Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][NH:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:22])=[CH:18][C:19]=3[Cl:21])[NH:14][C:13]=2[C:23]([O:25]CC)=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.O.[OH-].[Li+].Cl>O>[C:1]1([S:7]([CH2:10][NH:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:22])=[CH:18][C:19]=3[Cl:21])[NH:14][C:13]=2[C:23]([OH:25])=[O:24])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCS(=O)(=O)c1ccccc1
Yield: 70.6 %

Procedure:
Mix 3-[(phenylsulfonyl)methylamino]-2-carbethoxy-4,6-dichloroindole (185 mg, 0.433 mmol), tetrahydrofuran (25 mL) and water (25 mL). Add lithium hydroxide monohydrate (2.6 mmol) and stir at room temperature for 3 days, then at reflux for 5 hours. Pour into 1N hydrochloric acid (200 mL) and extract into ethyl acetate. Dry (MgSO4) and evaporate the solvent in vacuo. Recrystallize (ethyl acetate/hexane) to give the title compound (122 mg, 71%); mp 286°-90° C.
Reaction SMILES: [CH3:1][C:2]1([CH:23]=O)[CH2:6][O:5][C:4]([C:7]2[CH:8]=[N:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH:18]3[CH3:22])=[CH:11][CH:12]=2)=[N:3]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClC(Cl)C>[CH3:1][C:2]1([CH2:23][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH:18]3[CH3:22])=[N:9][CH:8]=2)=[N:3]1
Reactant: CC1CCCN1CCCOc1ccc(C2=NC(C)(C=O)CO2)cn1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: CC1CCCN1CCCOc1ccc(C2=NC(C)(CN3CCCC3)CO2)cn1
Temperature: 22 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A solution of 4-methyl-2-{6-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridin-3-yl}-4,5-dihydro-1,3-oxazole-4-carbaldehyde ax57 (273 mg, ca. 80% pure, ca. 0.66 mmol) in dichloroethane (4 ml) is treated with pyrrolidine (0.27 ml, 3.28 mmol) and sodium triacetoxyborohydride (0.35 g, 1.64 mmol), and the turbid solution is stirred at 22° C. overnight. Fresh pyrrolidine (0.145 ml, 1.64 mmol) and sodium triacetoxyborohydride (0.35 g, 1.64 mmol) are added and the solution is stirred for an additional 2 hours at room temperature. Water is then added and the mixture stirred vigorously for 5 minutes. Extraction is performed with dichloromethane until the organic extract does not contain significant UV-active spots. The combined organic layers are dried over sodium sulfate and concentrated to yield a brown oil. The product is purified by chromatography over silicagel (eluent: gradient 10 to 20% triethylamine in 90 to 80% hexanes) to afford 66 mg of 5-[4-methyl-4-(pyrrolidin-1-ylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-2-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridine 33.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([OH:24])[CH3:23])[C:13](=[O:25])[N:12]([CH3:26])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>[Pd].CO>[OH:24][C@@H:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[NH:8][CH:9]=[N:10][C:11]=2[N:12]([CH3:26])[C:13]1=[O:25]
Reactant: [H][H]
Reactant: C[C@H](O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H](O)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Yield: 62.6 %

Procedure:
(S)-7-benzyl-1(5-(4-nitrobenzoyloxy)hexyl)-3-methylxanthine (25 g, 49.5 mmol) was added to a solution for sodium hydroxide (3.36 g, 84 mmol) in methanol (200 ml). After stirring for 2 hours, the pH was adjusted to 4 by addition of 1 N hydrochloric acid solution. After concentrating under reduced pressure, the residue was partitioned between water (150 ml) and ethyl acetate (300 ml). The organic layer was washed with saturated aqueous sodium chloride solution (150 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20% hexane-ethyl acetate to provide (S)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (14 g). c) A mixture of (S)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (14 g, 39 mmol), acetic acid (100 ml), methanol (50 ml), and 10% palladium on carbon (5 g) was treated with hydrogen gels (40 psi) for 14 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-ethyl acetate to give (S)-1-(5-hydroxyhexyl)-3-methylxanthine (6.