Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:60])[C:17](=[O:59])[C:18]2[CH:58]=[CH:57][CH:56]=[C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:26][C:25]=3[C:36]3[CH:41]=[C:40]([C:42](=[O:55])[NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=4)[CH:39]=[CH:38][N:37]=3)=[O:22])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:61]OC(NC)C>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:61])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:60])[C:17](=[O:59])[C:18]2[CH:58]=[CH:57][CH:56]=[C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:26][C:25]=3[C:36]3[CH:41]=[C:40]([C:42](=[O:55])[NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:52])([F:53])[F:54])[CH:46]=4)[CH:39]=[CH:38][N:37]=3)=[O:22])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CNC(C)OC
Reactant: COCCNC(=O)N1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Product: COCCN(C)C(=O)N1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared according to the procedure described for the synthesis of N1-(2-(4-((2-methoxyethyl)carbamoyl)piperazin-1-yl)ethyl)-N3-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N1-methylisophthalamide Example 207 substituting methoxy-N-methylethanamine in place of 2-methoxyethanamine. LC-MS (ES, m/z): 843 [M+H]+ H-NMR (300 MHz, CD3OD, ppm): 8.99 (d, J=5.1 Hz, 1H), 8.77 (d, J=9.0 Hz, 1H), 8.46 (s, 1H), 8.19 (m, 3H), 7.90 (m, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.74˜7.67 (m, 4H), 7.62˜7.53 (m, 2H), 4.72 (s, 2H), 4.00 (s, 2H), 3.90˜3.65 (m, 9H), 3.57 (d, J=5.1 Hz, 1H), 3.47 (d, J=4.8 Hz, 1H), 3.34 (s, 3H), 3.12 (s, 3H), 2.97 (s, 3H), 2.04 (d, J=4.8 Hz, 4H), 1.83 (d, J=4.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12](O)=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:27])[CH3:26].[CH:28]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:30][CH2:29]1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:34][S:31]([CH:28]3[CH2:30][CH2:29]3)(=[O:33])=[O:32])=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:27])[CH3:26]
Reactant: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)NS(=O)(=O)C3CC3)cc(Cl)cc21
Yield: 20.1 %

Procedure:
A mixture of 6-chloro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (200 mg, 0.52 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (140 mg, 0.78 mmol), 4-dimethylaminopyridine (95 mg, 0.78 mmol), cyclopropane sulfonic acid amide (190 mg, 1.56 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [6-chloro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (51 mg, 20%) as a light yellow solid: MS (ESI) M+1=488.2.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH:5]1[CH2:10][CH2:9][O:8][CH:7]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:24][O:23][C:22]4[CH:25]=[C:26]5[C:30](=[CH:31][C:21]3=4)[CH2:29][CH2:28][O:27]5)[C:13]2=[O:32])[CH2:6]1.[Na]>ClC(Cl)C>[CH3:1][CH:2]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:24][O:23][C:22]4[CH:25]=[C:26]5[C:30](=[CH:31][C:21]3=4)[CH2:29][CH2:28][O:27]5)[C:13]2=[O:32])[CH2:6]1)[CH3:4]
Reactant: CC(C)=O
Reactant: O=C1N(CC2CNCCO2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: [Na]
Solvent: CC(Cl)Cl
Product: CC(C)N1CCOC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
To a solution of acetone (0.04 mL, 0.53 mmol) in dichloroethane (5 mL) was added 1′-(morpholin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.04 g, 0.11 mmol) and sodium triacetoxyhydroborate (0.11 g, 0.53 mmol), then the mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated to dryness, and the residue was purified by flash chromatography with ethyl acetate/methanol/ammonium hydroxide (15/1/0.1) to afford 1′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.02 g, 54%) as a colorless foam; 1H NMR (300 MHz, CDCl3) δ7.38-7.25 (m, 1H), 7.18-7.04 (m, 3H), 6.50 (s, 0.5H), 6.44 (s, 0.5H), 6.41 (s, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.7 Hz, 2H), 4.00-3.55 (m, 5H), 2.97 (t, J=8.7 Hz, 2H), 2.85-2.55 (m, 3H), 2.37-2.03 (m, 2H), 1.05-0.98 (m, 6H); MS (ES+) m/z 421.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([NH:30][C:31](=[O:33])[CH3:32])([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=2)[CH:12]1O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(OCC)C>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4](=[O:34])[C:5]([NH:30][C:31](=[O:33])[CH3:32])([C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=2)[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)=C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
2-Acetylamino-2-(6-octyl-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-malonic acid diethyl ester (compound A, 755 mg, 1.58 mmol)) is dissolved in acetic anhydride (5 mL) followed at 0° C. by a catalytic amount of ferric chloride (66 mg, 0.4 mmol). The reaction is stirred at 0° C. for an additional 2 hours, and 20 mL of diethyl ether is added. The reaction is carefully poured into 50 mL of ice cold water and the organic layer quickly separated. The organic layer is re-extracted with methylene chloride (2×20 mL) and the combined organic layers were washed once with brine (20 mL) and dried over magnesium sulfate. The organic layer is concentrated under vacuum and the residue is purified by column chromatography (silica gel, 10% ethyl acetate in hexanes) to provide 458 mg of compound B (60%). The complete synthesis is illustrated in FIG. 4.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].ClCC1([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[CH3:23])OCC(C)(C)CO1.[OH-].[Na+]>C(O)CO.O>[CH3:23][C:17]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[CH2:2][C:1]([OH:4])=[O:3]
Reactant: Cc1ccc(C)c(C2(CCl)OCC(C)(C)CO2)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1ccc(C)c(CC(=O)O)c1
Temperature: 182.5 °C
Yield: 94.4 %

