Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](O)=[O:9])[N:2]=1.Cl.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:9][CH2:8][CH2:7][C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1cccnn1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCc1cccnn1

Procedure:
3-Pyridazineacetic acid is esterified with anhydrous ethanolic hydrogen chloride and the resulting ethyl ester is reduced with lithium aluminium hydride in tetrahydrofuran to give 3-(2-hydroxyethyl)pyridazine. Treating this hydroxyethyl compound with thionyl chloride gives 3-(2-chloroethyl)pyridazine.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:18][C@H:17]2[NH:19][CH2:20][C@@H:12]1[CH2:13][CH:14]=[CH:15][CH2:16]2.[S:21]1[CH:25]=[C:24]([C:26](=[O:30])[CH2:27][CH2:28][Cl:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]1=2.CCN(C(C)C)C(C)C.Cl>C(OCC)C.CN1C(=O)CCC1>[S:21]1[CH:25]=[C:24]([C:26](=[O:30])[CH2:27][CH2:28][N:19]2[CH2:20][CH:12]3[N:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH2:18][CH:17]2[CH2:16][CH:15]=[CH:14][CH2:13]3)[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]1=2.[ClH:29]
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Reactant: O=C(CCCl)c1csc2ccccc12
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=C(CCN1CC2CC=CCC1CN2c1ccc2ccccc2c1)c1csc2ccccc12
Temperature: 160 °C

Procedure:
Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (50 mg, 0.189 mmol), 1-benzo[b]thiophen-3-yl-3-chloro-propan-1-one (50 mg, 0.22 mmol) and DiPEA (0.1 mL, 0.57 mmol) were placed in a μW tube with NMP (2 ml), and heated to 160° C. for 900 sec. The solvent was evaporated to yield a crude oil, which was purified via reverse phase chromatography (20% CH3CN to 90% CH3CN in water) to yield a residue which was then treated with 1N HCl in diethyl ether. The solvent was then evaporated under reduced pressure to yield the title compound as its corresponding HCl salt, as a residue.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:10][C:9]2([CH2:13][NH:12][CH2:11]2)[CH2:8]1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][N:23]=[C:24]=[O:25]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][C:24]([N:12]1[CH2:13][C:9]2([CH2:10][N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8]2)[CH2:11]1)=[O:25]
Reactant: c1cnc(N2CC3(CNC3)C2)nc1
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2(C1)CN(c1ncccn1)C2
Yield: 62 %

Procedure:
In analogy to the experimental procedure of example 1a) 2-Pyrimidin-2-yl-2,6-diaza-spiro[3.3]heptane instead of 6-(tert-butoxycarbonyl)-2,6-diaza-spiro[3.3]heptane oxalate was converted using 2,4-dichloro-1-(isocyanatomethyl)benzene into the title compound (32 mg, 62%) which was obtained as a colorless solid. MS (EI) m/e: 378.1 (M+H)+.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=O)[O:2]1.C1C[O:15][CH2:14][CH2:13]1>C(OCC)C.O.[Zn+2].[Br-].[Br-].[Cl-].[Cl-].[Zn+2]>[CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:5]=[CH:13][CH:14]=[O:15])[CH:7]=[CH:8][CH:9]=2)[O:2]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: C1CCOC1
Agent: [Br-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: O
Product: O=CC=Cc1cccc2c1OCO2
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-methylenedioxybenzaldehyde (150 mg) in 5 mL THF was added 22 mg of ZnBr2. With stirring, 250 mg of α,α-bis(trimethylsilyl)-t-butylacetaldimine (7) was added, and stirring was continued overnight. The solution was cooled to 10° C., then hydrolyzed by the addition of a solution of ZnCl2 (22 mg) in diethyl ether/water (5 mL each), followed by stirring at room temperature for 1 h. The solids were removed by filtration through Celite and the filtrate extracted with diethyl ether (2×). The combined ether extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound as a brown oil (150 mg): 1H NMR (CDCl3) δ 6.09 (s, 2H), 6.14 (s, 1H), 6.86-6.98 (m, 4H), 7.43 (d, 1H, J=9.6 Hz), 9.69 (d, 1H, J=4.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:10][CH2:11][CH2:12][Cl:13])[CH:3]=1
Reactant: ClCCCBr
Reactant: Oc1cccc(Br)c1
Product: ClCCCOc1cccc(Br)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-bromophenol and 1-bromo-3-chloropropane.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:39]=[CH:38][C:14]([C:15]([N:17]3[CH2:22][CH2:21][C:20](=[C:23]4[C:32]5[CH:31]=[CH:30][S:29][C:28]=5[C:27](=[O:33])[CH2:26][C:25]5[CH:34]=[CH:35][CH:36]=[CH:37][C:24]4=5)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:12]=2)[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[BH4-].[Na+]>CO>[OH:33][CH:27]1[C:28]2[S:29][CH:30]=[CH:31][C:32]=2[C:23](=[C:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[C:14]3[CH:13]=[CH:12][C:11]([N:3]4[C:4]5[CH:9]=[CH:8][N:7]=[CH:6][C:5]=5[N:10]=[C:2]4[CH3:1])=[CH:39][CH:38]=3)[CH2:18][CH2:19]2)[C:24]2[CH:37]=[CH:36][CH:35]=[CH:34][C:25]=2[CH2:26]1
Reactant: Cc1nc2cnccc2n1-c1ccc(C(=O)N2CCC(=C3c4ccccc4CC(=O)c4sccc43)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2cnccc2n1-c1ccc(C(=O)N2CCC(=C3c4ccccc4CC(O)c4sccc43)CC2)cc1
Yield: 34.6 %