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[N:62]=[C:61]([N:66]1[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1)[CH:60]=[CH:59]2>ClCCl>[F:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[N:62]=[C:61]([N:66]1[CH2:67][CH2:68][N:69]([C:19](=[O:20])[CH2:18][O:17][CH:14]3[CH2:15][CH2:16][CH:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:23])([F:24])[F:25])[CH:6]=4)[CH2:12][CH2:13]3)[CH2:70][CH2:71]1)[CH:60]=[CH:59]2
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: Fc1ccc2nc(N3CCNCC3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3cc(F)ccc3n2)CC1
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl) oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added EDAC.HCl (79.1 mg, 0.41 mmol), HOBt (55.9 mg, 0.41 mmol), triethylamine (83.7 mg, 0.83 mmol) and 6-fluoro-2-(piperazin-1-yl)quinoline (70.2 mg, 0.30 mmol) at room temperature. After stirred overnight, the reaction mixture was then diluted with dichloromethane (100 ml) and washed with water (2×100 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% methanol in dichloromethane to afford 1-[4-(6-fluoroquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (80 mg, 48%); (ES, m/z): [M+H]+ 576.20; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J=8.8 Hz, 1H), 7.94-7.99 (m, 1H), 7.72-7.78 (m, 1H), 7.31-7.37 (m, 2H), 7.02 (t, J=8.0 Hz, 1H), 6.87 (s, 1H), 6.64 (dd, J=2.4 Hz, 9.2 Hz, 1H), 4.48 (d, J=7.6 Hz, 1H), 4.28 (s, 2H), 3.75-3.81 (m, 7H), 3.41-3.49 (m, 2H), 2.17-2.19 (m, 4H), 1.50-1.58 (m, 2H), 1.28-1.36 (m, 3H).
Reaction SMILES: [Br-:1].C(O[C:7]([N:9]([CH2:11][C:12]([O:14][C:15]1[C:52]([CH3:53])=[CH:51][C:18]([CH2:19][N+:20]2[CH:21]=[N:22][N:23]([CH2:25][C@@:26]([C:43]3[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=3[F:50])([OH:42])[C@H:27]([C:29]3[S:30][CH:31]=[C:32]([C:34]4[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=4)[N:33]=3)[CH3:28])[CH:24]=2)=[CH:17][C:16]=1[CH3:54])=[O:13])C)=O)(C)(C)C.C(OC(=O)C)C.Cl>C(OC(=O)C)C>[Br-:1].[C:40]([C:37]1[CH:36]=[CH:35][C:34]([C:32]2[N:33]=[C:29]([C@H:27]([CH3:28])[C@:26]([C:43]3[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=3[F:50])([OH:42])[CH2:25][N:23]3[CH:24]=[N+:20]([CH2:19][C:18]4[CH:17]=[C:16]([CH3:54])[C:15]([O:14][C:12](=[O:13])[CH2:11][NH:9][CH3:7])=[C:52]([CH3:53])[CH:51]=4)[CH:21]=[N:22]3)[S:30][CH:31]=2)=[CH:39][CH:38]=1)#[N:41]
Reactant: Cc1cc(C[n+]2cnn(C[C@](O)(c3cc(F)ccc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc(C)c1OC(=O)CN(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CNCC(=O)Oc1c(C)cc(C[n+]2cnn(C[C@](O)(c3cc(F)ccc3F)[C@@H](C)c3nc(-c4ccc(C#N)cc4)cs3)c2)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a solution of 36 mg of 4-{4-[(tert-Butoxycarbonyl-methyl-amino)-acetoxy]-3,5-dimethyl-benzyl}-1-[(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,5difluoro-phenyl)-2-hydroxy-butyl]-1H-[1,2,4]triazol-4-ium bromide in ethylacetate(2 ml) was added dropwise 4N HCl ethylacetate solution(1 mL) and the mixture was stirred at r.t. for 4 hrs. The precipitate was filtered and washed with diethylether to give 1-{(2R,3R) -3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxy-butyl}-4-(3,5-dimethyl-4-methylaminoacetoxy-benzyl)-1H-[1,2,4]triazol-4-ium bromide (24.5 mg, 74% as HCl salt and as white solid);
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([CH:26]2[O:28][CH2:27]2)=[CH:24][CH:23]=1>CO>[CH2:1]([N:8]([CH2:27][CH:26]([OH:28])[C:25]1[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CO2)cc1
