Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH2:25]1[CH2:39][O:38][C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH2:28][CH2:29][CH2:30]Br)[O:26]1.O>COCCOC>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:30][CH2:29][CH2:28][C:27]1([O:26][CH2:25][CH2:39][O:38]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH3:10]
Reactant: BrCCCC1(c2ccccc2)OCCO1
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(CCCC1(c2ccccc2)OCCO1)(Cc1cccc2ccccc12)C(=O)OCC
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a solution of 1.1 g of 2-(1-naphthylmethyl)malonic acid diethyl ester in 20 ml of dry 1,2-dimethoxyethane was added 0.22 g of a 50% sodium hydride (suspension in oil) under cooling, the mixture was stirred for 1 hour. To the reaction mixture was added 1.0 g of 4,4-ethylenedioxy-4-phenylbutyl bromide obtained, the mixture was heated under reflux for 17 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 1.2 g of 2-(4,4-ethylenedioxy-4-phenylbutyl)-2-(1-naphthylmethyl)malonic acid diethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]([NH2:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:31][CH:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=3)[CH3:30])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
2000.0 mg (6.809 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 88A and 1417.0 mg (7.490 mmol) of 1-[3-(trifluoromethyl)phenyl]-ethanamine are placed in 10 ml of dimethylformamide and treated with 1104.0 mg (8.171 mmol) of HOBt. After 10 mins' stirring, 1697.0 mg (8.852 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at room temperature. For the workup, the reaction mixture is partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 200:1, then 100:1). A subsequent enantiomer separation by preparative HPLC on chiral phase [Method 14] yields 1460 mg (46% of theory) of the enantiomerically pure target compound (see also Example 81).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=O.O.NN.[OH-].[K+]>C(O)CO>[F:14][C:10]1[CH:9]=[C:8]([CH2:6][CH2:5][CH2:4][C:3]([OH:15])=[O:2])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CCC(=O)c1cccc(F)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: O=C(O)CCCc1cccc(F)c1
Yield: 70.8 %

Procedure:
Methyl-4-(3-fluorophenyl)-4-oxobutanoate (25.27 g), hydrazine hydrate (24.29 cm3) and potassium hydroxide pellets (20.50 g) were dissolved in ethylene glycol (150 cm3) and the mixture was heated at reflux for 1.25 h. The excess hydrazine hydrate was distilled off until the temperature at the still-head reached 160° C. The reaction mixture was then cooled, diluted with water (400 cm3) and the resultant aqueous mass was washed with diethyl ether (2×150 cm3) and then acidified with hydrochloric acid (5 M, 150 cm3). The acidic mixture was then extracted with diethyl ether (2×150 cm3) and the combined extracts were dried (Na2SO4) and the solvent was removed under reduced pressure to provide the title compound (15.51 g) as a dark oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:20][C:21]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=3[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:13][C:12]=2[F:18])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: Oc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(Cl)ccc1COc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Yield: 81.1 %

