Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:45]=[C:46]([Cl:48])[CH:47]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29](Cl)=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:34]1[N:38](C2CCCCO2)[N:37]=[CH:36][CH:35]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:49]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52].C([O-])([O-])=O.[Cs+].[Cs+].Cl.O1CCOCC1>C1(C)C=CC=CC=1.C(Cl)Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:45]=[C:46]([Cl:48])[CH:47]=1)[CH2:23][N:24]1[C:32]2[C:27](=[N:28][C:29]([N:49]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[NH:50][C:51]([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:34]1[CH:35]=[CH:36][NH:37][N:38]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](OCc1cc(Cl)cc(Cn2c(-c3ccnn3C3CCCCO3)cc3nc(Cl)ccc32)c1)(c1ccccc1)c1ccccc1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3cc[nH]n3)n2Cc2cc(Cl)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of 1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-5-chloro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[3,2-b]pyridine (2.7 g, 3.9 mmol, from Step 2), di-tert-butyl hydrazine-1,2-dicarboxylate (0.99 g, 4.3 mmol, Aldrich), Cs2CO3 (2.5 g, 7.8 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.30 g, 0.39 mmol, Aldrich) in toluene (25 mL) was degassed and heated at 140° C. for 3 hours. Additional di-tert-butyl hydrazine-1,2-dicarboxylate (0.50 g, 2.2 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.30 g, 0.38 mmol) were added and heating was continued for 1 hour. After addition of more di-tert-butyl hydrazine-1,2-dicarboxylate (0.20 g, 0.86 mmol) and heating for another 40 minutes, the mixture was cooled to room temperature and diluted with DCM, filtered and concentrated. The intermediate thus obtained was isolated by flash chromatography, eluting with a gradient from 0-25% EtOAc in hexanes (2.5 g). A solution of the intermediate in DCM (80 mL) at 0° C. was treated with 4.0 M HCl in dioxane (3.9 mL, 16 mmol). After stirring for 15 minutes, the reaction was quenched with aqueous ammonia. The reaction mixture was diluted with water, and the aqueous solution was extracted with three portions of EtOAc. The combined organic extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated. The title product was purified by flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes. Yield: (1.1 g, 35%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[OH-].[Na+]>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:11])=[O:10])[CH:7]=2)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1NS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NS(=O)(=O)c3ccccc3)c2)CC1
Yield: 78 %

Procedure:
N-(5-fluoro-2-nitrophenyl)benzenesulfonamide (2×0.50 g, 1.688 mmol) was treated with N-methyl-piperazine (2×4.65 g, 45.6 mmol) and put in two pyrex tubes and sealed. Each tube was put in a LabWell MW-10 microwave oven for 2 min at 50W. The reaction mixtures were combined and poured into 0.5 M NaOH (aq) and extracted with CH2Cl2, dried (MgSO4) and concentrated to give 0.99 g, (2.63 mmol) in 78% yield as a yellow solid. Anal (C17H20N4O4S) C, H, N, S; MS (posES-FIA) m/z=found: 377.4; Calcd: 376.12.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:21][C:20]([F:23])([F:22])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[C:27]([Cl:32])[CH:26]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][C:27]=2[Cl:32])[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:19][C:20]([F:22])([F:23])[CH2:21]1)=[O:17])=[O:5])[CH3:2]
Reactant: Fc1ccc(S)c(Cl)c1
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CC(F)(F)C1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(F)cc2Cl)C[C@H]1C(=O)N1CC(F)(F)C1

Procedure:
The title compound was prepared in analogy to Example 68/69, step 8, using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (Example 117, step 3) and 4-fluoro-2-chloro-benzenethiol. Light yellow solid. MS (EI): 422.7 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:31]=[C:32]([C:36](=[N:38]O)[NH2:37])[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:36]2[N:38]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:37]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1cccc(F)c1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 34 mg (0.22 mmol, 1.1 eq.) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 71 mg (68% of theory)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=1>C(#N)C>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(O)cc3)cn2c1
Temperature: 90 °C
Yield: 81.6 %