Procedure:
A solution of 1-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)benzoyl]-4-(10-oxo-9,10-dihydro -4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)piperidine (200 mg, 0.38 mmol) (Example 8) and sodium borohydride (200 mg) in methanol (20 ml) was stirred at room temperature for 4 hours and evaporated. The residue was partitioned between dichloromethane and water and the organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was triturated with hexane to give the title compound (70 mg, 35%) as a colourless foam which was characterised as a dihydrate. Found: C,67.9; H,5.4; N,9.6. C32H28N4O2S. 2 H2O requires C,67.5; H,5.6; N,9.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[CH:5]=[C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7]2=[O:12].C(=O)([O-])[O-:27].[Na+].[Na+].OO.[OH-].[K+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([OH:27])=[C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7]2=[O:12]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCC1=CC(=O)c2c(Cl)cccc2C1=O
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCC1=C(O)C(=O)c2c(Cl)cccc2C1=O
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1.7 parts of 5-chloro-2-dodecyl-1,4-naphthoquinone, 25 parts ethanol, 0.626 parts anhydrous sodium carbonate and 6.3 parts water was contacted with 1.13 parts of 30% hydrogen peroxide at 32° C. and then refluxed for 10 minutes. The resulting mixture was then cooled to 50° C. and a solution of 1.56 parts of potassium hydroxide in 49.5 parts of ethanol was added to it. The resulting deep red mixture was then heated to 50° C. over 25 minutes and the temperature held there for 45 minutes. After cooling to 10° C. the mixture was then contacted with 251 parts of 2.72% hydrochloric acid. The resulting yellow crystals were filtered, dried and purified by column chromatography on silica gel using 1-chlorobutane as eluent. Solvent removal gave 1.4 parts of 5-chloro-2-dodecyl-3-hydroxy-1,4-naphthoquinone, m.p. 102°-104.5° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:7]=[CH:6]2)[CH3:2].[F-].[NH4+]>C1COCC1.CO>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The Indole 9 (2.2 g, 7.29 mmol) was dissolved in THF (20 mL) and a solution of ammonium fluoride (NH4F; 1.4 g, 37.8 mmol) in MeOH (20 mL) was added and stirred for 72 hours at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 2NH3PO4, dried over MgSO4, filtered and evaporated to give compound 10 as an off white solid (1.06 g; M+1-146.2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-])=O.[H][H]>C(O)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc(CCC(=O)O)c1

