Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[C:9]([C:27]([O:29][CH3:30])=[O:28])([CH2:10][N:11]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)=[O:15])[N:12]=3)[CH2:8][CH2:7][C:6]=2[CH:31]=1.C(N(CC)CC)C.Cl[S:40][N:41]([CH3:51])[C:42](=[O:50])[O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[C:9]([C:27]([O:29][CH3:30])=[O:28])([CH2:10][N:11]([C:14]([N:16]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=4)[S:40][N:41]([CH3:51])[C:42]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:50])=[O:15])[N:12]=3)[CH2:8][CH2:7][C:6]=2[CH:31]=1
Reactant: COC(=O)C12CCc3cc(Cl)ccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Reactant: CCCCCCOC(=O)N(C)SCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCOC(=O)N(C)SN(C(=O)N1CC2(C(=O)OC)CCc3cc(Cl)ccc3C2=N1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of the title compound of Step E above (2.2 g, 0.005 mol) in 25 ml methylene chloride cooled to 0° C. was added triethylamine (1.0 g) and hexyl (chlorosulfenyl)(methyl)carbamate, (prepared in a manner similar to Example 1, Step D), (2.5 g 75% pure) dropwise at 0° C. The mixture was stirred at room temperature for additional one hour. The reaction mixture was concentrated under high vacuum and subjected to silica gel column chromatography using hexane-ether (1:1) as an eluent. The title compound (2.5 g) was obtained, melting point 128°-129° C. in high purity.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[C:8]=2[N:9]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c(-c3c(Cl)cccc3Cl)cc3cnc(N)nc32)cc1
Temperature: 50 °C

Procedure:
To a suspension of NaH (60% in mineral oil, 38 mg) in 8 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (208 mg, 0.68 mmol). The mixture was heated at 50° C. for 1 hour, resulting in a clear solution. 4-Methoxybenzyl chloride (130 μL, 0.95 mmol) was added, and the reaction mixture was heated at 50° C. for 30 minutes, then poured onto ice water. The resulting precipitate was removed by filtration and washed with water. The solid was purified by flash chromatography, eluting with 1:1 hexane:ethyl acetate, then dried in vacuo to provide 208 (72%) mg of 2-amino-6-(2,6-dichlorophenyl)-8-(4-methoxybenzyl)-8H-pyrido[2,3-d]pyrimidin-7-one; mp 208°-209° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([NH:37][CH3:38])[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[C:22]([CH3:39])=[C:21]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C=O>[CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([N:37]([CH3:48])[CH3:38])[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[C:22]([CH3:39])=[C:21]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNC1Cc2cc3cc(-c4nc(OCc5ccccc5)c(C(=O)OCc5ccccc5)c(OCc5ccccc5)c4C)ccc3n2C1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1c(-c2ccc3c(c2)cc2n3CC(N(C)C)C2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
The product from Example 415, Step 2 (31 mg, 0.05 mmol) was dissolved in 1,2-dichloroethane (1 mL). Aqueous 30% formaldehyde (1 drop, ˜0.2 mmol) was added to the mixture, followed by sodium triacetoxyborohydride (21 mg, 0.1 mmol). The mixture stirred at room temperature for 30 min. The mixture was loaded directly to silica gel, eluting with 0-8% MeOH in CH2Cl2 to afford product (25 mg, 78%). LC-MS 638.3 [M+H]+, RT 1.21 min.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH2:31][CH2:30][N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: OCCN1CCOCC1
Reactant: COc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Solvent: Cc1ccccc1
Product: COc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 117 °C
Reaction time: 2 h

