Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH:20]([CH3:25])[CH2:19]1.Cl>C1COCC1>[CH:9]([O:8][C:4]1[CH:3]=[C:2]([C:20]2([CH3:25])[CH:21]([OH:24])[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19]2)[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1cccc(Br)c1
Reactant: CC1CN(C)CCC1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(C2(C)CN(C)CCC2O)c1
Temperature: -70 °C
Reaction time: 2 h
Yield: 662.3 %

Procedure:
The 3-bromo-i-propoxybenzene (200 g, 0.08703 mol) was combined with THF (540 ml) under nitrogen and cooled to about -75° C. n-Butyl lithium (565 ml, 0.8306 mol) was added dropwise while maintaining the mixture at less than -70° C. After 2 hours 1,3-Dimethyl-4-piperidone (106.7 g, 0.8389 mol) was added while maintaining the temperature of the mixture between -80° C. and -70° C. After stirring 2 hours at -70° C., the reaction mixture was then added to 6N HCl (280 ml) while maintaining the temperature at 20°-25° C. The pH was adjusted to 1 with 12N HCl. The aqueous layer containing product was separated and heptane (320 ml) was added along with 50% NaOH (48 ml, pH=13-14) and the resulting mixture allowed to stand overnight. The mixture was heated to 45°- 50° C. and the upper layer was separated. The remaining aqueous layer was extracted with heptane (320 ml) at 45°-50° C. The combined organic fractions were washed with de-ionized water (120 ml) at 45°-50° C. The resulting organic layer was vacuum distilled at a pot temperature of about 55° C. at 100 mmHg. Crystallization from heptane and drying provided 151.8 g of 3-(3-i-propoxyphenyl)-1,3-dimethyl-4-hydroxypiperidine. Melting point 75.0°-76.0° C.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH2:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>CCCCCC>[CH3:16][Si:17]([CH3:19])([CH3:18])[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]([Si:17]([CH3:19])([CH3:18])[CH3:16])=[C:7]1[CH3:6]
Reactant: CC1=Cc2ccccc2C1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC1=C([Si](C)(C)C)c2ccccc2C1[Si](C)(C)C
Reaction time: 10 h
Yield: 85 %

Procedure:
500 ml of hexane and 70 ml of butyllithium (as a 2.5 molar solution in hexane) were introduced into a 1000 ml flask. 0.175 mol of 2-methylindene was added dropwise at the ambient temperature; the mixture was stirred for a further 10 hours. 0.18 mol of trimethylsilyl chloride was then added dropwise at room temperature; the mixture was stirred for a further 10 hours. LiCl was filtered off and 70 ml of butyllithium (as a 2.5 molar solution in hexane) were added to the clear filtrate. After further stirring for 10 hours, 0.18 mol of trimethylsilyl chloride was again added and the mixture was stirred for a further 10 hours. LiCl was filtered off and the solvent was removed in vacuo. Compound 54 remained as a colorless oil. Yield: 85% of the theoretical yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])[CH:5]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In DMF (12.5 ml), 3-bromomethyl benzoic acid methyl ester (831 mg) was dissolved. The solution was added with dipropylamine (971 μl) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, thereby obtaining the subject compound (858 mg) as a brown solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])[NH2:4].[F:14][CH:15]([F:21])[C:16](OCC)=O>>[F:14][CH:15]([F:21])[C:16]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[N:7][CH:8]=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])[N:4]=1
Reactant: CCOC(=O)C(F)F
Reactant: NC(=NO)c1cncc(C(=O)O)c1
Product: O=C(O)c1cncc(-c2noc(C(F)F)n2)c1
Yield: 30 %

Procedure:
This compound was synthesized from 5-(N′-hydroxycarbamimidoyl)nicotinic acid using ethyl difluoroacetate as described in example 1 step 5 (100 mg, yield 30%). 1H NMR (400 MHz, DMSO-d6) δ 13.94 (br s, 1H), 9.40 (d, J=2.1 Hz, 1H), 9.28 (d, J=2.1 Hz, 1H), 8.76-8.75 (t, J=2.1 Hz, 1H), 7.73-7.47 (m, 1H). MS (ESI) m/z: Calculated for C9H6F2N3O3: 241.03. found: 241.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:35])[NH:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:16])([F:15])[F:17])[CH:12]=[N:23][C:24]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:35])[NH:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1cc(F)cc2[nH]c(=O)ccc12
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cc(F)cc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(Cl)c1OC

