Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36]([NH:38][C@@H:39]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11].C(N(CC)CC)C.[Br:75][CH2:76][C:77](Cl)=[O:78]>C1COCC1>[Br:75][CH2:76][C:77]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36]([NH:38][C@@H:39]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:78]
Reactant: O=C(Cl)CBr
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCNC(=O)CBr)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
22 mg (0.023 mmol) of N-(6-aminohexyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 101) were dissolved in 9.5 ml of THF and admixed at 0° C. with 4.2 μl of triethylamine. A solution of bromoacetyl chloride in THF was added dropwise and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated and the residue was purified by preparative HPLC. Thus, 6.9 mg (26% of theory) of the title compound were obtained as a foam.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(=O)CC>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: BrCc1ccccc1
Solvent: CCC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2,4-dihydroxybenzaldehyde (5.52 g, 0.04 mmol), benzylbromide (5.7 ml, 0.048 mmol) and K2CO4 (6.64 g) in 90 ml of 2-butanone is stirred for 48 hours at room temperature and then heated to reflux for 8 hours. After cooling to room temperature and filtering, the filtrate is concentrated in vacuo and the residue chromatographed (25% EtOAc/Hexane) to obtain 4-benzyloxy-2-hydroxybenzaldehyde which is used directly in the next step.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@@H:8]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:13]2[N:9]1[C:10]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[C:11]1[C:26](=[O:27])[N:25]([CH3:28])[C:24](=[O:29])[N:23]([CH3:30])[C:12]1=2.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C@@H:8]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:13]2[N:9]1[C:10]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[C:11]1[C:26](=[O:27])[N:25]([CH3:28])[C:24](=[O:29])[N:23]([CH3:30])[C:12]1=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C2CC[C@@H](CO)n3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C2CC[C@@H](COS(C)(=O)=O)n3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Reaction time: 1.75 h

Procedure:
Methanesulfonyl chloride (0.483 mL, 6.20 mmol) was added to a solution of (7S)-7-(hydroxyl methyl)-1,3-dimethyl-10-(5-methylfuran-2-yl)-5-phenyl-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (1.3 g, 3.10 mmol) and triethylamine (1.296 mL, 9.30 mmol) in DCM (30 mL). The mixture was stirred at room temp. for 105 mins. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM. The organic extract was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 40-75% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:49])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][C:42]([CH3:48])([CH3:47])[C:43]([O:45]C)=[O:44]>>[C:43]([C:42]([CH3:47])([CH3:48])[CH2:41][CH2:40][CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:49])=[O:17])([OH:45])=[O:44]
Reactant: COC(=O)CCc1c(CCCCCCOS(C)(=O)=O)cccc1OCCCC(C)(C)C(=O)OC
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCCc2cccc(OCCCC(C)(C)C(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 126, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-[(5-methoxy-4,4-dimethyl-5-oxopentyl)oxy]-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester from the preceding example, followed by saponification, in 33.9% overall yield. The product was a colorless solid, mp 85°-87° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C@:7]12[CH2:15][NH:14][CH2:13][C@H:12]1[CH2:11][S:10][C:9]([NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:8]2.Cl[C:26]1[N:31]=[C:30]([C:32]([OH:35])([CH3:34])[CH3:33])[C:29]([F:36])=[CH:28][N:27]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:36][C:29]1[C:30]([C:32]([OH:35])([CH3:33])[CH3:34])=[N:31][C:26]([N:14]2[CH2:13][C@@H:12]3[C@@:7]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)([N:8]=[C:9]([NH:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:10][CH2:11]3)[CH2:15]2)=[N:27][CH:28]=1
Reactant: CC(C)(O)c1nc(Cl)ncc1F
Reactant: O=C(NC1=N[C@@]2(c3cnccn3)CNC[C@H]2CS1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(O)c1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cnccn3)C2)ncc1F
Temperature: 110 °C
Yield: 98.3 %