Procedure:
2.15 g (corresponding to 10.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 1.25 g (corresponding to 10.0 mmol) of 2-amino-5-methoxypyridine were dissolved in 50 mL, of acetonitrile. The resulting solution was refluxed in an oil bath at 90° C. for 3.5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 40 mL of water and 40 mL of methanol. Then, about 20 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using a ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 1.96 g (corresponding to 8.16 mmol) of 2-(4′-hydroxyphenyl)-6-methoxyimidazo[1,2-a]pyridine (FIG. 2, Step 5).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].CCO.[BH4-].[Na+].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)cc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2ccc(CO)cc2Cl)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An oven-dried 500 mL round-bottomed flask was charged with compound 10.4 (34.9 g, 95.7 mmol), EtOH (175 mL) and THF (17.5 mL). Next, sodium borohydride (1.10 g, 29.1 mmol) was added in 3 portions at 0° C., and the reaction was vigorously stirred at 0° C. for 1 h. The reaction mixture was poured into 463 mL of 0.25 N HCl at 0° C. and the product was extracted with 3×200 mL of AcOEt. The combined organics were washed sequentially with 2×200 mL of water and 100 mL of brine, dried over Na2SO4, and concentrated to a yellow oil, which was then purified by flash chromatography (SiO2 gel 60 N, eluted with 20% AcOEt/hexane—30% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to a slightly yellow oil (33.5 g). 1H NMR (400 MHz) (CDCl3) δ 7.37 (1H, d, J=1.5 Hz); 7.31-7.28 (2H, m); 7.05 (1H, dd, J=1.8, 8.2 Hz); 6.77 (1H, d, J=8.2 Hz); 6.72 (1H, d, J=8.3 Hz); 4.67 (2H, s); 4.61 (2H, d, J=5.9 Hz); 4.28 (2H, q, J=7.2 Hz); 2.29 (3H, s); 1.66 (1H, t, J=5.9 Hz); 1.31 (3H, t, J=7.2 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([NH:11]C(OC(C)(C)C)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[OH:27])=[CH:22][CH:21]=1>>[NH2:11][CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][CH2:2][N:31]1[CH2:32][CH2:33][CH:28]([CH:26]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=2)[OH:27])[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)NC(CCBr)c1ccccc1
Reactant: OC(c1ccc(F)cc1)C1CCNCC1
Product: NC(CCN1CCC(C(O)c2ccc(F)cc2)CC1)c1ccccc1

Procedure:
The procedure given in Example 2 was followed using 3-bromo-1-(tert-butoxycarbonyl)amino-1-phenyl propane and (4-fluorophenyl)-piperidin-4-yl-methanol as reactants, instead of d-1-bromo-2-(tert-butoxycarbonyl)amino-3-phenyl propane and hexamethyleneimine to give [1-(3-Amino-3-phenyl-propyl)-piperidin-4-yl]-(4-fluoro-phenyl)-methanol.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][C:20]([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[CH:19]2)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11](O)=[O:12])(=[O:5])=[O:4].[N:28]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N.Cl>CN(C)C=O>[CH3:1][N:2]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][C:20]([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[CH:19]2)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([NH2:28])=[O:12])(=[O:4])=[O:5]
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1C(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.1 %

