Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CS(C)=O.[OH:40][CH2:41][C@@H:42]1[CH2:46][C@@H:45]([OH:47])[CH2:44][NH:43]1>C(OCC)(=O)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:43]3[CH2:44][C@H:45]([OH:47])[CH2:46][C@H:42]3[CH2:41][OH:40])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Br:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Br
Reactant: OC[C@@H]1C[C@@H](O)CN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H](O)C[C@H]2CO)cc1-c1ccccc1Br
Temperature: 130 °C
Reaction time: 24 h
Yield: 47.6 %

Procedure:
A mixture of 800 mg (1.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-bromo-phenyl)-6-chloro-pyridin-3-yl]-N-methyl-isobutyramide, 4 ml dimethyl sulfoxide and 1.15 g (6.9 mmol) (2S,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine was stirred at 130° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with 100 ml ethyl acetate and washed with 200 ml 1 N sodium carbonate solution and 100 ml water. The combined aqueous layers were extracted twice with 100 ml ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. Purification by flash chromatography gave 434 mg (48%) of the title compound as a yellow foam.
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]1([C@@H:10]([NH2:13])[CH2:11][CH3:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:14]([C:16]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17]1)=O.Cl>C(O)C.O>[C:1]([CH:14]([NH:13][C@H:10]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:11][CH3:12])[C:16]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17]1)#[N:2]
Reactant: [C-]#N
Reactant: CCOC(=O)C1(C=O)CC1
Reactant: CC[C@H](N)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(C#N)N[C@@H](CC)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
An eggplant type flask was charged with 136 mg of potassium cyanide, 501 mg of (S)-1-phenylpropylamine and 1 ml of water. After adding 152 mg of ethyl 1-formylcyclopropane-1-carboxylate dissolved in 2 ml of ethanol, dropwise at room temperature, the resulting mixture was further mixed with 0.2 ml of concentrated hydrochloric acid, and stirred for 1 hour at the same temperature and then for 2 hours at 50° C. After confirming completion of the reaction, the reaction solution was mixed with ice water and extracted with ethyl acetate. Next, the resulting organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate and, after removing insoluble matter by filtration, the solvent was evaporated under a reduced pressure. Thereafter, the resulting residue was subjected to a silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 181 mg (59%) of a diastereomer mixture in the form of colorless oil. Formation ratio of the two diastereomers was calculated under the following analytical conditions.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.S(Cl)([Cl:23])(=O)=O>ClCCCl>[Cl:23][C:13]1[C:9]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=2)=[N:10][NH:11][CH:12]=1
Reactant: Brc1cc(Br)cc(-c2cc[nH]n2)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Clc1c[nH]nc1-c1cc(Br)cc(Br)c1
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
4 g (0.0132 mol) of 3-(3,5-dibromophenyl)pyrazole and 1 g of pyridine (0.0132 mol) are dissolved, at room temperature and with stirring, in 50 ml of 1,2-dichloroethane. 2 g (0.0145 mol) of sulphuryl chloride in 10 ml of 1,2-dichloroethane are then added dropwise at 50° C. and stirring is then continued for 30 min days at this temperature. After cooling, the precipitate is filtered and recrystallised from 200 ml of 1,2-dichloroethane. 2.9 g (yield: 66%; melting point: 188° C.) of 4-chloro-3-(3,5-dibromophenyl)pyrazole are obtained.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[F:27][C:28]1[CH:35]=[CH:34]C(C#N)=[CH:30][CH:29]=1>C1COCC1>[F:27][C:28]1[CH:35]=[CH:34][C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)=[CH:30][CH:29]=1
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: N#Cc1ccc(F)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(-c3ccc(F)cc3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.5 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (500 mg, 2.259 mmol) in THF (4.52 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (1.59 ml, 2.71 mmol) and the solution was stirred for 0.5 h before addition of 4-fluorobenzonitrile (274 mg, 2.259 mmol) in THF (4.52 ml). The resulting solution was warmed to RT and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected and washed with water to give 3-(4-fluorophenyl)-6-methoxyisoquinolin-1-ol (350 mg, 58% yield) as a solid after drying.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.B(F)(F)F.CCOCC.[CH:21](=[O:30])/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1COCC1>[OH:30][CH:21]([CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCC/C=C\C=O
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC/C=C\CC(O)C#C[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Trimethylsilylacetylene (6.9 g, 48.6 mmole) is dissolved in 125 ml dry THF in a flamed dried 500 ml 3-neck round bottom flask under nitrogen at -78° C. The solution is treated with n-butyllithium (29.9 ml, 46.3 mmole) slowly dropwise over 10 minutes and stirred 30 minutes at -78° C. The reaction mixture is subsequently treated slowly dropwise with boron trifluoride etherate (6.0 ml, 48.8 mmole) and the resultant mixture is stirred 20 minutes at -78° C. 3-Z-Nonenal (6.2 g, 44 mmole), in 3×12 ml dry THF, is added rapidly dropwise to the reaction mixture at -78° C. The reaction is warmed to 0° C. and stirred an additional 20 minutes. The mixture is quenched with 100 ml saturated sodium chloride, the layers separated, and the aqueous phase extracted with 3×60 ml diethyl ether. The organics are combined, dried over magnesium sulfate, and concentrated in vacuo to a dark yellow oil (10.5 g). The crude oil is chromatographed over 200 g silica gel (230-400 mesh), eluting with 6% ethyl acetate/hexane and collecting 60 ml fractions. Fractions 8-16 are combined and concentrated to afford 6.3 g of the title compound as a pale yellow oil. Following the above procedure gives the title compound having the physical characteristic described below:
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:9]([CH:10]=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1>C(O)(=O)C>[BrH:1].[NH2:3][C:4]1[N:5]=[CH:6][C:7]([Br:1])=[CH:8][C:9]=1[CH:10]=[O:11]
Reactant: Nc1ncccc1C=O
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: Nc1ncc(Br)cc1C=O
Reaction time: 8 h
Yield: 165.3 %

