slowly added to a suspension of N-methyl-N-pyrrolidin-3-ylacetamide (25.2 g) and cesium carbonate (57.6 g) in DMF (300 ml). After 2 hours, the reaction mixture was poured into water, and the resultant precipitate was filtered off with suction. Alternatively, the product can also be extracted with ethyl acetate and purified by chromatography after concentration. This results in the product with the molecular weight of 263.30 (C13H17N3O3): MS (ESI): 264 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:19]2[S:18](=[O:21])(=[O:20])[CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[NH:12][C:11]([CH3:22])=[C:10]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].C=O.[C:30]([BH3-])#N.[Na+].O>C(#N)C.CC(O)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:19]2[S:18](=[O:20])(=[O:21])[CH2:17][CH2:16][N:15]([CH3:30])[CH2:14][C:13]=2[NH:12][C:11]([CH3:22])=[C:10]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCNC2
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1=C(C)NC2=C(C1c1cccc(Cl)c1Cl)S(=O)(=O)CCN(C)C2
Reaction time: 0.25 h

Procedure:
A mixture of ethyl 9-(2,3-dichlorophenyl)-1,1-dioxo-2,3,4,5,6,9-hexahydro-7-methylpyrido-[2,3-f][1,4]thiazepine-8-carboxylate (0.500 g, 1.16 mmole) from Example 8, in acetonitrile (10 mL) was treated with formaldehyde (0.240 g, 37% aqueous solution) and sodium cyanoborohydride (0.062 g, 1.16 mmole). After 15 minutes, 6 drops of AcOH were added and the reaction was stirred for 1 hour. Then, 30 mL of water were added and the reaction mixture was extracted with 3×40 mL of chloroform. The pH was adjusted to 8 after the first extract. The combined organic extracts were dried with brine and Na2SO4 and then treated with 3 mL of triethylamine. After standing for 1.5 hours, the volatiles were removed under reduced pressure and the residue chromatographed (silica gel, 1.5% MeOH, 0.1% NH3 in CHCl3) to obtain the product as an oil which solidified on triturating with ether (0.479 g, 92% yield).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=2)[C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:23]1([C:27]([C:29]2[CH:34]=[N:33][C:32](Cl)=[CH:31][N:30]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:23]1([C:27]([C:29]2[N:30]=[CH:31][C:32]([O:22][C:20]3[CH:19]=[C:9]([CH:8]=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:21]=3)[C:10]([NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[O:11])=[N:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC3CCCC3)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(OC3CCCC3)c2)n1
Temperature: 120 °C
Yield: 91 %

Procedure:
3-(Cyclopentyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (200 mg, 0.67 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (159 mg, 0.80 mmol) and potassium carbonate (184 mg, 1.33 mmol) were dissolved/suspended in acetonitrile (3.5 mL). The reaction mixture was heated for 4 hours at 120° C. in a microwave reactor. The mixture was cooled, filtered and concentrated in vacuo. The crude product was chromatographed on silica, eluting with 0-5% methanol in DCM, to give the required product as a white foam (282 mg).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[N:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:3]=[C:4]3[CH:5]=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1cnc2[nH]ccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: c1cc(-c2cnc3[nH]ccc3n2)ccn1
Yield: 60 %

Procedure:
A 10 mL microwave vial was charged with 5-bromo-4,7-diazaindole (0.471 g, CASRN 875781-43-4), 4-pyridylboronic acid (0.58 g), 1M Na2CO3 (3 mL), 1,1′-(dppf)Pd(II)Cl2 (0.097 g) and MeCN (3 mL), capped and irradiated in a microwave reactor at 150° C. for 30 min. The reaction was cooled and partitioned between H2O and EtOAc. The aqueous layer was twice washed with EtOAc. The combined organic layers were washed once with brine, dried (MgSO4), filtered and concentrated to afford a solid residue. The crude purified by SiO2 chromatography eluting with an EtOH/EtOAc gradient (1 to 20% EtOH over 12 min) to afford 0.28 g of pure 2-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin (22).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([N:33]2[N:37]=[CH:36][CH:35]=[N:34]2)=[C:28]([CH:32]=1)[C:29]([OH:31])=O.CCN(C(C)C)C(C)C.Cl.[NH:48]1[CH2:51][CH2:50][C@H:49]1[C:52]([O:54][CH3:55])=[O:53]>C(Cl)Cl.O>[CH3:55][O:54][C:52]([C@@H:49]1[CH2:50][CH2:51][N:48]1[C:29](=[O:31])[C:28]1[CH:32]=[C:24]([CH3:23])[CH:25]=[CH:26][C:27]=1[N:33]1[N:37]=[CH:36][CH:35]=[N:34]1)=[O:53]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: COC(=O)[C@@H]1CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCN1C(=O)c1cc(C)ccc1-n1nccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TBTU (4.93 g, 15.4 mmol) was added to a rt solution of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid A-1-2 (2.40 mg, 11.8 mmol) and DIPEA (8.09 mL, 47.2 mmol) in DCM (24 mL) and after stirring for 15 min, (S)-methyl azetidine-2-carboxylate HCl (2.03 g, 13 mmol) was added and the resulting mixture was stirred at rt for 1 h. The rxn mixture was diluted with DCM and water, the layers were separated and the aq. layer was extracted with DCM (1×). The combined org. extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude was purified by FC (EtOAc/hept 5:1) to obtain the title compound A-2-1 as a white solid. LC-MS A: tR=0.70 min; [M+H]+=301.18.
Reaction SMILES: CO[C:3](=[O:26])[C:4]([CH:6]1[N:17]2[C:18]3[C:14]([CH:15]=[CH:16]2)=[CH:13][CH:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:10]=3[CH2:9][N:8]=[CH:7]1)=O.[F:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:33][NH:34]2)=[CH:30][CH:29]=1>>[C:22]([O:21][C:19]([CH:12]1[CH2:11][C:10]2[CH2:9][N:8]=[CH:7][CH:6]([C:4]3[C:3](=[O:26])[NH:40][C:38](=[O:39])[C:37]=3[C:32]3[C:31]4[C:35](=[CH:36][C:28]([F:27])=[CH:29][CH:30]=4)[NH:34][CH:33]=3)[N:17]3[C:18]=2[C:14]([CH:15]=[CH:16]3)=[CH:13]1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: COC(=O)C(=O)C1C=NCC2=c3c(ccn31)=CC(C(=O)OC(C)(C)C)C2
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Product: CC(C)(C)OC(=O)C1C=c2ccn3c2=C(CN=CC3C2=C(c3c[nH]c4cc(F)ccc34)C(=O)NC2=O)C1

Procedure:
Beginning with (6-(tert-butoxycarbonyl)-4,5-dihydro-6H-[1,4]diazepino[6,7,1-hi]indol-1-yl)oxoacetic acid methyl ester and 6-fluoroindole-3-acetamide, the title compound was prepared essentially as described in EXAMPLE 133.