Procedure:
In the same way as in Example 148, 173 mg (0.51 mmol) of (2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 90 mg (0.51 mmol) of 5-amino-7-fluoroquinolin-2(1H)-one and 0.32 ml of titanium tert-butoxide are reacted to give 5-{[(2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}-7-fluoroquinolin-2(1H)-one. 270 mg of crude imine are cyclized in the same way as in Example 148 at −30° C. with 7.6 ml (7.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-70%) yields 26 mg of desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:32]4[C:28](=[N:29][N:30]([CH3:33])[N:31]=4)[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:32]4[C:28](=[N:29][N:30]([CH3:33])[N:31]=4)[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1nc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3nn(C)nc23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(4-fluorophenyl)-4-(((2-methyl-6-(trifluoromethyl)-2H-benzo[d][1,2,3]triazol-4-yl)methoxy)methyl)piperidine-1-carboxylate (22 mg, 0.042 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1 mL) and stirred at room temperature for 30 min. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2M ammonia and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (5.3 mg, 0.084 mmol) and formalin (75 μl). After 5 min, the reaction was treated with 1 drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was diluted with ether and washed with 1M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia and concentrated to 13 mg (71%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 8.05 (s, 1H), 7.32 (m, 2H), 7.30 (s, 1H), 6.99 (m, 2H), 4.80 (s, 2H), 4.51 (s, 3H), 3.53 (s, 2H), 2.57 (m, 2H), 2.21 (m, 7H), 2.00 (m, 2H). Mass spec.: 437.08 (MH)+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:13](=[O:14])[N:6]12)=[O:4].O.[Li+].[OH-]>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[C:13](=[O:14])[N:6]3[CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH2:8][N:7]3[C:11]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:23]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)C1CCCn2c(-c3ccnc(Oc4ccccc4)n3)c(-c3ccc(F)cc3)c(=O)n21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCCn2c(-c3ccnc(Oc4ccccc4)n3)c(-c3ccc(F)cc3)c(=O)n21
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-(2-phenoxy-pyrimidin-4-yl)-3-oxo-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester, 22, (0.02 g, 0.0143 mmol) in methanol (1 mL) and water (1 mL) is added LiOH (0.016 g, 0.65 mmol). The reaction solution is stirred at room temperature for 3 hours then quenched by the addition of 1 N HCl (20 mL). The reaction solution is extracted with ethyl acetate (3×50 mL), the organic layers are combined, washed with brine, dried, and concentrated in vacuo to afford 0.012 g (63% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.45 (dd, J=4.6, 2.1 Hz, 1 H), 7.14-7.44 (m, 7 H), 6.84-6.95 (m, 3 H), 4.93 (dd, J=11.7, 9.3 Hz, 1 H), 4.23 (br d, J=12.9 Hz, 1 H), 3.04-3.11 (m, 1H), 2.46-2.52 (m, 2 H), 1.71-1.93 (m, 2 H), APCI/MS: 447 (M+H).
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1>CC#N>[CH3:6][C@H:3]([CH2:2][O:27][C:24]1[CH:23]=[CH:22][C:21]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]2)=[CH:26][CH:25]=1)[CH2:4][OH:5]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: C[C@@H](CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](CO)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 72 °C
Yield: 64.7 %