Procedure:
N-[(4aR,7aR)-7a-pyrazin-2-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (231 mg, 0.680 mmol) is dissolved in 1,4-dioxane (4 mL). 2-(2-Chloro-5-fluoro-pyrimidin-4-yl)propan-2-ol (648.60 mg, 3.40 mmol) and diisopropylethylamine (653 μL, 3.74 mmol) are added. The reaction is heated at 110° C. for 6 hours then cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (330 mg, 98%). ES/MS (m/e): 494 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][NH:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)[CH3:2].[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)[C:40](O)=[O:41])=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[C:51]([O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][C@H:39]([NH:38][C:36](=[O:37])[O:35][CH2:34][CH:32]2[C:33]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:40]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:18][CH2:19][CH3:20])[CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)=[O:41])=[CH:49][CH:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CCOC(CNCc1cccc2cccnc12)OCC
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(CN(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Yield: 17.3 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, 2,2-diethoxy-N-(quinolin-8-ylmethyl)ethanamine (Compound IX-3) (1.37 g, 5 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (2.76 g, 6 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=7:3 to 5:5) to obtain the title compound (0.62 g, 17%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:36][CH3:37])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:19]>C(O)C.N1CCCCC1>[CH2:36]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:37]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.9 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2.4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)amide as a yellow solid (57.3 mg, 47%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20]([C:32]4[CH:31]=[N:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=4)=[N:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1
Reactant: O=C(NCC1(c2cccnc2)CCCCC1)c1sc(Br)nc1C(F)(F)F
Reactant: COc1ccc(B(O)O)cn1
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: O
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(C(F)(F)F)c(C(=O)NCC3(c4cccnc4)CCCCC3)s2)cn1
Temperature: 110 °C

Procedure:
A mixture of 2-bromo-4-trifluoromethyl-thiazole-5-carboxylic acid (1-pyridin-3-yl-cyclohexylmethyl)-amide (44.8 mg), 2-methoxy-5-pyridineboronic acid (30.6 mg), Pd(PPh3)4 (5.8 mg) and Na2CO3 (42.4 mg) in dioxane (2 mL) and water (0.8 mL) is heated at 110° C. in an argon purged sealed vial for 2 h. The mixture is poured into water and extracted with EtOAc. The extract is concentrated and the residue is purified by PTLC (silica gel, 5% MeOH in methylene chloride) to give the title compound. MS (M+1)=477.19; RT=1.19 min. *IC50.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]=2[N:6]=1.[CH3:15][N:16]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[CH3:15][N:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:2]2[O:3][C:4]3[CH:14]=[CH:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:5]=3[N:6]=2)[CH2:18][CH2:17]1
Reactant: Sc1nc2c(ccc3ccccc32)o1
Reactant: CN1CCCNCC1
Solvent: ClC(Cl)Cl
Product: CN1CCCN(c2nc3c(ccc4ccccc43)o2)CC1

Procedure:
2-Mercapto-naphtho[1,2-d]oxazole (200 mg) was dissolved in chloroform (20 ml), N-methylhomopiperazine (2.48 ml) was added dropwise to the solution and then the mixture was stirred with heating for 2 days. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 2-(4-methyl-1-homopiperazinyl)naphtho[1,2-d]oxazole (137 mg).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].CO>Br.C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC(CNCCCOc1cnc3ccccc3c1)CC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)OC(CNCCCOc1cnc3ccccc3c1)CC2
Yield: 64.5 %

Procedure:
A solution of 7-{3-[(7-methoxy-chroman-2-ylmethyl-amino]-propanoxy}-quinoline (2.19 g, 5.7 mmol) in 48% aqueous HBr was heated to reflux for 3 hours. The reaction mixture was then allowed to cool to room temperature and basified with 1N sodium hydroxide until pH 12. The basic reaction mixture was extracted with ethyl acetate (2×100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. Chromatography (7% methanol in methylene chloride containing 1% ammonium hydroxide) afforded 1.34 g of the title compound (63% yield). The corresponding oxalate salt was prepared by adding an excess of oxalic acid in warm ethanol to a solution of the free base in warm ethanol; mp 195.5°-196.5° C.
Reaction SMILES: Cl.C[O:3][C:4]1[N:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12>O>[O:3]=[C:4]1[C:9]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:8][CH:7]=[N:6][NH:5]1
Reactant: COc1nnccc1-c1c(-c2ccccc2)nn2ccccc12
Agent: Cl
Solvent: O
Product: O=c1[nH]nccc1-c1c(-c2ccccc2)nn2ccccc12
Yield: 86 %

Procedure:
A concentrated hydrochloric acid (5 ml) was added to 3-(3-methoxypyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.50 g) and refluxed for 2 hours and 30 minutes. After cooling, to the reaction mixture was added water (10 ml). The precipitates were collected by filtration to give 3-(3-oxo-2,3-dihydropyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.41 g).
Reaction SMILES: N1C=CC=N1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.[C:16](OCC)(=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH2:14][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: c1cn[nH]c1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1

Procedure:
In a further embodiment, a pyrazole cyclization reaction is provided in Scheme 14A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The pyrazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydrazine hydrate to provide ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol and glacial acetic acid for about 2 to 16 hours. Ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate is then reduced with lithium aluminum hydride to provide 3-(4-fluorophenyl)-1H-pyrazol-5-yl-methanol. In one embodiment, the reduction is performed in THF at a temperature of about 0° C. to about room temperature overnight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde is then formed by oxidizing 3-(4-fluorophenyl)-1H-pyrazole-5-methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6]([C:13]#[N:14])[C:5]3[N:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3]1=2.S(=O)(=O)(O)[OH:20].C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6]([C:13](=[O:20])[NH2:14])[C:5]3[N:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3]1=2
Reactant: CC1CC(=O)Nc2nc(C#N)c3ncccc3c21
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1CC(=O)Nc2nc(C(N)=O)c3ncccc3c21
Yield: 63 %