Procedure:
By the method of Example 1, Step I, 0.49 g (0.0016 mole) of 3-chloro-2-(2-fluoro-4-hydroxyphenyl)-4,5,6,7-tetrahydroindazole and 0.52 g (0.002 mole) of methyl 2-(2-chloromethyl-5-chlorophenoxy)propionate (Example 2, Step E) were reacted in the presence of 0.41 g (0.003 mole) of anhydrous potassium carbonate in 30 mL of N,N-dimethylformamide, yielding 0.64 g of methyl 2-[2-[4-(3-chloro-4,5,6,7-tetrahydroindazol-2-yl)-3-fluorophenoxymethyl]-5-chlorophenoxy]propionate as a syrup. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.64 (d, 3H, JHH =8.0 Hz); 1.82 (m, 4H); 2.50 (t, 2H, JHH =4.0 Hz); 2.68 (t, 2H, JHH =4.0 Hz); 3.76 (s, 3H); 4.82 (q, 1H, JHH =8 Hz); 5.18 (s, 2H,); 6.7.8-7.40 (m, 6H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.[CH3:12][CH2:13][CH2:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18]>C1COCC1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:15]([OH:19])([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH3:12]
Reactant: CCCC(=O)CCC
Reactant: Brc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(O)(CCC)c1cccs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromothiophene (10.0 g, 61.5 mmol) in dry THF (60 mL) was cooled to −78° C. under nitrogen. A solution of n-BuLi (2.5 M, 27.0 mL, 67.5 mmol) was then added slowly, and the resulting mixture was stirred at −78° C. for 2 hours, before a solution of 4-heptanone (8.5 g, 74.4 mmol) in dry THF (10 mL) was added slowly. This mixture was stirred at −78° C. for an additional 1 hour, and then allowed to warm to room temperature, and stirred at room temperature overnight. Most of the solvent was removed in vacuo, and the residue was subjected to flash column chromatography on silica gel with a hexane:EtOAc (3:1, v/v) mixture, leading to a colorless oil as the product (10.2 g, 83.5%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[C:11]([CH2:19][CH2:20][NH:21][CH3:22])=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](O)(C(F)(F)F)=O.C=O>C(#N)C>[CH:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[C:11]3[CH2:19][CH2:20][N:21]([CH3:23])[CH2:22][C:10]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: CNCCc1cn(CCC2CCCCC2)c2ccc(C)cc12
Agent: C=O
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CCC2CCCCC2)CN(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared by General Method 4. 2-(1-(2-cyclohexylethyl)-5-methyl-1H-indol-3-yl)-N-methylethanamine (72 mg) was dissolved in acetonitrile (2 mL) containing 5% TFA and the reaction mixture was heated to reflux. 37% aqueous formaldehyde (0.02 mL) was added and the reflux was continued for additional 2 h. The reaction mixture was cooled to 25° C., concentrated under reduced pressure and partitioned between ethyl acetate and satd. Aqueous NaHCO3. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by silica gel chromatography (eluent EtOAc/EtOH/NH3: 9/1/0.1) to obtain 52 mg of product. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF. 1H NMR (DMSO) δ 7.5 (d, 1H), 7.4 (s, 1H), 6.9 (d, 1H), 4.3 (bs, 2H), 4.0 (t, 2H), 3.6 (bs, 2H), 2.8 (m, 5H), 2.3 (s, 3H), 1.8-0.7 (m, 13H). MS m/z observed 311. HPLC RT 5.93 min.
Reaction SMILES: [Cl:1][CH:2]([Cl:21])[C:3]([NH:5][C@H:6]([CH2:19][F:20])[C@H:7]([OH:18])[C:8]1[CH:13]=[CH:12][C:11]([Sn](C)(C)C)=[CH:10][CH:9]=1)=[O:4].Br[C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:32])[C:30]#[N:31])=[N:27][CH:28]=1>>[Cl:1][CH:2]([Cl:21])[C:3]([NH:5][C@H:6]([CH2:19][F:20])[C@@H:7]([C:8]1[CH:13]=[CH:12][C:11]([C:23]2[CH:28]=[N:27][C:26]([CH:29]([C:30]#[N:31])[CH3:32])=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)[OH:18])=[O:4]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CC(C#N)c1ccc(Br)cn1
Product: CC(C#N)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1

Procedure:
Following the general procedure of step 3, Example 4 and using the product of step 2, Example 4 and making non-critical variations but using the product of step 1, Example 23, the title compound is obtained (85 mg): 1H NMR (300 MHz, DMSO-d6) δ 1.61 (d, 3H), 4.25 (m, 1.5H), 4.40-4.60 (m, 2H), 4.70 (m, 0.5H), 4.91 (m, 1H), 5.99 (d, 1H), 6.53 (s, 1H), 7.48 (d, 2H), 7.55 (d, 1H), 7.70 (d, 2H), 8.13 (dd, 1H), 8.62 (bd, 1H), 8.89 (m, 1H). MS (ESI+) m/z 410 [M+H].
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[OH-].[K+].[CH3:19][C:20]1[N:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1>CN1CCCC1=O.O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[N:25][CH:24]=3)[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)c1c(n2CCc2cnc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.8 %

