Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[S:18](=[O:20])(=[O:19])[NH:17][C:16](=[O:21])[CH2:15]2)=[C:10]([OH:22])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:15][C:16](=[O:21])[NH:17][S:18]2(=[O:20])=[O:19])=[C:10]([O:22][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CN(c2ccc(Cc3ccccc3)cc2O)S(=O)(=O)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(c2ccc(Cc3ccccc3)cc2OC(=O)c2ccccc2)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-(4-benzyl-2-hydroxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (45 mg, 0.141 mmol) in DMF (0.2 mL) is added KOtBu (1.0 M in THF, 0.17 mL, 0.17 mmol). After it is stirred at ambient temperature for 5 min., benzoyl chloride (35 mg, 0.254 mmol) is added. After it is stirred at ambient temperature for 10 min., the reaction is quenched with 1N HCl solution. The residue is then purified by prep. HPLC using CH3CN (0.1% TFA)/water (5-70%) to give the title compound: MS (M−H)−=421.
Reaction SMILES: [C:1]([C:9]1[CH:35]=[CH:34][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:33]=[CH:32][C:23]([O:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][NH2:38]>>[CH3:36][O:37][N:38]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:35]=[CH:34][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:32][CH:33]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: CON
Reactant: CCOC(=O)C(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Product: CCOC(=O)C(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4ccccc4)ccc32)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
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[C:23]([CH:24]=O)=[CH:22][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.Cl.NO.[N:40]1C=CC=CC=1.C(O)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[C:23]([C:24]#[N:40])=[CH:22][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(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C#N)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 63.6 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.57 g), hydroxylamine hydrochloride (0.13 g), pyridine (0.24 g) and ethanol (20 mL) was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Acetic anhydride (20 mL) was added to residue, and the mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy)-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbonitrile as colorless crystals (0.36 g, 62%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 167-168° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:29](=[CH:30][CH:31]=2)[O:28][C:15]2([CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH2:14][C:13]3=[O:32])[CH:7]=[N:6][CH:5]=1.[ClH:34]>CO.O1CCOCC1>[ClH:34].[ClH:34].[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:29](=[CH:30][CH:31]=2)[O:28][C:15]2([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH2:14][C:13]3=[O:32])[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O3)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-(1′-tert-butoxycarbonyl-4-oxospiro[chroman-2,4′-piperidin]-6-yl)nicotinic acid methyl ester (22.0 g, 48.6 mmol) was suspended in MeOH (110 mL) and 4 N HCl in dioxane (220 mL) was added thereto, and stirred at room temperature for 14 hours. The solvents were removed in vacuo and the resulting solid was washed with MeOH/Et2O (50 mL/200 mL) to obtain the intended compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([O-:14])=[O:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A slurry of methyl 3-hydroxy-4-nitrobenzoate (5.5 g, 0.028 mol), iodooctane (10.0 g, 0.042 mol) and potassium carbonate (20 g) in 100 mL DMF was stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with 500 mL H2O, then extracted with ether/ethyl acetate (9/1, 2×200 mL). The combined organic solution was washed with 400 mL H2O, dried over sodium sulfate, and concentrated to form methyl 4-nitro-3-octoxybenzoate as an off-white oil (8.7 g, 100%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f41) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[NH2:17][C:18]([CH3:34])([CH2:21][N:22]1[N:26]=[C:25]2[C:27]([Cl:33])=[CH:28][C:29]([Cl:32])=[C:30]([Cl:31])[C:24]2=[N:23]1)[C:19]#[N:20]>C1COCC1>[C:19]([C:18]([NH:17][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([O:6][C:2]([F:16])([F:1])[CH:3]([F:5])[F:4])=[CH:8][CH:9]=1)([CH3:34])[CH2:21][N:22]1[N:26]=[C:25]2[C:27]([Cl:33])=[CH:28][C:29]([Cl:32])=[C:30]([Cl:31])[C:24]2=[N:23]1)#[N:20]
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(OC(F)(F)C(F)F)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(OC(F)(F)C(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 169, except using a solution of 4-(1,1,2,2-tetrafluoroethoxy)benzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (0.075 mmole, described in Example 39) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (4.2 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=524, RT=0.72 min.
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Mg+2].[O-]CC.Br[CH2:23][CH:24]([CH3:26])[CH3:25]>>[CH3:23][CH:24]([CH3:26])[CH2:25][CH:9]([C:2](=[O:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(C)CBr
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Mg+2]
Product: CCOC(=O)CC(=O)C(CC(C)C)C(=O)OCC
Yield: 61.9 %