Procedure:
7 g (0.02 moles) of (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid and toluene (25 ml) are warmed gently to form a solution. A slight excess (1.05 molar equivalents) of 2-morpholinoethanol (3 g, 0.021 moles) and toluene (25 ml) are added. The reaction mixture is stirred for half an hour and then heated to reflux at an initial pot temperature of 117° C. (which increases a few degrees during reflux) under a Dean-Stark trap for 80 hours. The reaction mixture is cooled, washed with water (2×15 ml), 10% aqueous sodium bicarbonate (2×15 ml) and finally with water (15 ml). The toluene layer is stripped to a volume of about 20 ml in vacuo, n-hexane (30 ml) is added and the resulting slurry is aged at room temperature for 2 hours. The product is filtered, washed with n-hexane (ca. 10 ml) and dried in vacuo at 60° C. to yield 2-(morpholin-4-yl)ethyl (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](O)(=[O:14])[CH2:10][CH2:11][C:12]#[CH:13].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13]
Reactant: C#CCCC(=O)O
Reactant: CNc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C#CCCC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of N-methylbenzenamine (110 mg, 1.02 mmol) in DCM (3 mL) was successively added at R.T. 4-pentynoic acid (100 mg, 1.02 mmol), HOBT (171mg, 1.12 mmol) and EDCI.HCl (293 mg, 1.53 mmol). The reaction was stirred at R.T. overnight. The reaction was quenched with water. The organic layer was separated and washed with 1M NaHCO3 and water. The solvent was removed under reduced pressure to afford 150 mg N-methyl-N-phenylpent-4-ynamide (Yield: 78%) as an orange oil which cn be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][N:12]([C:20](Cl)=[O:21])[CH:11]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:5]2=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36]([CH2:38][NH2:39])[C:35]([CH3:40])=[N:34]1>C(N(CC)CC)C>[CH3:32][N:33]1[CH:37]=[C:36]([CH2:38][NH:39][C:20]([N:12]2[CH2:13][CH:14]([CH2:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:31])[CH:11]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[F:30])=[O:21])[C:35]([CH3:40])=[N:34]1
Reactant: Cc1nn(C)cc1CN
Reactant: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: CCN(CC)CC
Product: Cc1nn(C)cc1CNC(=O)N1CC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 9, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonylchloride prepared in Example 8 (57 mg, 0.12 mmol) was reacted with C-(1,3-dimethyl-1H-pyrazol-4-yl)methylamine (Oakwood) (22 mg, 0.18 mmol) and triethylamine to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1,3-dimethyl-1H-pyrazol-4-ylmethyl)-amide as a white solid (Yield, 19 mg, 28%).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:11](=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([NH:21][CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[N:9][N:8]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([C:7]1[C:20]2[C:11](=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([NH:21][CH2:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])=[N:9][N:8]=1)[C:29](=[O:31])[CH3:30]
Reactant: CN(C)CCCNc1nnc(NCCCN(C)C)c2cc3ccccc3cc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(CCCN(C)C)c1nnc(NCCCN(C)C)c2cc3ccccc3cc12

Procedure:
A solution of 1,4-bis[N-(3-dimethylaminopropyl) amino]-2,3-diaza-anthracene (0.76 g) in pyridine (0.6 ml) and acetic anhydride (94 ml) is left at room temperature for 15 hours. After distillation of the solvent at reduced pressure the residue is dissolved in ethyl acetate (20 ml) and the organic solution is washed with 5% sodium bicarbonate (2×15 ml) and with brine (5 ml). Drying over sodium sulphate and removal of the solvent at reduced pressure gives 0.57 g of 1-[N-(3-dimethylaminopropyl)-N-(acetyl)amino]-4-[N-(3-dimethylaminopropyl)amino]-2,3-diaza-anthracene.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=C=O)=[CH:15][CH:14]=1.O>[O-]CC.[Na+].CC(N(C)C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(NC(=O)c2ccc(O)cc2)cc1
Temperature: 30 °C
Reaction time: 0.42 h
Yield: 81.2 %