Procedure:
To a solution of 8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.00046 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.13 g, 0.0023 mol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.14 g, 0.00116 mol) was added and stirred for further 3 h. At 80 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC. to get the desired compound as yellow oil (0.032 g, 20% yield). 8-Ethyl-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.032 g, 0.000095 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.00 0095 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.030 g, 75% yield).
Reaction SMILES: [CH3:1][SH:2].Cl[C:4]1[S:5][C:6]([C:12](=[O:14])[CH3:13])=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O>C(O)C>[CH3:1][S:2][C:4]1[S:5][C:6]([C:12](=[O:14])[CH3:13])=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: CS
Solvent: O
Solvent: CCO
Product: CSc1sc(C(C)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Liquid methylmercaptan (4 ml) was added to a solution of 0.82 g of Na in 50 ml of absolute ethanol. The resulting solution was added to a solution of 7.2 g of 2-chloro-3-nitro-5-acetylthiophene in 200 ml of absolute ethanol in 15 minutes at 5° C. After stirring at room temperature for 30 minutes, 100 ml of water was added, after which the precipitate was sucked off and washed successively with water and isopropanol. The precipitate was boiled a moment with 300 ml of carbontetrachloride, cooled down, and sucked off. After drying the title compound was obtained in a yield of 6.4 g; m.p. 191°-193° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>C(Cl)Cl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[O:19]1[CH2:20][CH2:21][N:16]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:15])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCOCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CCNCC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-tert-butyloxycarbonylpiperazine (1.0 g, 5.34 mmol) was dissolved in 5 mL of THF:water (1:1) and cooled in an ice bath. Triethylamine (1.45 mL, 10.68 mmol), followed by 4-morpholinocarbonyl chloride (0.752 mL, 6.4 mmol) in 5 mL of ether were added, and stirred at 0° C. for 1 hour and at room temperature for 2 hours. Solvents were removed and 40 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with brine (30 mL×3) and dried over anhydrous sodium sulfate. After filtered, the filtrate was concentrated in vacuo to yield 1.39 g of N-tert-butyloxycarbonyl-N'-morpholinocarbonyl-piperazine in 87% yield as a solid. MS m/z M+H=300, M+NH4 =317; H1 -NMR (in CDCl3) δ=1.49 (s, 9H, Boc), 3.25 (m, 8H, 4×CH2), 3.52 (m, 4H), 3.65 (m, 4 H). The obtained N-tert-butyloxycarbonyl-N'-morpholinocarbonyl-piperazine (1.38 g, 4.62 mmol) was dissolved in 10 mL of 20% trifluoroacetic acid in methylene chloride and stirred at room temperature for 1 hour. Solvent and trifluoro acetic acid were removed to obtain N-morpholinocarbonylpiperazine trifluoroacetic acid salt in quantitative yield. MS m/z M+H=200, H1 -NMR (in MeOH-d4) δ=3.22 (m, 4H), 3.3 (m, 4H), 3.45 (m, 4H), 3.65 (m, 4H). The obtained N-morpholinocarbonylpiperazine trifluoroacetic acid salt is dissolved in 30 mL of acetonitrile and cooled in an ice bath. Solid sodium bicarbonate is added to the acetonitrile solution and stirred for an additional 2 hours. Solid is filtered off and the filtrate is concentrated in vacuo to yield N-morpholinocarbonylpiperazine. Following the procedure of Example 6, but replacing 1-benzylpiperazine with 1-morpholinocarbonylpiperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-morpholinocarbonylpiperazine (1.212 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5 to yield the pure title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[O:17]C)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[OH:17])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(Cl)cc1-n1c(=O)[nH]c2cc(Cl)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1-c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5-Chloro-1-(5-chloro-2-methoxy-phenyl)-1,3-dihydro-benzimidazol-2-one (4 g, 13 mmol) in dichloromethane was cooled to −10° C., and boron tribromide (14.6 ml 1 M solution in dichloromethane 14.6 mmol) was added. The reaction mixture is stirred at room temperature for 6 hours, poured into water (app. 200 ml), and stirred for 15 minutes and filtrated. The title compound was crystallized from toluene/heptane. M.p. 256-257° C.
Reaction SMILES: C([NH:3][C:4]([CH3:21])([CH:18]([CH3:20])[CH3:19])[C:5]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6])=O.[ClH:22]>CO.O>[ClH:22].[NH2:3][C:4]([CH3:21])([CH:18]([CH3:19])[CH3:20])[C:5]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(NC=O)C(C)C)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Temperature: 80 °C