Procedure:
A suspension of 100 g (0.52 moles) of 3-nitrocinnamic acid in 800 ml glacial acetic acid and 100 ml of methanol was hydrogenated at 50 pounds per square inch over 2.5 g 10% palladium on carbon until four equivalents of hydrogen were absorbed. The catalyst was filtered off, the filtrates combined and the solvent was concentrated in vacuo leaving a brown glass of 3-aminobenzenepropanoic acid. To this was added 1 liter of ethanolic hydrochloric acid which was brought to reflux for five hours. The solvent was evaporated off in vacuo leaving a purple solid. Recrystallization from ethyl acetate yielded 88.0 g of ethyl 3-aminobenzenepropanoate hydrochloride, mp 132°-135° C., (74% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: Clc1nccc(-c2cccc(CNc3cccnc3)c2)n1

Procedure:
Intermediate 1 was coupled with 3-aminopyridine following procedure B. LC-MS showed the product had the expected M+H+ of 297.
Reaction SMILES: Br[CH:2]=[CH:3][CH:4]=[C:5]([CH3:10])[CH:6]=[CH:7][O:8]C.C([Li])(C)(C)C.[CH3:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]=1/[CH:25]=[CH:26]/[C:27]([CH3:29])=O.Cl>CCOCC>[CH3:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:23])([CH3:24])[C:18]=1/[CH:25]=[CH:26]/[C:27](/[CH3:29])=[CH:8]/[CH:7]=[CH:6]/[C:5](/[CH3:10])=[CH:4]/[CH:3]=[O:2]
Reactant: COC=CC(C)=CC=CBr
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
6-Bromo-3-methyl-1-methoxy-1,3,5-hexatriene (0.257 g; 1.26 mmol) is dissolved in ether (10 cc) is introduced, under an argon atmosphere, into a 25 cc round flask fitted with a thermometer and a magnetic stirrer. The flask is cooled to -70° C. tert-Butyllithium (1.2 cc, 1.8N in pentane; 2.1 mmol, i.e. 1.7 equivalent) is then added over 7 minutes while the temperature is kept below -68° C. The solution becomes slightly coloured from pale yellow to light chestnut-brown. It is stirred for 90 minutes at 70° C. β-Ionone (0.23 g; 1.196 mmol, i.e. 0.95 equivalent) dissolved in ether (3 cc) is then added. The mixture is stirred for 90 minutes at -30° C. 1N hydrochloric acid (4.5 cc) is added at -60° C. and the mixture is then stirred vigorously for 1 hour at 10° C. After phase separation, extraction with ether and evaporation of the solvent, a crude product (0.44 g) is obtained, which is purified by flash chromatography on silica, eluting with a mixture of petroleum ether and diethyl ether (98/2 by volume). Retinal (0.187 g) is obtained in this manner in 55% yield. The structure of the product is confirmed by the infrared spectrum and the proton nuclear magnetic resonance spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:3]=1[CH3:16].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:3]=1[CH2:16][Br:17]
Reactant: Cc1c(Br)cc(Br)nc1-c1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccccc1-c1nc(Br)cc(Br)c1CBr
Reaction time: 6 h

Procedure:
To a suspension of 6.3 g of 4,6-dibromo-2-(2-chlorophenyl)-3-methylpyridine (COMPOUND W-1) in 75 mL of CCl4 was added 3.7 g of N-bromosuccinimide and 420 mg of benzoyl peroxide. The mixture was heated to reflux and stirred at this temperature for 6 h, then cooled and concentrated. The residue was dissolved in 150 mL of 1:1 hexanes-Et2O and filtered through a pad of silica gel, then purified in two batches by flash chromatography on Biotage 40M columns, eluting with a gradient system of 99:1 to 97:3 hexanes-Et2O, to yield the title compound as a white solid.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2.[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:18][N:19]([CH3:24])[S:20]([N:3]([CH3:2])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2)(=[O:22])=[O:21]
Reactant: CNc1cccc2cc(-c3nccs3)[nH]c12
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of N-methyl-2-(1,3-thiazol-2-yl)-1H-indole-7-amine hydrochloride (100 mg) in pyridine (3 mL) was added dimethylsulfamoyl chloride (200 μL). The reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give. the title compound (88 mg, yield 69%) as yellow crystals. melting point 123° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([N:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[C:11]1=O)([CH3:9])[CH3:8].O>O1CCCC1>[CH:7]([N:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)([CH3:9])[CH3:8]
Reactant: CC(C)N1CC(C)(C)NC(C)(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CC(C)(C)NC(C)(C)C1