Procedure:
p-Hydroxybenzoic acid (69.06 grams, 0.50 mole), sodium ethoxide catalyst (0.155 gram, 0.225% wt. of the p-hydroxybenzoic acid used) and dimethylacetamide solvent (400 grams) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at 80° C. p-Methoxyphenylisocyanate (78.30 grams, 0.525 mole) is added dropwise over a ten minute period with cooling of the reactor exterior to maintain the 80° C. reaction temperature. After an additional ten minutes at 80620 C., heating of the reactor commenced and a 160° C. temperature is achieved 25 minutes later. After three hours at the 160° C. reaction temperature, the reactor is cooled to 30° C. then the contents poured into two liters of deionized water. A precipitated white powder is recovered via filtration of the aqueous slurry then dissolved into one liter of boiling methanol. After cooling the methanol solution to 5° C., a first crop of white crystalline product is filtered off and dried at 90° C. under vacuum to a constant weight of 67.9 grams. The methanol solution is concentrated by rotary evaporation to a 300 milliliter volume then cooled to 5° C. until a second crop of white crystalline product appeared. After filtration, drying of the product to constant weight provided an additional 30.8 grams to give a total isolated yield of 81.2% of 4-hydroxy-4'-methoxybenzanilide.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[CH:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:13]([OH:15])=[O:14]>O.C(O)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:12]([S:10][C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)[C:13]([OH:15])=[O:14])=[CH:26][CH:25]=1
Reactant: O=C(O)C(Br)CCCCCc1ccc(Cl)cc1
Reactant: Cc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(SC(CCCCCc2ccc(Cl)cc2)C(=O)O)cc1
Reaction time: 8 h

Procedure:
A solution of 2.12 g (53 mmol) of caustic soda in 5 ml of water is added under nitrogen, at 0° C., to a solution of 3.27 g (26.3 mmol) of p-thiocresol in 50 ml of ethanol. Then a solution of 8.4 g (26.3 mmol) of 2-bromo-7-(4-chlorophenyl)heptanoic acid in 5 ml of ethanol is added and the cooling bath is removed. Then stirring is continued for 6 at room temperature; the mixture is let stand overnight and concentrated by evaporation. The residue is taken up in water, washed with ether and acidified with hydrochloric acid. The precipitated oil is extracted with methylene chloride. The extracts are dried and concentrated. The concentrate is chromatographed with a mixture of toluene and dioxane (5:1) on silica gel. Yield: 6.6 g (69% of theory) of 7-(4-chlorophenyl)-2-(4-methylphenylthio)heptanoic acid, M.P. 58°-61° C.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:6]=2[N:7]=1)[CH3:2].[CH2:26]([O:28][C:29]([C:31]1[N:32]=[C:33]([CH2:36]Br)[O:34][CH:35]=1)=[O:30])[CH3:27]>>[CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[N:22]([CH2:36][C:33]4[O:34][CH:35]=[C:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[N:32]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2c(o1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CCOC(=O)c1coc(CBr)n1
Product: CCOC(=O)c1coc(Cn2cc(C3c4ccc(C)cc4C=Cc4oc(CC)nc43)c(=O)[nH]c2=O)n1

Procedure:
The subtitle compound was prepared from the product from example 1 step (vii) (6.5 g) and 2-[bromomethyl]-4-oxazolecarboxylic acid ethyl ester (Coll. Czech Chem. Comm., 1967, 32, 2155) (1.69 g) by the method of example 1 step (viii). Purification was by chromatography eluting with 60-66% ethyl acetate in toluene.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]2[S:15][C:16]([C:19]3[C:23]([CH3:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[O:21][N:20]=3)=[CH:17][CH:18]=2)=[O:13])[CH2:7]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(#N)C>[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:2][C:3]([NH:5][C@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]3[S:15][C:16]([C:19]4[C:23]([CH3:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[O:21][N:20]=4)=[CH:17][CH:18]=3)=[O:13])[CH2:7]2)=[O:4])[CH2:38][CH2:37]1
Reactant: CN1CCNCC1
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@H](NC(=O)CCl)C3)s2)noc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](NC(=O)CN4CCN(C)CC4)C3)s2)noc1C(F)(F)F
Reaction time: 72 h
Yield: 85.1 %