Procedure:
To a solution of 3-({methyl[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]amino}sulfonyl)thiophene-2-carboxylic acid (100 mg), 1H-1,2,3-benzotriazol-1-ol (46 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (58 mg) in N,N-dimethylformamide (2 mL) was added 28% aqueous ammonia (1 mL), and the mixture was stirred at room temperature for 12 hr. To the reaction mixture was added 1N hydrochloric acid was added, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was crystallized from diethyl ether-hexane to give the title compound (57 mg, yield 57%) as colorless crystals. melting point 269° C.
Reaction SMILES: [F:1][C:2]([F:28])([C:7]1[CH:11]=[C:10]([NH:12][C:13](=O)[O:14]C2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)[C:3]([F:6])([F:5])[F:4].COC1C=C2C(=CC=1OC)N=C[N:35]=C2OC1C=C(C=CC=1)N.C(N(C(C)C)CC)C>C1COCC1>[F:28][C:2]([F:1])([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:14])[NH2:35])[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=1)[C:3]([F:5])([F:6])[F:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C(F)(F)C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Agent: CCN(CC)C(C)C
Solvent: C1CCOC1
Product: NC(=O)Nc1cc(C(F)(F)C(F)(F)F)nn1-c1ccccc1
Temperature: 60 °C
Yield: 73.5 %

Procedure:
A stirred mixture of phenyl 3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (199 mg, 0.50 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (100 mg, 0.34 mmol), N,N-diethylisopropylamine (88 mg, 0.68 mmol) in THF (1 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to afford the crude product. Purification via preparative HPLC afforded 14346,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-yl)urea (80 mg, 39%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) 89.35 (s, 1H), 8.82 (s, 1H), 8.54 (s, 1H), 7.55-7.61 (m, 7H), 7.36-7.40 (m, 2H), 7.18 (m, 1H), 6.95 (m, 1H), 6.88 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z 601 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][C@@H:16]([C@@H:22]([O:35][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[C@@H:23]([O:25]CC1C=CC(OC)=CC=1)[CH3:24])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][C@@H:16]([C@@H:22]([O:35][Si:36]([CH:37]([CH3:39])[CH3:38])([CH:40]([CH3:42])[CH3:41])[CH:43]([CH3:45])[CH3:44])[C@@H:23]([OH:25])[CH3:24])[CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CO[C@@H](C)[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)CCC(C)C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)CC[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](C)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(2S,6R)-2-((tert-Butoxycarbonyl)amino)-6-((1R,2S)-2-((4-methoxybenzyl)oxy)-1-((triisopropylsilyl)oxy)propyl)-9-methyldecanoic acid (8.55 g, 13.1 mmol) was dissolved in THF (40 ml) in a high pressure reactor with a stir bar. To the resulting solution was added 5% Pd/C (1.40 g, 0.656 mmol) was added, the reactor was sealed and purged with H2 (4×), and then charged to 600 psi with H2 at room temperature. The reactor was heated to 50° C. for 12 h and then stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite® and concentrated to yield the title compound as a colorless oil contaminated with 20% p-methoxytoluene (7.76 g, 89: 1H NMR (400 MHz, CDCl3) δ 5.05-4.92 (m, 1H), 4.37-4.22 (m, 1H), 3.89 (qd, J=6.4, 3.5 Hz, 1H), 3.83-3.78 (m, 1H), 1.93-1.77 (m, 2H), 1.74-1.45 (m, 5H), 1.45 (s, 9H), 1.45-1.19 (m, 2H), 1.19 (d, J=5.1 Hz, 3H), 1.14-1.02 (m, 24H), 0.87 (d, J=6.6 Hz, 6H); ESIMS m/z 554.5 ([M+Na]+).
Reaction SMILES: O=[C:2]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[CH:3]=O.[F:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][C:16]2[N:17]([NH2:22])[C:18]([NH2:21])=[N:19][N:20]=2)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][C:16]2[N:17]3[N:22]=[CH:3][C:2]([C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)=[N:21][C:18]3=[N:19][N:20]=2)=[CH:13][CH:12]=1
Reactant: O=CC(=O)c1cccs1
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Product: Fc1ccc(Cc2nnc3nc(-c4cccs4)cnn23)cc1

