Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([C:11]([OH:13])=O)[NH:9][N:10]=1.[NH2:14][C@@H:15]([CH3:31])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1>>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:11]([C:8]3[NH:9][N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[CH:7]=3)=[O:13])[CH3:31])[N:18]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: O=C(O)c1cc(-c2ccco2)n[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2ccco2)n[nH]1
Yield: 16.97 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 5-(2-furyl)-2H-pyrazole-3-carboxylic acid (3.42 g, 19.18 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (5 g, 19.18 mmol). The product was purified by flash chromatography and recrystallization from acetonitrile, respectively. Yield 16.97%. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 4.30 (dd, 1H), 4.42 (dd, 1H), 4.53-4.63 (m, 1H), 6.50 (dd, 1H), 6.62 (d, 1H), 6.67 (d, 1H), 6.94 (s, 1H), 7.48 (dd, 1H), 7.53 (d, 1H), 7.68 (d, 1H), 7.73-7.84 (m, 2H), 8.02 (s, 1H), 13.70 (broad s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>>[Si:30]([O:29][CH2:28][CH2:27][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]2=[N:3][C:2]=3[NH2:1])=[CH:19][CH:18]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)cc12

Procedure:
2-(4-(2-(Tert-butyldimethylsilyloxy)ethoxy)phenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 139, but using (2-bromoethoxy)(tert-butyl)dimethylsilane.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH:24]=O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.C(OP([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(OCC)=O)C.[H-].[Na+]>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22](/[CH:24]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-5-carbaldehyde (1.0 g), ethyl diethylphosphonoacetate (0.52 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.10 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}-2-propenoate as colorless crystals (0.87 g, yield 74%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][NH:23][C:24](=[O:26])[O-:25])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:23][CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([N:15]2[C:7]3=[C:8]4[S:14][CH:13]=[CH:12][C:9]4=[N:10][CH:11]=[C:6]3[N:5]=[C:4]2[C@H:2]([OH:1])[CH3:3])[CH2:17][CH2:18]1.[C:24]([OH:25])([C:28]([F:33])([F:32])[F:27])=[O:26]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CNC(=O)[O-])CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1

Procedure:
[(trans-4-{2-[(1R)-1-Hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)methyl]carbamate (0.21 g, 0.49 mmol) was treated with trifluoroacetic acid (0.7 mL, 9 mmol) in dichloromethane (2 mL) at room temperature for 1 h. The mixture was stripped to dryness to give the desired product as TFA salt (0.35 g, 79%). LCMS calculated for C17H23N4OS (M+H)+: m/z=331.1. Found: 331.0.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19]([NH:21][NH2:22])=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH:23](O)=[O:24]>>[CH:23]([NH:22][NH:21][C:19](=[O:20])[CH2:18][CH2:17][S:16][C:7]1[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=1)=[O:24]
Reactant: O=CO
Reactant: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(SCCC(=O)NNC=O)cc(C(C)(C)C)c1O
Yield: 89 %

Procedure:
A solution of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide (0.70 g, 2.16 mmol) in 96% formic acid (5.6 mL) is stirred overnight. The reaction mixture is concentrated in vacuo, diluted with ethyl acetate and washed once with a saturated solution of sodium bicarbonate, twice with water, and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives an oil which is crystallized from ethyl acetate/hexane to afford 0.68 g (89%) of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid 2-formylhydrazide, mp 158.0°-159.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][C:29]#[N:30])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[NH4+].[Cl-]>CN(C=O)C>[NH:34]1[C:29]([CH2:28][N:15]2[CH2:16][CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=3)[N:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:33][CH:32]=4)=[CH:12][CH:11]=3)[C:14]2=[O:31])=[N:30][N:36]=[N:35]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2nnn[nH]2)CC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 220 °C