Procedure:
3.9 g (0.103 mol) of lithiumaluminium hydride are introduced into 100 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere, while stirring and cooling. A solution of 19.8 g (0.1 mol) of 1-isopropyl-3,3,5,5-tetramethyl-2-piperazinone (obtainable, for example, in accordance with Synthesis 1981, page 40, or J. Organ. Chem., 45 (1980), 754-59) in 75 ml of anhydrous tetrahydrofuran is added dropwise at room temperature, whereupon the reaction temperature rises to 6020 C. The mixture is then stirred overnight at room temperature. After dropwise addition of about 10 ml of water, the mixture is subsequently stirred for 2 hours and the precipitate is then filtered off with suction. The filtrate is dried over potassium carbonate and concentrated in vacuo and the crude product which remains as a colourless oil is further processed without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1.[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)[CH2:16][CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:10]=[C:11]([NH:14][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[S:12][CH:13]=1
Reactant: Nc1nc(-c2c(F)cccc2Cl)cs1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3c(F)cccc3Cl)cs2)cc1

Procedure:
The title compound was prepared from 4-(2-chloro-6-fluorophenyl)-1,3-thiazol-2-amine (62 mg) and 4-n-propylbenzenesulfonyl chloride (59 mg) as descibed in the synthetic METHOD B to give a white solid (30.7 mg) with purity >90%: MS (pos) m/z 411.3, 413.3; MS (neg) m/z 409.5, 411.5.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]([CH2:9][CH2:10][OH:11])[O:7][CH2:8][C:4]=2[CH:3]=1.[Si:14](OCC[C@H]1C2C=CC(Br)=CC=2CCO1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[C:17]([Si:14]([O:11][CH2:10][CH2:9][CH:6]1[C:5]2[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][C:4]=2[CH2:8][O:7]1)([CH3:16])[CH3:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: OCCC1OCc2cc(Cl)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(Br)ccc21
Product: CC(C)(C)[Si](C)(C)OCCC1OCc2cc(Cl)ccc21

Procedure:
Prepared from 2-(5-chloro-1,3-dihydro-2-benzofuran-1-yl)ethanol, as described for the preparation of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethyl tert-butyl(dimethyl)silyl ether, to yield tert-butyl-[2-(5-chloro-1,3-dihydro-2-benzofuran-1-yl)ethoxy]-dimethylsilane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])=[CH:6][C:7]=1[Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(CC(=O)NCCCO)cc1
Product: Nc1ccc(CC(=O)NCCCO)cc1Br

Procedure:
The title compound was prepared from 2-(4-amino-phenyl)-N-(3-hydroxy-propyl)-acetamide (as prepared in the previous step) and NBS according to the procedure in Example 7, step (c). Mass spectrum (ESI, m/z): Calcd. for C1H15BrN2O2, 287.0 (M+H). found 287.0.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]#[N:18])[CH:11]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:16][C:14]1[N:13]=[C:12]([C:17]#[N:18])[CH:11]=[C:10]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:15]=1
Reactant: OCC(F)(F)F
Reactant: Cc1cc(Cl)cc(C#N)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(F)(F)F)cc(C#N)n1
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
Into 8 ml of N,N-dimethylformamide was suspended 0.22 g of sodium hydride (60% oily), and 0.47 g of trifluoroethyl alcohol was added at 10° C. After stirring for 10 minutes, 0.6 g of 4-chloro-6-methylpyridine-2-carbonitrile was added at 0° C., the mixture was stirred for 1 hour, and the reaction solution was poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert-butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.79 g of 6-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15]C(=O)C)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO.O>C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][OH:15])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCc1ccc(Oc2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: OCc1ccc(Oc2ccccc2)cn1
Yield: 107.7 %