Procedure:
A mixture of 4.1 g [0.05 mol] of sodium acetate and 10.75 g [0.04 mol] of 2-chloromethyl-5,5-dimethyl-2-(2,5-dimethylphenyl)-[1,3]dioxane in 50 ml of ethylene glycol is heated at 180 to 185° C. for 5 hours. It is then allowed to cool to 90 to 95° C., 20 ml of 30% strength sodium hydroxide solution are added, and the mixture is heated at 100 to 105° C. for 1 hour. The reaction mixture is diluted with 80 ml of water at room temperature and extracted twice with 10 ml of methylene chloride each time. The aqueous phase is then adjusted to pH 1 with conc. hydrochloric acid, and the solid is filtered off with suction, washed twice with 20 ml of water each time and dried. 6.20 g of white solid are obtained with a purity of 99.3% (GC). The yield is thus 93.7% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:18])[O:19][CH2:20][CH3:21])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Cl
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Using a method analogous to that disclosed in Example 1, Step A, of U.S. Pat. No. 4,552,585, a solution of 10.0 grams (0.071 mole) of 3-chloro-4-methylaniline in 100 mL of chloroform was stirred, and 16.7 grams (0.212 mole) of pyridine was added. Ethyl chloroformate, 9.2 grams (0.085 mole), was then added dropwise during a 20 minute period. During the addition the reaction mixture temperature was held between 25°-30° C. with external cooling. Upon completion of addition the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was washed into a separatory funnel with 50 mL of chloroform, and the solution was washed with two 100 mL portions of water and 100 mL of aqueous 5% hydrochloric acid. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a waxy solid residue. The residue was recrystallized from hexane to yield 12.2 grams of ethyl (3-chloro-4-methylphenyl)carbamate; m.p. 51°-52° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([F:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:14]1(C(N2C=CN=C2)N)C=CN=[CH:15]1>C1COCC1>[NH2:14][C:15]1[O:12][C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:8]([F:13])=[CH:9][CH:10]=2)[N:1]=1
Reactant: COC(=O)c1c(F)ccc(O)c1N
Reactant: NC(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)c1c(F)ccc2oc(N)nc12
Temperature: 25 °C

Procedure:
To a solution of methyl 2-amino-6-fluoro-3-hydroxybenzoate (0.4 g, 2.2 mmol) in THF (10 mL) was added di-(1H-imidazole-1-yl)methanamine (0.44 g, 2.75 mmol) at room temperature and the resulting reaction mixture was heated at reflux for 16 h. The reaction mixture cooled to room temperature and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL), and the solution was treated with saturated aqueous ammonium chloride (25 mL). The organic layer was separated and the aqueous layer was extracted with additional CH2Cl2 (2×100 mL). The combined organic phase was washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford a yellow solid. The solid was triturated from ether to afford methyl 2-amino-5-fluorobenzoxazole-4-carboxylate. MS consistent.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[CH:10]([CH:24]3[O:28][CH2:27][CH2:26][O:25]3)[CH2:9][CH2:8][C@@:7]4([OH:29])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.N1C=CN=C1.[C:35]([Si:39]([CH3:42])([CH3:41])Cl)([CH3:38])([CH3:37])[CH3:36].O>CN(C=O)C>[Si:39]([O:20][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][C@H:6]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:23][CH2:22][C@:12]45[C:13]=2[C:14]=1[O:21][C@H:11]4[CH:10]([CH:24]1[O:25][CH2:26][CH2:27][O:28]1)[CH2:9][CH2:8][C@@:7]35[OH:29])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reaction time: 0.67 h
Yield: 80 %