Procedure:
To a solution of 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)acetonitrile (21.8 mg, 0.046 mmol) in DMF (1.0 mL) are added NaN3 (60 mg, 0.92 mmol) and NH4Cl (49 mg, 0.92 mmol). The reaction mixture is heated at 220° C. for 15 min in a microwave reactor. After cooling down to room temperature and removal of the solvent, the residue is purified by preparatory LC/MS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.58-7.45 (m, 4H), 7.26 (d, 2H), 7.19 (d, 2H), 6.87 (m, 4H), 5.24 (dd, 1H), 4.95 (d, 1H), 4.69 (d, 1H), 4.10 (t, 1H), 3.48 (dd, 1H); HPLC-MS calculated for C24H18ClF3N6O2 (M+H+) 515.1, found 515.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:42])[C:20]=2[N:21]2[CH2:26][CH2:25][CH:24]([C:27]([N:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[O:28])[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:42])[C:20]=2[N:21]2[CH2:26][CH2:25][CH:24]([C:27]([N:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)=[O:28])[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(c3c(F)cncc3NC(=O)c3c(N)nn4cc(F)cnc34)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-butyl 4-(1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carbonyl)piperazine-1-carboxylate prepared using procedure similar to Example 4 was dissolved in a mixture of DCM (5 mL)/TFA (1 mL, 12.98 mmol) and stirred at RT for 90 min. then concentrated in vacuo. The residue was purified by fractionlynx. Clean fractions were freeze dried to yield 2-amino-6-fluoro-N-(5-fluoro-4-(4-(piperazine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. MS (ES+) 486.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH2:11].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: COC(=O)c1cccc(O)c1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
To a solution of 0.748 g (4.48 mmol) of the product of Example 30 in 10.0 mL of pyridine was added 0.928 g (4.48 mmol) of p-methoxybenzenesulfonyl chloride. The reaction mixture was stirred for 24 h at room temperature and then diluted with chloroform and washed with 5% HCl solution and water. The organic layer was then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether-hexanes and the resulting solid was filtered and dried to provide 0.86 g (57%) of the desired product as a tan solid. Electrospray Mass Spec: 338.2 (M+H)+
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH2:5](O)[CH2:6][CH:7]([OH:9])[CH3:8]>>[CH:3]([CH:1]1[O:9][CH:7]([CH3:8])[CH2:6][CH2:5][O:2]1)=[CH2:4]
Reactant: CC(O)CCO
Reactant: C=CC=O
Product: C=CC1OCCC(C)O1
Yield: 99 %

Procedure:
When acrolein is condensed with 1,3-butanediol, the product obtained is 2-vinyl-4-methyl-1,3-dioxane (99 percent yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][CH:5]=1.C1(C)C=CC(S(O[CH2:24][CH2:25][Cl:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:24][CH2:25][Cl:26])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCCCl)c(OC)c1
Yield: 88.6 %

Procedure:
By using an identical method as in Example 46, 77 g of 4-hydroxy-5-methoxy-benzoic acid methyl ester, 99.2 g of 2-chloroethyl p-toluene sulfonate, 77.7 g of potassium carbonate, and 1.7 g (4.1 mmol) of methyl-tricapryl ammonium chloride was converted to 91.6 g of the title compound: mass spectrum (electrospray, m/e,): M+H 245.0
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35]Br)=[CH:29][CH:28]=2)=[O:26])=[C:23]([OH:39])[CH:22]=1>>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][O:20][C:21]2[CH:38]=[CH:37][C:24]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:1][C:2]4[CH:3]=[CH:4][C:5]([C:8]5[O:9][C:10]6[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=6[N:12]=5)=[CH:6][CH:7]=4)=[CH:29][CH:28]=3)=[O:26])=[C:23]([OH:39])[CH:22]=2)=[CH:7][CH:6]=1
Reactant: O=C(c1ccc(OCCBr)cc1)c1ccc(OCCBr)cc1O
Reactant: Oc1ccc(-c2nc3ccccc3o2)cc1
Product: O=C(c1ccc(OCCOc2ccc(-c3nc4ccccc4o3)cc2)cc1)c1ccc(OCCOc2ccc(-c3nc4ccccc4o3)cc2)cc1O

Procedure:
The 2-(4-hydroxyphenyl) benzoxazole was reacted with 4,4'-bis(2-bromoethoxy)-2-hydroxybenzophenone as in Example 1 to produce Compound IV.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][CH:6]=1.[Cl:7][C:8]([Cl:13])([Cl:12])[C:9](Cl)=[O:10].C([O-])([O-])=O.[K+].[K+]>C(OCC)C>[Cl:7][C:8]([Cl:13])([Cl:12])[C:9]([C:4]1[NH:3][C:2]([CH3:1])=[CH:6][CH:5]=1)=[O:10]
Reactant: Cc1ccc[nH]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1ccc(C(=O)C(Cl)(Cl)Cl)[nH]1
Reaction time: 1 h