Procedure:
A solution of bromine (1.05 mL, 20.0 mmol) in acetic acid (20 mL) was added to a solution of 2-amino-3-pyridinecarboxaldehyde (2.5 g, 20 mmol) in acetic acid (50 mL) at room temperature. The reaction mixture was then stirred overnight. The resulting precipitate was filtered and washed with diethyl ether to give the title compound as a white solid (4.66 g, 80%).
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)[N:9]=2.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>ClCCl.CO>[CH:29]1([CH2:28][N:7]2[C:6]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:31][CH2:30]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CO
Solvent: CS(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC4CC4)c3n2)cn1
Reaction time: 2.5 h
Yield: 87.6 %

Procedure:
A dimethyl sulfoxide solution (0.8 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (78.3 mg, 0.20 mmol) and piperazine (67.6 mg, 0.78 mmol) was heated at 140° C. and stirred for 2.5 hours. The mixture was left standing to cool followed by the addition of dichloromethane-methanol (10:1) and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=5:1) to give the title compound (76.5 mg, 89%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1)=[O:3].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[I:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:13][N:14]([CH3:16])[CH3:15])=[CH:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(I)cc1
Product: CN(C)C=CC(=O)c1ccc(I)cc1

Procedure:
A solution of 4-iodoacetophenone (6.15 g) in N,N-dimethylformamide dimethyl acetal (6.5 ml) was heated at reflux for 8 hours. The reaction mixture was evaporated and the solid residue was recrystallised from acetonitrile to give 1-(4-iodophenyl)-3-dimethylamino-2-propen-1-one (4.38 g), as a solid, m.p. 117°-118° C.; NMR(CDCl3): 2.60-3.50(6H,br.d), 5.64(1H,d), 7.62(2H,d), 7.77(2H,d) and 7.80(1H,d), m/z 302(M+H). A mixture of 1-(4-iodophenyl)-3-dimethylamino-2-propen-1-one (3.0 g) and hydroxylamine hydrochloride (0.73 g) in 1:1 dioxane/water (30 ml) was stirred at ambient temperature for 48 hours. Addition of water gave a solid which was collected by filtration, washed with water, and purified by flash column chromagatography on silica gel using 1:1 (v/v) ethyl acetate/pentane as eluent. There was thus obtained 5-(4-iodophenyl)-isoxazole (0.6 g); microanalysis found: C, 39.4; H, 2.3; N, 4.8%; C9H6INO requires: C, 39.9; H, 2.23; N, 5.17%; NMR(CDCl3): 6.54(1H,d), 7.52(2H,d), 7.83(2H,d) and 8.28(1H,d); m/e 272(M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH:12]1([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]2[CH2:26][C:27](OCC)=[O:28])[CH2:14][CH2:13]1>O>[CH:12]1([CH2:15][N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]2[CH2:26][C:27]([NH:10][C:9]([NH2:11])=[NH:8])=[O:28])[CH2:13][CH2:14]1
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccccc2C(=O)N1CC1CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: N=C(N)NC(=O)CC1c2ccccc2C(=O)N1CC1CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 76.4 %