Procedure:
(S)-3-Bromo-2-methylpropan-1-ol (6.2 g, 40 mmol) was dissolved in dry CH3CN (100 mL) and dry, pulverized K2CO3 (10.4 g, 75 mmol) was introduced followed by 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (11.0 g, 50 mmol). The reaction mixture was heated at 72° C. for 20 h, cooled and filtered. The filtrate was evaporated to an oil, which was applied to a column of silica gel. Elution initially with hexanes, gradually increasing polarity to a mixture of hexanes/ethyl acetate (3:2) as eluent, provided the title compound (7.56 g, 64%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:23]([CH2:35]C)[CH:22]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[BH4-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([CH2:19][CH3:20])([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]([OH:34])[C:30]([CH3:32])([CH3:31])[CH3:33])=[C:23]([CH3:35])[CH:22]=3)[CH2:17][CH3:18])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(CC)c3)cc(C)c2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC(O)C(C)(C)C)c(C)c3)cc(C)c2o1
Yield: 68.1 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-ethyl-phenyl]-1-ethyl-propyl}-7-methyl-benzofuran-2-carboxylic acid ethyl ester (1.87 g, 3.91 mmol) in THF (50 mL) is reacted with NaBH4 (0.45 g, 11.7 mmol) analogous to Example 22 to obtain the title compound (1.28 g, 68%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:15][C:16](=[O:27])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:26])[CH:20]=1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:25][C:22]3[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][C:16]([OH:27])=[O:15])=[CH:20][C:21]=3[F:26])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)CCc1ccc(O)c(F)c1
Reactant: ClCc1cccnc1SC1CCC1
Product: O=C(O)CCc1ccc(OCc2cccnc2SC2CCC2)c(F)c1
Yield: 81 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 23 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.041 g, 82%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19](Cl)=[O:20]>>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19]([O:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:20]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: OCCn1ccnc1
Product: O=C(OCCn1ccnc1)c1ccc2ccccc2c1
Yield: 81 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 2-(1H-imidazol-1-yl)ethanol was used instead of the triethanolamine, and 2-naphthoyl chloride was used instead of the benzoyl chloride, to give 2-(1H-imidazol-1-yl)ethyl 2-naphthalenecarboxylate in a yield of 81%.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]2[N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[NH2:16][CH2:17][C@@:18]([CH3:23])([CH:20]1[CH2:22][CH2:21]1)[OH:19]>>[CH:20]1([C@:18]([OH:19])([CH3:23])[CH2:17][NH:16][C:12]([C:8]2[CH:7]=[CH:6][C:5]3[CH2:4][CH2:3][C:2]([CH3:1])([CH3:15])[CH2:11][C:10]=3[N:9]=2)=[O:14])[CH2:22][CH2:21]1
Reactant: C[C@](O)(CN)C1CC1
Reactant: CC1(C)CCc2ccc(C(=O)O)nc2C1
Product: CC1(C)CCc2ccc(C(=O)NC[C@](C)(O)C3CC3)nc2C1

Procedure:
The title compound was synthesized in analogy to Example 1, using 7,7-dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid and (αR)-α-(aminomethyl)-α-methyl-cyclo-propanemethanol (CAN 912454-48-9) as starting materials, LC-MS (UV peak area/EIC) 99.3%, 303.2078 (M+H)+.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].O>CN(C)C=O>[C:13]([C:12]1[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=1[N:10]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=1)(=[O:9])=[O:8])(=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a stirred solution of 5.0 g of compound H in 10 cc of dimethylformamide was added 0.56 g of 63% sodium hydride in 5 cc of dimethylformamide under ice-cooling and the mixture was stirred for 30 minutes. Then, 2.3 cc of t-butyl bromoacetate was added dropwise at the same temperature and stirring was continued for 16 hours. Water was added to the reaction mixture and the desired compound was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was washed with hexane to obtain 6.31 g of compound I. Yield: 95.4%.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH:15]([OH:18])([CH3:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:18][CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)O
Reactant: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)OC(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 2.7 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in benzene and 1 ml of isopropanol were reacted to obtain 1.7 g of isopropyl (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+84° (c=1.25% in chloroform).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH2:3]1>[Cl-].[NH4+].C(O)C.[Fe]>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:4]1[CH2:3][C:2]([CH3:1])([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5]1
Reactant: CC1(C)CC(c2ccccc2[N+](=O)[O-])Nc2ccc(C#N)cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC1(C)CC(c2ccccc2N)Nc2ccc(C#N)cc21
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To a suspension of 4,4-dimethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile (2 g, 6.54 mmol) in saturated aqueous ammonium chloride and ethanol was added iron powder at room temperature. After addition, the resulting mixture was stirred at reflux under nitrogen for 3 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The solvent of ethanol in filtrate was removed under reduced pressure and the water phase was extracted with ethyl acetate. The combined organic phase was dried, concentrated to give 2-(2-aminophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile as white solid (1 g, yield 56%). The product was used for the next step without further purification. LC/MS m/e obsd. (ESI+) [(M+H)+] 228.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[C:4]([O:25][CH3:26])[N:3]=1.[O:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1>>[O:27]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[CH:13]=[C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]5)[CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[C:4]([O:25][CH3:26])[N:3]=2)=[CH:28]1
Reactant: OB(O)c1ccoc1
Reactant: COc1cc(-c2cnc3ccc(NC4CCCC(O)C4)cn23)cc(Cl)n1
Product: COc1cc(-c2cnc3ccc(NC4CCCC(O)C4)cn23)cc(-c2ccoc2)n1