Procedure:
Diethyl 3-oxopentanedioate (45.5 ml, 0.25 mol) was added to a suspension of magnesium ethoxide (prepared from magnesium turnings (9 g, 0.375 mol) and iodine (0.1 g) in dry ethanol (275 ml)), and the mixture was heated under reflux for 90 min. 1-Bromo-2-methylpropane (54 ml, 0.5 mol) was added, and the reaction was heated under reflux for 16 h. Further 1-bromo-2-methylpropane (27 ml, 0.25 mol) was added to the boiling mixture, and after 3 h the solvent was evaporated in vacuo. The residue was partitioned between 2N hydrochloric acid and ether. After extracting the aqueous phase with ether, the combined organics were washed successively with water, 5% sodium bicarbonate, water and brine, then were dried (Na2SO4) and evaporated in vacuo. The residue was distilled to give the title compound as a colourless oil (40 g, 62%), bp 118°-120° C. (1mmHg).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Product: CSc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)cc1
Yield: 68.3 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 68.3%).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[S:14][C:13]([NH2:16])=[N:12][C:11]=3[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1COCC1>[CH:1]1([C:7]2[C:15]3[S:14][C:13]([NH:16][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=4)=[N:12][C:11]=3[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C2CCCCC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCCCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Temperature: 70 °C
Yield: 13.7 %

Procedure:
To a solution of 0.05 g (0.19 mMol) 7-cyclohexyl-4-methoxy-benzothiazol-2-ylamine in 2 ml THF were added 0.1 ml ethyl diisopropyl amine and 0.027 ml (0.23 mMol) 4-fluoro-benzoyl chloride. The reaction mixture was heated to 70° C. for 2 h. The solvent was evaporated to dryness, the residue taken up in dichloro methane and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated to dryness in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane 1:9, 1:4) to yield 0.01 g (14%) of N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-4-fluoro-benzamide as a light yellow solid; F.p.: 192-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:31][CH2:32][CH3:33])=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:45])[C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][C:36]([N:35]([CH3:45])[CH3:34])=[O:44])[CH2:43][CH2:42]3)=[O:21])[C:10]([C:23]3[C:24]([O:31][CH2:32][CH3:33])=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1nc(SC)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CCOc1nc(SC)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12) was reacted with N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C31H36N7O3SCl2 [(M+H)+] 656.1972, observed 656.1973.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:12][CH3:13])[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]1[Cl:11].[C:14]1(=[O:19])[O:18][CH:17]=[CH:16][O:15]1>>[Cl:11][C:4]12[C:3]([O:2][CH3:1])([O:12][CH3:13])[C:7]([Cl:8])([C:6]([Cl:9])=[C:5]1[Cl:10])[CH:17]1[CH:16]2[O:15][C:14](=[O:19])[O:18]1
Reactant: COC1(OC)C(Cl)=C(Cl)C(Cl)=C1Cl
Reactant: O=c1occo1
Product: COC1(OC)C2(Cl)C(Cl)=C(Cl)C1(Cl)C1OC(=O)OC12
Temperature: 90 °C
Reaction time: 63 h
Yield: 94.5 %

Procedure:
In a 500 mL 3N RB flask equipped with a water condenser, N2 flow adapter and thermometer, was placed 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopentadiene (20.7 g, 0.078 mol) and vinylene carbonate (6.7 g, 0.078 mol). The mixture was heated to 90° C. for 4 h, then at 60° C. for 63 h. The reaction was judged complete by TLC and upon cooling, the product solidified, was recrystallized from THF and filtered to provide a white solid (25.80 g, 94%). (TLC 20% EtOAc/hexanes Rf 0.29); 1H NMR (400 MHz, CDCl3) δ 5.13 (s, 2H), 3.59 (s, 3H), 3.56 (s, 3H); GCMS m/z 348 (M)+; mp 160–162° C.; Anal. Calcd. for C10H8Cl4O5: C, 34.32; H, 2.30. Found C, 34.32; H, 2.27.
Reaction SMILES: [OH2:1].[OH2:2].[C:3]1([CH:9]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32])[N:29]=4)[N:26]=3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[C:36]1([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]([CH3:35])([CH3:34])[C:31]([O:33][C:34](=[O:2])[C:30]([CH3:35])([C:28]5[N:29]=[C:24]6[CH:23]=[CH:22][C:21]([NH:20][CH2:19][CH2:18][CH2:17][N:14]7[CH2:15][CH2:16][CH:11]([O:1][CH:9]([C:36]8[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=8)[C:3]8[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=8)[CH2:12][CH2:13]7)=[N:26][N:25]6[CH:27]=5)[CH3:31])=[O:32])[N:29]=4)[N:26]=3)[CH2:15][CH2:16]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O
Reactant: CC(C)(C(=O)O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Solvent: CCO
Product: CC(C)(C(=O)OC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 90.8 %

Procedure:
In 500 mL of ethanol, 3.20 g (5.67 mmol) of the 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate obtained in Example 135A was dissolved under heating, followed by concentrating at atomospheric pressure until the total volume became 250 mL. After standing at room temperature, the crystals formed were collected by filtration, washed with ethanol and dried to yield 2.67 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([N:12]([CH3:16])[C:13](Cl)=[O:14])(=[O:11])=[O:10].C(N(CC)CC)C.[CH3:24][NH:25][C:26]1[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([CH3:34])[N:27]=1>O1CCCC1>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH3:34])[N:27]=[C:26]([N:25]([CH3:24])[C:13]([N:12]([CH3:16])[S:9]([C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])=[O:14])[N:31]=1
Reactant: CNc1nc(C)cc(OC)n1
Reactant: CN(C(=O)Cl)S(=O)(=O)c1cc(Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C)nc(N(C)C(=O)N(C)S(=O)(=O)c2cc(Cl)ccc2Cl)n1