Procedure:
2-Methyl-1H-pyrrole (Intermediate 31, 10 g, 0.123 mmol) in anhydrous diethyl ether (30 ml) was added dropwise over 1 h to a stirred solution of trichloroacetyl chloride (29 g, 0.16 mmol) in anhydrous Et2O (100 ml). The mixture was stirred for a further 1 h then K2CO3 (10 g/30 ml) was added slowly through a dropping funnel. The organic phase was dried over Na2SO4 and treated with decolorizing charcoal (3 g) for 30 min at room temperature. The resulting purple solution was concentrated and triturated with n-hexanes to give the title compound as a purple solid. (16.72 g). NMR (CDCl3): 2.36 (s, 3H), 6.04 (dd, 1H), 7.45 (dd, 1H), 10.344 (s, 1H).
Reaction SMILES: C(OC([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][OH:24])=[C:14]([NH:25][C:26]([C:28]2[NH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][C:33]([O:37][CH3:38])=[C:32]([O:39][CH3:40])[C:31]=3[O:41][CH3:42])=[O:27])[CH:13]=1)=O)C1C=CC=CC=1>C1COCC1.[Pd]>[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][OH:24])=[C:14]([NH:25][C:26]([C:28]2[NH:29][C:30]3[C:35]([CH:36]=2)=[CH:34][C:33]([O:37][CH3:38])=[C:32]([O:39][CH3:40])[C:31]=3[O:41][CH3:42])=[O:27])[CH:13]=1
Reactant: COc1cc2cc(C(=O)Nc3cc(NC(=O)OCc4ccccc4)c4ccccc4c3CCO)[nH]c2c(OC)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)Nc3cc(N)c4ccccc4c3CCO)[nH]c2c(OC)c1OC
Reaction time: 72 h
Yield: 76.2 %

Procedure:
A solution of 2-[4-(N-benzyloxycarbonylamino)-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethanol (0.14 g, 0.25 mmol) in THF (10 mL) was added to a suspension of 10% Pd/C (0.1 g) in chilled THF (10 mL) and the suspension was hydrogenated under H2 atmosphere at room temperature for 3 days. The suspension was filtered over Celite and the filtrate was concentrated in reduced pressure. The residue was crystallized with diisopropylether to yield 2-[4-amino-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethanol (0.083 g, 76%) as a pale yellow solid: mp 172-180° C. (decomp.); 1H NMR (CDCl3, 500 MHz) δ 9.85 (s, 1H), 9.28 (s, 1H), 7.86 (d, 8.5, 1H), 7.86 (d, 8.0, 1H), 7.54 (s, 1H), 7.50 (t, 8.0, 1H), 7.43 (t, 8.5, 1H), 7.03 (d, 2.0, 1H), 6.84 (s, 1H), 4.18 (t, 5.5, 2H), 4.09 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 3.33 (t, 7.0, 2H);); FABMS (NBA) m/z 435 (M+H+), IR (neat) νmax 3291, 2936, 1638, 1595, 1541, 1509, 1464, 1432, 1410, 1305, 1264, 1106, 1047, 996, 909, 833, 757, 731 cm−1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=O.[Cl:13][C:14]1[N:19]=[N:18][C:17]([NH2:20])=[CH:16][CH:15]=1>CCO>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=3)[C:8]#[N:9])[N:20]=2)[N:19]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Solvent: CCO
Product: N#Cc1cccc(-c2cn3nc(Cl)ccc3n2)c1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
A solution of 3-(2-bromoacetyl)benzonitrile and 6-chloropyridazin-3-amine (1 mmol) in EtOH was heated to reflux overnight. Then the mixture was cooled to r.t., and the precipitate was filtered to give 3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)benzonitrile with a yield of 52.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([O-])([O-])(OCC)[CH3:22].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH3:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
To a suspension of 2.84 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in a mixture of 100 parts by volume of ethanol and 5 parts by volume of ethyl orthoacetate is added 1 part of concentrated sulfuric acid with stirring. The mixture is further stirred for 30 minutes, and about 100 parts by volume of a saturated aqueous sodium bicarbonate solution is added. The mixture is concentrated under reduced pressure. The resulting crystals are collected by filtration, washed with water and dried to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine as colorless crystals. Recrystallization from acetone-n-hexane gives colorless needles melting at 226°-227° C.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][N:10]=2)=[CH:3][CH:2]=1.C1COCC1>CO.[OH-].[Na+].Cl>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(OCc2ccc(-c3ccccc3)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCc2ccc(-c3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
To a solution of methyl 6-(4-biphenylylmethoxy)nicotinate (2.0 g) in methanol (20 ml)/THF(40 ml) was added iN aqueous sodium hydroxide (13 ml) at room temperature. After stirring at room temperature for 4 hr the reaction mixture was diluted with 1 N hydrochloric acid (13 ml) and concentrated. The precipitate was collected by filtration and washed with water and diethyl ether sequentially to obtain the titled compound (1.6 g) as amorphous powder.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:27])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22]([C:24](O)=[O:25])[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:27])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22]([C:24]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:25])[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)O)nc2c1
Reactant: COCCN
Product: COCCNC(=O)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Yield: 19.8 %