Procedure:
The title compound is prepared from (1SR,3SR)-3-[3-(2-Chloro-6-methoxy-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Intermediate O) and 3-furyl boronic acid using a procedure analogous to that described in Example 2.3.
Reaction SMILES: [CH:1]1(/[CH:8]=[C:9](\[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)/[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:28]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:28][C:15]1[S:14][C:13]([NH:12][C:10](=[O:11])/[C:9](/[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:8]/[CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2nccs2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2ncc(Br)s2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
A suspension of (E)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-acrylamide (prepared in Example 5, 202 mg, 0.5 mmol) and N-bromosuccinimide (89 mg, 0.5 mmol) in carbon tetrachloride (2 mL) at 25° C. was treated with benzoyl peroxide (6 mg, 0.025 mmol). The resulting reaction mixture was heated to 90° C. where it was stirred overnight at this temperature. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (25 mL). The organic phase was then washed with water (1×30 mL) and a saturated aqueous sodium chloride solution (1×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded the (E)-N-(5-bromo-thiazol-2-yl)-3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-acrylamide (86 mg, 36%) as a white solid: mp 159-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH:11]([Mg]Cl)([CH3:13])[CH3:12].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]([OH:8])[CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(C(O)C(C)C)cc1
Reaction time: 1 h

Procedure:
A solution of 1.5 ml 4-methoxy-benzaldehyde in 10 ml of toluene is added dropwise at 8° C. to 7.4 ml of a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran. Then the mixture is allowed to come up to ambient temperature and stirred for 1 hour. Then the reaction is stopped by the addition of semisaturated aqueous ammonium chloride solution. The phases are separated and the aqueous phase is extracted with toluene. The combined organic phases are washed with semisaturated aqueous ammonium chloride solution and dried on magnesium sulphate. The solvents are eliminated in vacuo and the product thus obtained is further reacted directly.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH3:16][NH:17][CH3:18]>O1CCCC1>[CH3:1][C:2]1[C:3]([S:12]([N:17]([CH3:18])[CH3:16])(=[O:14])=[O:13])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1C
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 33.5 g of the product from Example 9 in 300 ml tetrahydrofuran was cooled to 5°-10° and treated with dimethylamine. The resulting suspension was stirred at room temperature for one hour, filtered, and the filtrate concentrated in vacuo to afford a pale yellow solid. Recrystallization from n-butyl chloride gave 26.7 g of the title compound as a white solid, m.p. 40°-43°; NMR (CDCl3): δ 2.75 (3H, s, CH3), 2.8 (6H, s, SO2N(CH3)2), 3.85 (3H, s, CO2CH3), 7.25-7.55 (1H, m), 7.85-8.25 (2H, m).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34](=[O:36])[CH3:35])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:42]>Cl.O1CCOCC1>[ClH:42].[ClH:42].[CH2:37]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:23]([C:34](=[O:36])[CH3:35])[CH:22]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(C)=O)c1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(C(C)=O)c1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-[5-(3-acetyl-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.17 mmol) in DCM (2.0 mL), 4.0 M HCl in dioxane (2.0 mL) was added and stirring continued for 30 min. Solvent evaporated, resulting solid was washed with ether, dried to provide 1-{5-[3-butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}ethanone dihydrochloride salt (60 mg).