Procedure:
To 3.0 g of N-[(2,5-dichlorophenyl)sulfonyl]-N-methylcarbamyl chloride in 50 ml of tetrahydrofuran containing 1.0 g of triethylamine is added 1.5 g of 2-methylamino-4-methoxy-6-methylpyrimidine. After stirring at reflux for several hours, the precipitated salts are filtered off and the filtrate is concentrated to yield N-[N-(4-methoxy-6-methylpyrimidin-2-yl)-N-methylaminocarbonyl]2,5-dichloro-N-methylbenzenesulfonamide.
Reaction SMILES: [OH:1][C:2]1([C:31](O)=[O:32])[CH2:7][CH2:6][CH:5]([N:8]2[C:16]([NH:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])=[N:15][C:14]3[C:9]2=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=3)[CH2:4][CH2:3]1.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C1COCC1>[CH:34]1([NH:39][C:31]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:8]3[C:16]([NH:17][C:18]4[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=4[F:26])=[N:15][C:14]4[C:9]3=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=4)[CH2:4][CH2:3]2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)O)CC3)c2n1
Reactant: NC1CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)NC4CCCC4)CC3)c2n1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1-Hydroxy-4-{2-[(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}cyclohexanecarboxylic acid (0.200 g, 0.4 mmol) was dissolved in 4 mL of dry THF. Cyclopentyl amine (0.079 mL, 0.8 mmol) was added neat followed by di-isopropyl amine (0.105 mL, 0.6 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) was added last, as a solid in one portion at room temperature (0.177 g, 0.4 mmol). The reaction was complete within 10 min as confirmed by LC-MS. DMF was removed under reduced pressure. The residue was triturated in saturated aqueous sodium bicarbonate. The resulting beige solid was collected by filtration and washed with water. The crude product was re-crystallized from hot methanol-water. The crystals were dried in vacuum oven. (141 mg, 66% yield) M+1: 532.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=2)=[CH:53][CH:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:52]=[CH:53][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=2)=[CH:55][CH:56]=1
Reactant: COc1ccc(-c2cccc(N)c2)cc1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
DIEA (0.0144 mL, 0.083 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.016 g, 0.075 mmol) and HATU (0.032 g, 0.083 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-biphenyl-3-ylamine (0.015 g, 0.075 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.015 g of product in 52% yield: LCMS (ESI) m/z 388 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>O1CCOCC1>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1Nc1ccccc1)c1ccc(Br)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 100 °C
Yield: 90 %

Procedure:
To a suspension of amide (1) (9.6 g, 26 mmol) in anhydrous 1,4-dioxane (100 mL) was added POCl3 (9.2 mL, 100 mmol) slowly. The whole was then heated at about 100° C. overnight. After cooling to room temperature, the mixture was poured into ice (200 g) with stirring. Filtration, followed by recrystallization in DCM/hexanes gave a pale grey solid (8.2 g, in 90% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7](O)=[O:8])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]([NH2:29])=[NH:28]>>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([NH:28][C:27]([NH2:29])=[NH:26])=[O:8])(=[O:3])[CH3:2]
Reactant: N=C(N)N
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(=O)c1cc(C(=O)NC(=N)N)ccc1O

Procedure:
1.0 eq. of 3-acetyl-4-hydroxybenzoic acid was reacted in accordance with Variant A with 1.1 eq. of carbonyldiimidazole and 5 eq. of guanidine. Colorless crystals, mp 218°-221° C.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][C@H:28]([CH3:30])[NH:27][CH2:26][C@@H:25]1[CH3:31].C(O)(C)C>Cl>[C:1]1([C:7]2[N:16]=[C:15]([N:27]3[CH2:26][C@H:25]([CH3:31])[N:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)[CH2:29][C@@H:28]3[CH3:30])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: C[C@H]1CN(c2ccccn2)[C@@H](C)CN1
Agent: Cl
Solvent: CC(C)O
Product: C[C@H]1CN(c2nc(-c3ccccc3)nc3ccccc23)[C@@H](C)CN1c1ccccn1
Temperature: 25 °C

Procedure:
A mixture containing 8.4 g (0.03 mole) of 2-phenyl-4-chloroquinazoline, 6.3 g (0.0335 mole) of 1-(2-pyridyl)-cis-2,5-dimethylpiperazine and 200 ml of isopropanol was refluxed for 6 hrs. The resulting reaction mixture was filtered after cooling to room temperature. A crystalline solid was obtained. The crude product was dissolved in 3N hydrochloric acid and extracted with ether. The aqueous acidic solution was adjusted to pH=7.5 and filtered. Yield of crystalline solid was 4.3 g, m.p. 68°-70° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (232 mg, 0.80 mmol) and 3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K10) (270 mg, 0.82 mmol) according to the general procedure M. Obtained as a yellow foam (287 mg, 66%).