Procedure:
17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxy-6-(1,3-dioxolan-2-yl)morphinan (3.85 g, 10 mmol) was dissolved in 10 ml of DMF, then imidazole (0.68 g, 10 mmol) and tert-butyl dimethyl chlorosilane (1.5 g, 10 mmol) were added with stirring. The whole system was reacted at a temperature ranging from 20° C. to 25° C. for 40 min. After the reaction was complete, water was added to the system and the resultant mixture was extracted with diethyl ether for 3 times. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated for crystallization to afford a white solid of 4.0 g. Yield: 80%. Melting point: 107.7-109.3° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10](I)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([S:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH3:11]
Reactant: CCI
Reactant: Fc1ccc(S)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1ccc(F)c(F)c1
Reaction time: 2 h

Procedure:
A solution of 3,4-difluorothiophenol (3 g), ethyl iodide (1.6 ml), potassium carbonate (2.64 g) and DMF (40 ml) were charged to a flask and stirred for 2 h. The solution was partitioned between ethyl acetate and water. The organic extracts were dried (MgSO4) and evaporated under reduced pressure to give the subtitle compound (3.84 g).
Reaction SMILES: [C:1]1([S:7]([C:10]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)=[C:11](Cl)Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][NH2:24]>O1CCCC1>[C:1]1([S:7]([C:10]2[N:14]=[C:15]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[O:22][C:11]=2[CH2:23][NH2:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: O=C(NC(=C(Cl)Cl)S(=O)(=O)c1ccccc1)c1cccnc1
Solvent: C1CCOC1
Product: NCc1oc(-c2cccnc2)nc1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(1-Phenylsulfonyl-2,2-dichlorovinyl)nicotinamide (0.4 g, 1.120 mmol) is dissolved in tetrahydrofuran, mixed with methylamine (2.607 ml, 2M in tetrahydrofuran, 4.480 mmol) and stirred overnight at room temperature. The resulting precipitate was filtered off with suction and discarded, the mother liquor was concentrated in a rotary evaporator and the residue was crystallized using a small amount of isopropanol, filtered off with suction and dried in air.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>O1CCCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:19]2[CH:18]=[CH:17][C:16]([S:13]([NH:12][C:6]3([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]3)(=[O:14])=[O:15])=[CH:21][CH:20]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 99.4 %

Procedure:
A solution of 4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid ethyl ester (12.1 grams, 0.0286 mole) in tetrahydrofuran (190 mL) was treated with aqueous 3 M sodium hydroxide solution (95 mL, 0.286 mole) and stirred at room temperature for 4 days. The solvent was evaporated under vacuum and the residue partitioned between water and diethyl ether. The aqueous layer was washed with diethyl ether, acidified to pH 1 with 3N aqueous hydrochloric acid solution and extracted with dichloromethane. After washing with water, the organic extract was dried over sodium sulfate, and concentrated to give 4-[4-(4-fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic acid (11.241 grams, 99%) as a yellowish solid foam.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[N:19]=[N:18][C:17](=[O:20])[CH2:16][CH:15]3[CH3:21])=[CH:10][CH:9]=2)[CH:4]=1)=[O:2].[BH4-].[Na+].C(Cl)Cl.CO.O>C(O)C.CN(C)C=O>[OH:2][CH2:1][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:12][CH:13]=2)[CH:4]=1
Reactant: CC1CC(=O)N=NC1c1ccc(-n2ccc(C=O)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(CO)c2)cc1
Yield: 58.8 %