Procedure:
2-Chloro-N-{(S)-1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-acetamide (35 mg, 0.08 mmol, as prepared in Example 56) was dissolved in acetonitrile (3 mL) containing anhydrous K2CO3, treated with N-methylpiperazine (18 μL, 0.16 mmol), and stirred for 3 days. The reaction mixture was then evaporated and treated with water to provide a homogeneous solution which was extracted with EtOAc (2×4 mL), dried over MgSO4, filtered, and evaporated to afford product as an foam (34 mg, 85%). 1H NMR (CDCl3) 1.60-1.76 (m, 3H), 1.88-1.98 (m, 1H), 2.22 (s, 3H), 2.29 (d, J=1.3, 3H), 2.32-2.52 (m, 8H), 2.92 (s, 2H), 3.52 (br s, 1H), 3.48 (br s, 2H), 3.72-4.46 (m, 3H), 7.32-7.44 (br m, 3H). 19F NMR −63.1. LC/MS 4.59 min, [M+1]+ 500.
Reaction SMILES: [OH:1][CH:2]([C:5]1[C:13]2[O:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[C:9]=2[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:6]=1[CH3:32])[CH2:3][CH3:4]>CCCCCC.C(OCC)(=O)C>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:10]2[C:9]3[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:28])([CH3:30])[CH3:29])[C:6]([CH3:32])=[C:5]([C:2](=[O:1])[CH2:3][CH3:4])[C:13]=3[O:12][CH2:11]2)=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: CCC(O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 18 %

Procedure:
Using a diastereo mixture of N-(7-(1-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in the synthesis in Examples 30 and 31, the title compound was synthesized in the same manner as in Example 32. Yield: 18%. Melting point: 163-164° C. (hexane-ethyl acetate).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[O:12][CH:13]=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([NH:8][C:9]([C:11]1[O:12][C:13]([Br:17])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccoc1C(=O)NCc1ccccc1
Solvent: CC#N
Product: Cc1cc(Br)oc1C(=O)NCc1ccccc1
Reaction time: 16 h
Yield: 11.1 %

Procedure:
To a stirred solution of N-benzyl-3-methylfuran-2-carboxamide (1.18 g, 5.49 mmol) in acetonitrile (25 mL) was added N-bromosuccinimide (0.98 g, 5.49 mmol). The reaction mixture was stirred for 16 hours, and then partitioned between ethyl acetate (100 mL) and water (75 mL). The organic layer was washed with 1 N sodium hydroxide solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-20% ethyl acetate in hexanes to afford N-benzyl-5-bromo-3-methylfuran-2-carboxamide as a colorless solid (0.18 g, 11%): 1H NMR (300 MHz, CDCl3) δ 7.38-7.27 (m, 5H), 6.54 (br s, 1H), 6.28 (s, 1H), 4.58 (d, J=5.9 Hz, 2H), 2.40 (s, 3H); MS (ES+) m/z 294.1 (M+1), 296.1 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1
Reactant: Nc1cccc(O)c1
Reactant: Nc1cn2nc(I)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(Oc2ccc3nc(N)cn3n2)c1
Yield: 36.8 %

Procedure:
A mixture of 6-iodoimidazo[1,2-b]pyridazin-2-amine (390 mg, 1.5 mmol), 3-aminophenol (491 mg, 4.5 mmol), potassium carbonate (415 mg, 3.0 mmol) and N,N-dimethylformamide (3 mL) was stirred using a microwave synthesizer at 180° C. for 40 min. The reaction mixture was diluted with water and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→60/40). The objective fraction was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol=100/0→80/20) and precipitated from ethyl acetate to give the title compound (133 mg, yield 37%) as a purple solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[CH3:31])[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[CH:16][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(Cl)Cl.[CH3:40][OH:41]>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:34])=[O:35])([CH3:32])[CH3:31])[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[CH:16][C:3]=1[CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:40]([NH:5][CH:6]([CH3:11])[CH3:7])=[O:41]
Reactant: CC(C)(c1cc(-c2ccc(F)c(CNc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: CO
Solvent: ClCCl
Product: CC(C)NC(=O)N(Cc1cc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)ccc1F)c1ccc(S(C)(=O)=O)cc1