Procedure:
2 g (0.008 mol) of 1-methyl-6-cyano-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one are allowed to stand for 3 hours at room temperature in 40 ml of 96% strength sulphuric acid. After neutralization using aqueous Na2CO3 solution, the mixture is extracted repeatedly with methylene chloride, the combined organic bases are dried and then evaporated in vacuo, and the residue is chromatographed on silica gel with chloroform/methanol 98:2. 1.29 g (63% of theory) of 1-methyl-6- carbamoyl-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one are obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.NN.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl>C(O)C>[N:1]1([C:6]2[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCOc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: NN
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: NCCCCCCCCCCOc1ccc(-n2ccnc2)cc1

Procedure:
2-[10-[4-(1H-imidazol-1-yl)phenoxy]decyl]-1H-isoindole-1,3(2H)-dione (Example 65) is converted to the free amino derivative by treatment with hydrazine in a refluxing ethanol solution. A portion is converted to its dihydrochloride salt by treatment with concentrated hydrochloric acid in ethanol to give the desired compound, m.p. 190°-192° C. The free base is obtained by treatment with excess 10N NaOH.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=O.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[N:1]=1
Reactant: O=c1ccc2ncccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2ncccc2n1
Temperature: 100 °C

Procedure:
A 250 mL round bottomed flask charged with 1,5-naphthyridin-2(1H)-one (2.98 g, 20.37 mmol) and phosphorus oxychloride (40 ml, 437 mmol) was heated at 100° C. for 3 h. The reaction was cooled to room temperature and excess POCl3 was removed in vacuo. The residue was poured onto ice and neutralized with NaHCO3. The mixture was extracted with DCM (4×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (ISCO (80 gram)) eluting with EtOAc:DCM (0:1→1:4) to give 1.08 g (32%, 2 steps) of a light-yellow amorphous solid. ESI-MS 164.9, 166.9 [M+1].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH3:21])=C(Cl)[N:13]=1>>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH3:21])=[C:9]([NH:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: O=CNc1ccc(Cl)nc1
Product: Cn1cnc2c(Nc3ccc(Cl)nc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(6-chloro-pyridin-3-yl)-formamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]#[N:19])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:20][NH:21][CH3:22]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]([N:21]([CH3:22])[CH3:20])=[NH:19])[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CNC
Reactant: CS(=O)(=O)c1cccc(-c2ccccc2NC#N)c1
Product: CN(C)C(=N)Nc1ccccc1-c1cccc(S(C)(=O)=O)c1

Procedure:
A mixture of N-(3'-methanesulphonyl-2-biphenylyl)-cyanamide (2.7 g) and 33% ethanolic dimethylamine solution (25 ml) was heated under reflux for 3 hours to give N-(3'-methanesulphonyl-2-biphenylyl)-N',N'-dimethylguanidine (m.p. 113°-114° C.) which was recrystallised from ethylacetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1N)C(=O)O
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of (S)-2-tert-butoxycarbonylamino-3-(2-nitro-phenoxy)-propionic acid (7.6 g, 23.3 mmol, leq) and 10% Pd/C (496 mg) in MeOH (215 mL) was hydrogenated at 1 atm for 2 h. After the theoretical uptake of hydrogen, the reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and the residue was tritrurated with hexanes to give a solid that was filtered and washed with hexanes to give (S)-3-(2-amino-phenoxy)-2-tert-butoxycarbonylamino-propionic acid (3.8 g, 55%) as a white solid which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8].[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=2)[CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8])[CH:20]=1
Reactant: CS(=O)(=O)NCc1cccc(N)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
5.309 g N-(3-Amino-benzyl)-methanesulfonamide (obtained in Step 2, 26.5 mmol) and 4.739 g 4,6-dichloropyrimidine (31.81 mmol) was dissolved in 120 cm3 of isopropyl-alcohol, 6.93 cm3 N,N-diisopropyl-ethylamine (5.140 g, 39.76 mmol) was added and the mixture was refluxed for four days. The reaction mixture was cooled to room temperature and the precipitated compound was filtered off. The light yellow product was washed well with diethyl-ether and air-dried. 3.612 g N-[3-(6-Chloro-pyrimidin-4-ylamino)-benzyl]-methanesulfonamide was obtained in more than 98% purity and in 44% overall yield. For analitical results and compound identification see Table 1. The compound was used as a starting material in the preparation of Example 2-32 and 75.