Procedure:
General procedure A was followed with the reaction of oxo-thiophen-2-yl-acetaldehyde and 5-(4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine to provide 3-(4-fluoro-benzyl)-7-thiophen-2-yl-[1,2,4]triazolo[4,3-b][1,2,4]triazine and 3-(4-fluoro-benzyl)-6-thiophen-2-yl-[1,2,4 ][triazolo 1,2,4,-b][1,2,4]triazine (example 5).
Reaction SMILES: [CH:1](O)=[O:2].[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([NH2:54])([C:16](=[O:53])[NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]=[C:21]3[C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([C:16](=[O:53])[NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:22]=[C:21]3[C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)([NH:54][CH:1]=[O:2])[CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: O=CO
Agent: CN(C)c1ccncc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC=O)(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
Formic acid (17 mg, 0.36 mmol) was added to a solution of 3-Amino-3-[3-(4-fluoro-phenyl)-1 trityl-indazol-5-ylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1P) 250 mg, 0.367 mmol); 2-Chloro-4,6-dimethoxy-1,3,5-triazine (77 mg, 0.44 mmol); DMAP (10 mg) and NMM (50 mg, 0.49 mmol) in MeCl2 (3 ml) at room temperature. The solvent was evaporated and residue chromatographed on silica gel eluting with 3% v/v MeOH/MeCl2 yielding 4P as a white solid (210 mg, 80%) ESMS (MH 710).
Reaction SMILES: Cl.F[C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F.C1(S([Cl:41])(=O)=O)C=CC=CC=1>>[ClH:41].[CH2:28]([N:27]1[CH2:31][CH2:30][N:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([NH:13][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=3)(=[O:12])=[O:11])=[CH:15][CH:16]=2)[CH2:25][CH2:26]1)[CH3:29]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCCN(c2ccc(NS(=O)(=O)c3ccc(F)c(F)c3)c3ccccc23)CC1
Agent: Cl
Product: CCN1CCN(c2ccc(NS(=O)(=O)c3ccccc3)c3ccccc23)CC1

Procedure:
The title compound was prepared from (intermediate 3 after reduction according to Method A) 4-(4-ethyl-1-piperazinyl)-1-naphthylamine (0.241 g, 0.945 mmol) and benzenesulfonyl chloride (0.121 mL, 0.945 mmol) by the method described above to yield HCl-salt 0.210 g (51%); 1H NMR (CD3OD) δ 8.19–8.15 (m, 1H), 7.94–7.90 (m, 1H), 7.70–7.66 (m, 2H), 7.56–7.46 (m, 2H), 7.44–7.36 (m, 3H), 7.19 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 3.75–3.40 (m, 6H), 3.34 (q, J=7.6 Hz, 2H), 3.25–3.10 (m, 2H), 1.43 (tr, J=7.6 Hz, 3H); MS(posEI) m/z 387 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1>CO.[Pd]>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CCc2cnc3[nH]c(C4=CCN(C)CC4)cc3n2)cc(OC)c1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCc2cnc3[nH]c(C4CCN(C)CC4)cc3n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine (from Example 23, 10 mg, 26.4 μmol) in methanol (1 mL), Pd/C (10% w/w, 3.2 mg, 3.0 μmol) was added. The reaction mixture was then stirred under the atmosphere of H2 at ambient temperature. After 3 hours, the palladium catalyst was filtered and the crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.0 mg, 30%) as its TFA salt. LCMS calculated for C22H29N4O2 (M+H)+: m/z=381.2. Found: 381.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=4[C:22](O)=[O:23])=[CH:16][CH:17]=3)[N:12]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:11]=2)[CH:3]=1.[CH:35]1([C:38]#[C:39][CH2:40][NH2:41])[CH2:37][CH2:36]1>>[CH:35]1([C:38]#[C:39][CH2:40][NH:41][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[NH:19][C:15]2[CH:14]=[C:13]3[C:18]([C:10]([CH:9]=[CH:8][C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)=[N:11][N:12]3[CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[CH:17][CH:16]=2)[CH2:37][CH2:36]1
Reactant: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Reactant: NCC#CC1CC1
Product: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)NCC#CC4CC4)ccc23)c1