Procedure:
The product was prepared in the same manner as described in example 62 using 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (140 mg, 0.379 mmole) and 2-methoxyethanamine (163 l, 1.9 mmole) as starting materials. The reactions affords 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-N-(2-methoxyethyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (32 mg, 19.8%) as a white solid. mp: 159-161° C., MS: m/z=427.3 (M+H+).
Reaction SMILES: O[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[Cl-:18]>>[Cl:18][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCOc1ccc(CO)cc1
Reactant: [Cl-]
Product: CCOC(=O)CCCOc1ccc(CCl)cc1

Procedure:
Ethyl 4-(4-(chloromethyl)phenoxy)butanoate 13i was prepared from 29b according to the protocol described for the compound 13h in Example 26 (Scheme 9). The title chloride 13i was isolated as colorless oil in 96% yield (1.25 g). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.2 Hz); 2.06 (2H, m); 2.18 (2H, t, J=7.2 Hz)); 4.00 (2H, t, J=6.4 Hz); 4.14 (2H, q, J=7.2 Hz); 4.54 (2H, s); 6.83 (1H, s); 6.86 (1H, s); 7.27 (1H, m); 7.29 (1H, s). MS (ESI): m/z=258.10 (M+H+).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.C(O[C:30]([N:32](C)[C@H:33]([CH3:37])[C:34](O)=[O:35])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([NH:22][C:34](=[O:35])[C@H:33]([NH:32][CH3:30])[CH3:37])[CH2:20][CH2:21]3)=[CH:23][CH:24]=2)[CH2:2]1
Reactant: C[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN[C@H](C)C(=O)NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of Intermediate M (100 mg, 0.276 mmol), (R)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (67 mg, 0.33 mmol), TEA (0.115 mL, 0.828 mmol), and TBTU (106 mg, 0.331 mmol) in DMF (2 mL) is heated at 60° C. overnight. The reaction is diluted with EtOAc, rinsed with sat. NaHCO3, and the organics dried and concentrated. The residue is purified by silica gel chromatography eluting with 0-10% MeOH/DCM. The pooled and concentrated product fractions are treated with 4M HCl in 1,4-dioxane (5 mL) and stirred overnight. The reaction is concentrated and purified by reverse phase HPLC eluting with 10-90% MeCN in water (0.1% TFA). The concentrated product fractions are dissolved in MeOH and eluted through a carbonate resin cartridge to afford the title compound 261. (LC/MS method 16: ES+ m/z 411.4 [M+H]+, Rt=0.33 min)
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=3)=[O:26])[CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[CH3:11][C:12]1[C:13]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([N:5]4[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]4(=[O:10])=[O:9])=[CH:29][CH:28]=3)=[O:26])[CH2:23][CH2:24]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C(C)C)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 14.9 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (300 mg) described in Preparation Example 6 and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (421 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 4, the title compound (68 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:6][CH:5]=[C:4]([F:18])[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:18])[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(F)ccc1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1nc(F)ccc1C(=O)O
Yield: 96.1 %

Procedure:
A solution of benzyl 2-amino-6-fluoropyridine-3-carboxylate (2.0 g, 0.008 mole) in ethanol (250 ml) containing 5 percent Palladium on charcoal was shaken in a hydrogen atmosphere (50 psi was the initial pressure) using a Paar apparatus. Hydrogen uptake ceased after 10-15 minutes. After purging the hydrogen from the system, the catalyst was removed by filtration, and the solvent evaporated to give 1.2 g (94 percent) of the desired acid. Recrystallization from water gave an analytical sample: m.p.=205-214 decompose.