Procedure:
A suspension of 2-formamido-2,3-dimethyl-N-(p-tolylsulfonyl)butyramide (99.4 g, 0.318 mols) in 500 mL of methanol, 500 mL of water, and 500 mL of aqueous HCl 10% is heated at 80° C. until all the solid has dissolved (one hour). The reaction mixture is concentrated to 1/3 of the volume and the resulting precipitate is filtered off. After drying the title product is obtained as a white solid, having mp 161°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[CH:5]=[O:6].[BH4-].[Na+]>CO>[F:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH2:5][OH:6])[CH:7]=1
Reactant: COc1ccc(F)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)cc1CO
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a solution of 2-Methoxy-5-fluorobenzaldehyde (11.093 g, 1 equiv.-available from Aldrich Chemical Company) in methanol at −10° C. under nitrogen atmosphere was added NaBH4 (7.515 g, 2.7 equiv.) portionwise. The solution was allowed to warm to room temperature and after 30 minutes the reaction solvent was removed under reduced pressure and replaced with dichloromethane. This solution was poured onto ice water and further extracted with dichloromethane. The organic fractions were collected and dried (MgSO4) and the solvent removed under reduced pressure to give the title compound as an oil (9.794 g, 87%). 1H NMR (300 MHz, CDCl3): δ 2.58 (m, 1H), 3.81 (s, 3H), 4.63 (d, 2H, J=6.3 Hz), 6.78 (dd, 1H, J=8.9 and 4.3 Hz), 6.94 (td, 1H, J=8.5 and 3.1 Hz), 7.04 (dd, 1H, J=8.7 and 3.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25]([CH:27]1[CH2:29][CH2:28]1)=O)=[O:4].Cl.[NH2:32][NH2:33]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[NH:32][N:33]=[C:25]([CH:27]2[CH2:29][CH2:28]2)[CH:24]=1)=[O:4]
Reactant: NN
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(=O)C1CC1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CC2)n[nH]1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-cyclopropyl-3-oxo-thiopropionyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 398a) was reacted with hydrazine hydrochloride (CAS Reg. No. 2644-70-4) to give the title compound as brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Oc1cccc2cnccc12
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)COc1cccc2cnccc12

Procedure:
In 10 ml of acetonitrile, 1.0 g of 5-hydroxyisoquinoline and 1.52 ml of ethyl bromoacetate were added in the presence of 2.07 ml of DBU and the resultant mixture was refluxed for 8 hr. The reaction mixture was evaporated under reduced pressure and the resultant residue was redissolved in 1N-HCl, washed with ethyl acetate. The aqueous layer was made alkaline with sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and subjected to a silica gel column chromatography (chloroform) to give 1.46 g of ethyl 5-isoquinolyl-oxyacetate. The ester was dissolved in 30 ml of ethanol, mixed with 6.5 ml of 1N-NaOH aqueous solution and stirred for 12 hr. The reaction mixture was evaporated under reduced pressure, neutralized by the addition of 1N-HCl and the precipitated crystals were filtered, washed with water and dried to give 0.68 g of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1C
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)#[CH:25]>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:25]=2)=[CH:27][CH:28]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#Cc1ccc(F)cc1
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1-c1ccc(F)cc1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1-ethynyl-4-fluorobenzene. MS (+ESI) m/z: 391.1.
Reaction SMILES: [CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@H:16]([CH3:21])[C:17]([O:19]C)=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1.[OH-].[Li+]>C1COCC1>[CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@H:16]([CH3:21])[C:17]([OH:19])=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: COC(=O)[C@@H](C)NC(=O)c1cccc2c1NC1CCCC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1cccc2c1NC1CCCC21)C(=O)O

Procedure:
Following the procedure of method 7D, methyl (2R)-2-[(1,2,3,3a,4,8b-hexahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoate (2.7 mmol, 0.77 g) was hydrolyzed to the acid using 1 M aqueous lithium hydroxide (5.9 mL) in THF (20 mL) to yield an orange oil which was used directly in the next step.