Procedure:
Prepared in two steps according to the procedures described in EXAMPLE 41 but using the {2-fluoro-5-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzyl}-(4-methanesulfonyl-phenyl)-amine from present Step 4 as the starting material. Flash chromatography (CH2Cl2:MeOH; 96:4) afforded the compound as a foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8].Cl[C:12]1[N:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1.N1C(C)=CC=CC=1C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:10][C:12]2[N:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)=[N:4][N:5]([CH3:9])[C:6]=1[S:7][CH3:8]
Reactant: CSc1c(Cl)c(O)nn1C
Reactant: COc1cnnc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1cnnc(Oc2nn(C)c(SC)c2Cl)c1
Yield: 26 %

Procedure:
4-Chloro-1-methyl-5-(methylthio)-1H-pyrazol-3-ol which is a known compound (2.7 g, 0.015 mole), 3-chloro-5-methoxypyridazine (1.45 g, 0.01 mole), and 2,6-lutidine (1.4 mL, 0.012 moles) were heated to reflux in toluene (40 mL) under N2 for 18 h. The mixture was then poured into aqueous ammonium chloride and extracted 3×100 mL with ethyl acetate. The organic layers were washed with water and brine, dried (MgSO4), filtered and evaporated in vacuo. The crude solid was purified by flash chromatography to give 3-[[4-chloro-1-methyl-5-(methylthio)-1H-pyrazol-3-yl]oxy]-5-methoxypyridazine (1.1 g, 26% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH3:18])[C:5]=2[N:4]=[C:3]1/[CH:19]=[CH:20]\[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1.II.S([O-])([O-])(=O)=S.[Na+].[Na+].C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][CH2:17][CH3:18])[C:5]=2[N:4]=[C:3]1/[CH:19]=[CH:20]/[C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C\c3ccc(C(=O)O)cc3)n2C)n(CCC)c1=O
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(C(=O)O)cc3)n2C)n(CCC)c1=O
Yield: 59.3 %

Procedure:
A solution of 1.25 g (3.15 mmol) of Compound 18 obtained in Example 17 and 40 mg (0.32 mmol) of iodine in 125 ml of toluene was heated under reflux for 6.5 hours. After cooling, a 0.1M aqueous solution of sodium thiosulfate and chloroform were added thereto, followed by stirring. The precipitated crystals were collected by filtration, and recrystallized from ethanol to give 740 mg (yield 59%) of Compound 19 as ocher needles.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][OH:12]>C1C=CC=CC=1>[CH3:11][O:12][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C)cc1
Reaction time: 20 h

Procedure:
544 g. of 4-methyl-benzoic acid was boiled with 550 ml. of thionyl chloride until a clear solution was obtained. After the excess thionyl chloride was distilled off, the residue was fractionated, yielding 605 g. of 4-methyl-benzoyl chloride; b.p. 91°/9 mm Hg., nD24 = 1.5532. This was dissolved in 550 ml. of absolute benzene and the so-formed solution added to a mixture of 248 ml. of absolute methanol and 550 ml. of absolute benzene. After the exothermic reaction had terminated, the reaction mixture was boiled for a further 20 hours, then concentrated in vacuo and the product, 4-methyl-benzoic acid methyl ester, isolated by conventional means. It could be purified by distillation, and the purified product boiled at 91°/9 mm Hg., m.p. 32°.