Procedure:
Prepared in a similar manner to that described for Example 6 above, except using 2-[3-[2-(4-methyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid and 3-Cyclopropyl-prop-2-ynylamine. 1H NMR (DMSO-d6): δ 9.88 (1H, bs), 8.93 (1H, bt), 8.46 (1H, d, J=4.9 Hz), 8.08 (1H, d, J=8.7 Hz), 7.85 (1H, d, J=16.4 Hz), 7.69 (1H, d, J=7.6 Hz), 7.54–7.40 (5H, m), 7.14–7.11 (2H, m), 6.90 (1H, t, J=6.1 Hz), 5.81 (1H, d, J=7.5 Hz), 4.02 (2H, d, J=3.6 Hz), 3.95–3.85 (1H, m), 3.79–3.72 (1H, m), 2.49–2.35 (1H, m), 2.35 (3H, s), 2.15–2.01 (2H, m), 1.87–1.55 (3H, m), 1.30–1.25 (1H, m), 0.77–0.70 (2H, m), 0.59–0.54 (2H, m).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]O)[CH:13]=2)[N:6]=1)=[O:4].C1(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.O>C1COCC1>[CH3:1][NH:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:34]=[N+:35]=[N-:36])[CH:13]=2)[N:6]=1)=[O:4]
Reactant: CNC(=O)c1nc(-c2cccc(CO)c2)cnc1N
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)c1nc(-c2cccc(CN=[N+]=[N-])c2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
3-Amino-6-(3-hydroxymethyl-phenyl)-pyrazine-2-carboxylic acid methylamide (1.00 g, 3.87 mmol) was dissolved in THF (20 mL) followed by the addition of diphenylphosphoryl azide (0.63 mL, 5.42 mmol) and DBU (0.43 mL, 5.42 mmol). It was stirred at room temperature overnight. The reaction mixture was poured into water (100 mL), and extracted with ethyl acetate (2×50 mL) then dried over anhydrous sodium sulfate and filteration, concentration and purified by column chromatography (50% Ethylacetae/bexanes) to give 3-amino-6-(3-azidomethyl-phenyl)-pyrazine-2-carboxylic acid methylamide, 728 mg (66.4% yield): MS (EI) for C13H13N7O0: 284.12 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[C:16]4[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[NH:19][C:15]=4[N:14]=[CH:13]3)[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.[OH-].[Na+].Cl>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([N:12]3[C:16]4[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[NH:19][C:15]=4[N:14]=[CH:13]3)[CH:9]=[CH:10][CH:11]=2)=[CH:2]1
Reactant: CCOC(=O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(ncn2-c2cccc(-c3ccsc3)c2)[nH]1
Yield: 68 %

Procedure:
To a stirred solution of ethyl 1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate (500 mg, 1.5 mmol, prepared as described in the procedure for example 5) in THF (10 mL) was added aqueous sodium hydroxide (416 mg in 4 mL H2O, 10.4 mmol) and the mixture heated at reflux for 16 hr. After this time, the cooled mixture was acidified with 2M HCl to pH 6 and the resulting precipitate collected by filtration, and washed with water and hexane. The filtrate was concentrated to about half the volume and extracted with ethyl acetate (2×75 mL). The combined organic phases were washed with saturated aqueous sodium chloride, and dried over sodium sulfate and evaporated in vacuo to yield a brown solid. The solids were combined and purified by silica gel chromatography eluting with MeOH:CH2Cl2 10%→25%) to yield 312.7 mg (68%) 1-(3-thien-3-ylphenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ=8.39 (s, 1H), 8.07 (d, 2.4 Hz, 1H), 8.04-8.02 (m, 1H), 7.72-7.69 (m, 3H), 7.69-7.57 (m, 3H), 6.66 (br s, 1H). MS (ES+): m/z 338.13 (100) [MH+].