Procedure:
4.2 g (15 millimoles) of 6-[p-(3-formylpyrrol-1-yl)-phenyl]-5, 6-dihydro-5-methylpyridazin-3-one (Example 1A) were dissolved in 50 ml of ethanol and 20 ml of dimethylformamide (DMF), and 1.15 g (30 millimoles) of sodium borohydride were added. The mixture was stirred for 6 hours at 60° C. (conversion monitored by thin layer chromatography using SiO2 and 9:1 CH2Cl2 /CH3OH), after which 50 ml of water were added, the mixture was extracted with ethyl acetate, the ethyl acetate phase was dried and the solvent was stripped off in a rotary evaporator to give a yellow crystalline solid. Recrystallization from DMF/H2O gave 2.5 g of 6-[p-(3-hydroxymethyl-pyrrol-1-yl)-phenyl]-4, 5-dihydro-5-methylpyridazinone of melting point 184°-186° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 3-hydroxy-2,2-dimethylpropanoate (600. mg, 4.54 mmol) in DMF (9.0 mL), cooled to 0° C., was added NaH (120. mg, 4.99 mmol). After warming to ambient temperature for 30 minutes, the reaction was cooled to 0° C., prior to the introduction of benzyl bromide (854 mg, 4.99 mmol). After warming to ambient temperature, the reaction was heated to 50° C. for 4 hours, before being allowed to return to ambient temperature. The bulk of the DMF was removed in vacuo, and the residue was diluted with water and EtOAc. The organic layer was washed several times with water and then once with saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated in vacuo, to yield a residue which was applied to a silica gel column for purification, eluting with 100% DCM. The resulting impure material was applied again to silica gel and eluted with a gradient of CH2Cl2:hexanes—85:15 to 100:0. Clean product-containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=223 (M+1).
Reaction SMILES: O1CCCC1.B.[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17](O)[C:18]2[C:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[C:20]3[C:28](=[CH:29][C:30]=2[CH:31]([CH3:33])[CH3:32])[O:27][C:23]2([CH2:26][CH2:25][CH2:24]2)[CH2:22][C:21]3=[O:34])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.CO>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]2[C:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[C:20]3[C:28](=[CH:29][C:30]=2[CH:31]([CH3:33])[CH3:32])[O:27][C:23]2([CH2:26][CH2:25][CH2:24]2)[CH2:22][C@@H:21]3[OH:34])=[CH:15][CH:16]=1)([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Agent: B
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1Cc1ccc(C(C)(C)C)cc1)[C@@H](O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
Under argon, 1.4 mg (0.009 mmol) of (1R,2S)-1-aminoindan-2-ol are dissolved in 2 ml of abs. tetrahydrofuran, 66 μl (0.37 mmol) of borane/,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 45 mg (0.092 mmol) of 6-[(4-tert-butylphenyl)(fluoro)methyl]-5-(4-fluorophenyl)-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 55A), dissolved in 2 ml of abs. tetrahydrofuran, are added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature for 15 h. 2 ml of methanol are added and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product is purified by thick-layer chromatography (mobile phase: cyclohexane/ethyl acetate 10:1). This gives 33.5 mg (77% of theory, 80% ee) of the title compound. Chromatographic separation of 60 mg of Example 36 on a chiral phase [column: Chiralpak AD-H, 250×20 mm; mobile phase: isopropanol/isohexane 3:97; flow rate: 15 ml/min; 24° C.; detection: 260 nm] gives 45 mg of the title compound having an ee of >99%.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:22]([CH3:24])[CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH:22]([CH3:24])[CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COc1ccc(-n2cc(C(O)C3CCCCC3)c(C(C)C)n2)cc1
Product: COc1ccc(-n2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C(C)C)n2)cc1
Yield: 24.7 %

Procedure:
Using cyclohexyl[1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]methanol (0.70 g) synthesized in Example 52(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.55 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.28 g, 24%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@:9]1([CH3:17])[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][O:52][C@@H:53]([C@@H:71]1[CH2:75][CH2:74][CH2:73][N:72]1[C:76](=[O:95])[CH2:77][C@@H:78]([O:93][CH3:94])[C@@H:79]([N:84]([CH3:92])[C:85](=[O:91])[C@H:86]([CH:88]([CH3:90])[CH3:89])[NH2:87])[C@@H:80]([CH3:83])[CH2:81][CH3:82])[C@@H:54]([CH3:70])[C:55]([NH:57][C@H:58]([C:66]([O:68][CH3:69])=[O:67])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:56]>ClCCl.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@:9]1([C:14]([NH:87][C@H:86]([C:85]([N:84]([CH3:92])[C@@H:79]([C@@H:80]([CH3:83])[CH2:81][CH3:82])[C@H:78]([O:93][CH3:94])[CH2:77][C:76]([N:72]1[CH2:73][CH2:74][CH2:75][C@H:71]1[C@H:53]([O:52][CH3:51])[C@@H:54]([CH3:70])[C:55]([NH:57][C@H:58]([C:66]([O:68][CH3:69])=[O:67])[CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)=[O:56])=[O:95])=[O:91])[CH:88]([CH3:89])[CH3:90])=[O:16])[CH3:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@]1(C)C(=O)O
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](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
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](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
To a solution of #157 (109 mg, 0.448 mmol, 1 eq.) in dichloromethane (3 mL) and N,N-dimethylformamide (0.5 mL), was added diisopropylethylamine (0.234 mL, 1.34 mmol, 3 eq.) followed by HATU (205 mg, 0.538 mmol, 1.2 eq.). The reaction stirred for 15 minutes and #114 (284 mg, 0.448 mmol, 1 eq.) was added. After stirring at room temperature for 2 hours, the mixture was diluted with dichloromethane (10 mL), washed with 10% citric acid (3×5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (Gradient: 0 to 100% acetone in heptane) afforded #161 (185 mg, 48%). LC-MS (Protocol Q): m/z 858.3 [M+H+], retention time=2.25 minutes.