Procedure:
N-[(2-Cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 2.9 g of potassium tert-butoxide, 2.5 g of guanidinium chloride and 1.5 g of ethyl (2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, followed by addition of 20 cm3 of water. The aqueous phase is extracted with 3 times 100 cm3 of ethyl acetate. The organic extracts are combined and then concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 35° C. The residue is taken up in water, triturated, filtered off and then dried in a desiccator. 1.2 g of N-[(2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine are thus obtained in the form of an off-white powder melting at 229° C. Mass spectrum: DCI: m/e 287 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>N1C=CC=CC=1.C(Cl)Cl>[C:23]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: C[C@]12CC[C@H](OC(=O)c3ccccc3)CC1=CC[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 5.0 g of 3β-hydroxy-15β,16β-methylene-5-androsten-17-one in 50 ml of pyridine was combined under ice cooling with 5 ml of benzoyl chloride and then stirred for 17 hours at room temperature. After the addition of 10 ml of water, the mixture was stirred for another hour; then the reaction solution was diluted with methylene chloride and washed with sodium carbonate solution and water. After drying and evaporation, the residue was triturated with diisopropyl ether and vacuum-filtered, thus obtaining 6.4 g of 3β-benzoyloxy-15β,16β-methylene-5-androsten-17-one, mp 250°-258° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C>O1CCOCC1.O>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To 0.117 g of D-valine in 2.5 mL dioxane and 2.5 mL of water, cooled in an ice bath, was added 0.31 g of 4′-nitro-1,1′-biphenyl-4-sulfonyl chloride, followed by 0.4 mL of triethylamine, The reaction was then stirred at room temperature overnight. After concentrating the reaction mixture in vacuo, the residue was extracted with ethyl acetate and 1N HCl. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.35 g of N-[(4′-nitro-1,1′-biphenyl-4-yl)sulfonyl]-D-valine as a solid. Yield 74.5%. m.p. 165-167° C.; MS: 377.0 (M−H)−.
Reaction SMILES: CC1(C)CC(C)(C)C2C(=C(C)C=C([C:14]([OH:16])=[O:15])C=2)O1.[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24](Br)[C:23]([O:33][CH2:34][O:35][CH3:36])=[CH:22][C:21]1=2.[Li]C(C)(C)C>>[CH3:36][O:35][CH2:34][O:33][C:23]1[C:24]([C:14]([OH:16])=[O:15])=[CH:25][C:26]2[C:27]([CH3:31])([CH3:30])[CH2:28][CH2:29][C:20]([CH3:37])([CH3:19])[C:21]=2[CH:22]=1
Reactant: Cc1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C
Reactant: COCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Agent: [Li]C(C)(C)C
Product: COCOc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C

Procedure:
Using the same procedure as for the synthesis of 2,2,4,4,8-pentamethyl-6-chromanoic acid (Compound A1) but using 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxymethoxy-2-bromonaphthalene (Compound J. 722 mg, 2.21 mmol) and 2.86 ml of t-BuLi (4.87 mmol, 1.7 M solution in hexane), the title compound was obtained as a white solid (143 mg).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[CH2:12]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][C:2]([NH:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[O:21][CH3:20])=[N:1]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc2ncccc12
Reactant: BrCc1ccccc1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2c(OCc3ccccc3)cccc2n1

Procedure:
The title compound, MS: m/e=371.4 (M+H+), was prepared in accordance with the general method of example 47 from 5-quinolinol (CAS 578-67-6), benzyl bromide and 2-methoxybenzylamine.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCN=[N+]=[N-])cc1
Agent: [Pd]
Product: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCN)cc1
Yield: 94.9 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-[4-(2-azidoethoxy)phenyl]-2-(2-phenoxyethyl)propionate (538 mg) and palladium on carbon (5%, 500 mg) and the reaction mixture was treated to afford the title compound (476 mg) as a syrup.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[S:11][CH2:12][CH2:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=O)C.[BH4-].[Li+].CO>C1COCC1>[OH:3][CH2:4][C:6]1[N:7]=[CH:8][S:9][C:10]=1[S:11][CH2:12][CH2:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: CCOC(=O)c1ncsc1SCCS(=O)(=O)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(CCSc1scnc1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of 4-ethoxycarbonyl-5-[2-(phenylsulfonyl)ethylthio]thiazole (702 mg, 2 mmol) in 20 ml of THF was added lithium borohydride (2M, 1 ml) and methanol (0.16 ml, 4 mmol) at -30° C. The reaction mixture was allowed slowly warm up to room temperature and stirred overnight. The solvent was removed under reduced pressure and the crude residue was subjected to chromatography by using dichloromethane and methanol as the eluent to give the title compound (400 mg, 65%). 1H NMR (CDCl3) δ 2.55 (s, 1H), 3.00 (t, 2H, J=6), 3.40 (t, 2H, J=6), 4.71 (s, 2H), 7.6 (t, 2H, J=7), 7.68 (t, 1H, J=7), 7.82 (d, 2H, J=7), and 8.80 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C)=[C:5](SC)[C:4]=1/[CH:17]=[C:18](\[CH3:22])/[C:19]([OH:21])=[O:20].C1(=O)C2C(=CC=CC=2)[C:26](=[O:33])C=C1/C=C(\C)/C(O)=O>CCOCC>[CH3:26][O:33][C:5]1[C:6](=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:2])[C:4]=1/[CH:17]=[C:18](\[CH3:22])/[C:19]([OH:21])=[O:20]
Reactant: COc1c(/C=C(\C)C(=O)O)c(SC)c(OC)c2ccccc12
Reactant: C/C(=C\C1=CC(=O)c2ccccc2C1=O)C(=O)O
Solvent: CCOCC
Product: COC1=C(/C=C(\C)C(=O)O)C(=O)c2ccccc2C1=O