Procedure:
A mixture of 2-methyl-5-phenoxy-pyridine (3.6 g, 19 mmol) described in Manufacturing Example 121-1-1,3-chloroperoxybenzoic acid (5.6 g, 33 mmol), and methylene chloride (80 mL) was stirred at room temperature for 45 minutes. Aqueous sodium sulfite was added to the reaction solution, and the organic layer was separated and was washed with 5 N aqueous sodium hydroxide (7 mL). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g). 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g, 16 mmol) and acetic anhydride (20 mL) were stirred for 40 minutes at 115° C. Acetic anhydride was evaporated under a reduced pressure, aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the organic layer was separated. The ethyl acetate solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate=2:1) to obtain an acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g). Acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g, 12 mmol), 5 N aqueous sodium hydroxide (8.0 mL), and methanol (20 mL) were stirred for 20 minutes at 60° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound (2.6 g, 65%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]23[CH2:15][CH2:14][CH2:13][N:12]2[CH2:11][CH2:10][CH2:9]3)=[CH:4][C:3]=1[CH3:16].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:16][C:3]1[CH:4]=[C:5]([C:8]23[CH2:15][CH2:14][CH2:13][N:12]2[CH2:11][CH2:10][CH2:9]3)[CH:6]=[N:7][CH:2]=1
Reactant: Cc1cc(C23CCCN2CCC3)cnc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cncc(C23CCCN2CCC3)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
7a-(6-Chloro-5-methyl-3-pyridinyl)-hexahydro-1H-pyrrolizine (274 mg, 1.16 mmol, from Example 19c) and LAH (1.0M in THF, 1.2 mL, 1.16 mmol) were added to THF (4.5 mL), and the mixture was stirred at room temperature for 4 hours. An additional amount of LAH (1.0M in THF, 1.2 mL, 1.16 mmol) was added, and the reaction was stirred overnight. A further amount of LAH (2 equivalents) was added, and the reaction was stirred at room temperature for 24 hours and at 80° C. for 5 hours. The reaction was quenched with 10% K2CO3 solution, and the resulting slurry was filtered. The filtrate was diluted with EtOAc and 15% NaOH, and the phases were separated. The aqueous phase was extracted with methylene chloride, and all the organic solutions were combined, dried and concentrated. The residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford the title compound as an oil (116 mg, 49%): 1H NMR (CDCl3, 300 MHz) δ1.57-1.71 (m, 2H), 1.77-2.06 (m, 6H), 2.32 (s, 3H), 2.66-2.74 (m, 2H), 3.12-3.19 (m, 2H), 7.63 (s, 1H), 8.24 (s, 1H), 8.50 (s, 1H); MS (CI/NH3) m/z: 203 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C@@H:17]([OH:20])[CH2:18][NH2:19])[CH:13]=2)[NH:8][C:7]=1[CH3:21])=[O:5])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:34]=[CH:35][C:36]=1[N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)[CH2:26][CH:27]1[S:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C@@H:17]([OH:20])[CH2:18][NH:19][CH:40]3[CH2:41][CH2:42][N:37]([C:36]4[CH:35]=[CH:34][C:25]([CH2:26][CH:27]5[S:31][C:30](=[O:32])[NH:29][C:28]5=[O:33])=[CH:24][C:23]=4[F:22])[CH2:38][CH2:39]3)[CH:13]=2)[NH:8][C:7]=1[CH3:21])=[O:5])[CH3:2]
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2F)CC1
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(OC[C@@H](O)CN)cc12
Product: CCOC(=O)c1c(C)[nH]c2ccc(OC[C@@H](O)CNC3CCN(c4ccc(CC5SC(=O)NC5=O)cc4F)CC3)cc12

Procedure:
The title compound was prepared from 5-((2S)-3-amino-2-hydroxy-propoxy)-2-methyl-1H-indole-3-carboxylic acid ethyl ester (which was obtained in Example 141) and 5-[3-fluoro-4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 61) according to the procedure of Example 73 as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=7.1 Hz, 3H), 1.56-1.63 (m, 2H), 2.03 (m, 2H), 2.61 (s, 3H), 2.67-2.75 (m, 4H), 2.88-2.96 (m, 4H), 3.04-3.07 (m, 2H), 3.95-3.97 (m, 2H), 4.05 (m, 2H), 4.25 (q, J=7.1 Hz, 2H), 4.61-4.66 (m, 1H), 5.52 (brs, 1H), 6.79 (dd, J=8.7, 2.5 Hz, 1H), 6.94-7.03 (m, 2H), 7.24-7.29 (m, 2H), 7.46 (d, J=2.3 Hz, 1H) 11.65 (s, 1H); MS (ES) m/z: 599.1 (MH+); HRMS for C30H36FN4O6S(MH+): 599.2339. Found: 599.2333.