Procedure:
Compound 55 was prepared from 99h (0.180 g, 0.565 mmol) as described above for 30a to give 0.063 g (0.22 mmol, 38%) of the product as a red fluffy solid following flash chromatography (2:3 Et2O:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH:11]=O)[NH:8][C:7]=12.[CH2:13]([NH2:15])[CH3:14].[BH4-].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH2:11][NH:15][CH2:13][CH3:14])[NH:8][C:7]=12
Reactant: CCN
Reactant: O=Cc1cc2ccnc(Cl)c2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNCc1cc2ccnc(Cl)c2[nH]1
Product: Cl
Reaction time: 2 h
Yield: 42 %

Procedure:
7-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (Example 138) (75 mg, 0.42 mmol) was dissolved in methanol (3 mL). Ethylamine (0.23 mL, 2 M in tetrahydrofuran) was added. After 2 h, sodium borohydride (25 mg, 0.67 mmol) was added. After an additional 2 h, the reaction mixture was quenched by addition of 5% aqueous sodium bicarbonate. The reaction mixture was extracted with diethyl ether, dried (magnesium sulfate), and evaporated to dryness (50 mg, 52% crude). The crude material was dissolved in acetonitrile and treated with hydrochloric acid (0.24 mL, 1 M in diethyl ether) to give N-[(7-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl]-N-ethylamine hydrochloride (47 mg, 0.19 mmol, 42%) as an off-white powder: mp 242-245° C. dec.; 1H NMR (300 MHz, CD3OD) δ1.40 (3H, t, J=7.3 Hz), 3.24 (2H, q, J=7.3 Hz), 4.57 (2H, s), 7.09 (1H, s), 7.92 (1H, d, J=6.1 Hz), 8.1 (1H, d, J=6.1 Hz); ESI MS m/z 210 [C10H12ClN3+H]+; HPLC (H2O/CH3CN 75:25 to 0:100 over 20 min, hold for 10 min) 94.5%, tR=8.0 min.
Reaction SMILES: C([Mg]Br)#C.CON(C)[C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)=O.[Cl-].[NH4+].[O:23]1CC[CH2:25][CH2:24]1>>[CH2:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]([C:8]#[C:25][CH:24]=[O:23])[CH2:19]1
Reactant: CON(C)C(=O)N1CCc2ccccc2C1
Reactant: C1CCOC1
Agent: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: O=CC#CN1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
9.08 ml of a 0.5 molar solution of ethynylmagnesium bromide in tetrahydrofuran were added dropwise within 20 min. to a solution of 1 g of 3,4-dihydro-1H-isoquinoline-2-carboxylic acid methoxy-methyl-amide in 5 ml of tetrahydrofuran under argon at 0° C. The reaction mixture was stirred at 0° C. for 1 h. and at room temperature for 1 h. The orange solution was poured into 50 ml of a saturated ammonium chloride solution and extracted twice with 50 ml of ethyl acetate each time. The combined organic phases were washed twice with 50 ml of water each time, once with 50 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 0.48 g (57%) of 1-(3,4-dihydro-1H-isoquinolin-2-yl)-propynone was obtained as a yellowish oil. MS (EI): 185M30 .
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[C:11]([O:15][C:16]([CH2:18][S:19][C:20]([CH3:32])([CH3:31])[C@H:21]([NH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22](O)=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:22](=[O:23])[C@@H:21]([NH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:20]([S:19][CH2:18][C:16]([O:15][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:17])([CH3:31])[CH3:32])=[O:10]
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)(C)SCC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC)C(C)(C)SCC(=O)OC(C)(C)C
Yield: 52.4 %

Procedure:
Reaction of 0.44 g of (L)-proline methyl ester hydrochloride and 0.86 g of 3-tert.-butoxycarbonylmethylsulfanyl-2-(R)-ethoxycarbonylamino-3-methyl-butyric acid according to the procedure described in example 91b yielded 0.60 g (52%) of the title compound as a colorless oil. (−)-APCI-MS: 474 (MH+).