Reactant: COc1ccc(CCNCc2ccccc2)cc1OC
Solvent: CO
Product: COc1ccc(CCN(Cc2ccccc2)CC(O)c2ccc(Cl)cc2)cc1OC

Procedure:
Similarly 5.42 g. (0.02 mol) of N-benzyl-3,4-dimethoxyphenethylamine and 4.64 g. (0.03 mol) of p-chlorostyrene oxide are reacted in methanol to give N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-chlorophenyl)ethylamine. The hydrochloride of this ethylamine is dissolved in methanol and hydrogenated with 0.5 g. of 10% palladium-on-carbon in 10 ml. of ethyl acetate at room temperature and 60 psi. for about 90 minutes. The filtered reaction mixture is evaporated in vacuo to yield N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(4-chlorophenyl)ethylamine hydrochloride, m.p. 167°-171° C.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1>O>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Oc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2F)cn1
Temperature: 60 °C
Yield: 55.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.7 mmol) was mixed with 3-5 ml of dry dimethylformamide and 2-fluorophenol (0.24 ml, 2.7 mmol) was added to the stirred suspension. When the gas evolution was ceased the reaction mixture was heated at stirring at 60° C. and 5-bromo-2-nitropyridine (0.5 g, 2.5 mmol) was added to the reaction mixture in one portion. The reaction mixture was stirred at 60° C. for about 12 hours. The reaction mixture was then mixed with 50 ml of water and extracted into methylene chloride (3×20 ml). Organic extract was washed with water and brine, dried over magnesium sulfate and concentrated by rotary evaporation. The resulting mixture was purified by column chromatography on silica (30 g, EtOAc/hexane 1:3) to give 326 mg (57% yield) of desired product.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([O:10][C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[CH:2]=1.P([O-])([O-])([O-])=O>>[N+:7]([C:6]1[CH:1]=[CH:2][C:3]([OH:10])=[CH:4][CH:5]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: O=P([O-])([O-])[O-]
Product: O=[N+]([O-])c1ccc(O)cc1
Temperature: 37 °C
Reaction time: 0.08 h

Procedure:
With 0.5 ml of a substrate solution containing 20 mM 4-nitrophenyl-α-D-glucopyranoside was mixed 1.0 ml of 0.1M phosphate buffer (pH 7.0), and the mixture was pre-heated at 37° C. for 5 minutes. Thereafter, 0.5 ml of an enzyme solution was added thereto and the reaction was conducted at 37° C. for 5 minutes, followed by determination of changes in absorbance per minute at 400 nm. The enzyme activity producing 1 μmol of 4-nitrophenol per minute under the above-mentioned conditions was taken as one unit.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:28]1[C:37]2[C:32](=[C:33]([NH:38][NH2:39])[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[N:28]1[C:37]2[C:32](=[C:33]([N:38]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])=[CH:16][CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:39]3)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: NNc1cccc2ncccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2ncccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and quinolin-5-yl-hydrazine according to the method described for example 43. MS: M=498.1 (M+H)+
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([OH:25])=O)[C:18]1=[O:26].[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([CH3:34])[N:29]1[CH2:35][CH2:36][NH2:37].O>CN(C)C=O>[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([CH3:34])[N:29]1[CH2:35][CH2:36][NH:37][C:23](=[O:25])[CH2:22][N:19]1[CH2:20][CH2:21][CH:17]([OH:16])[C:18]1=[O:26]
Reactant: O=C(O)CN1CCC(O)C1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1.30 g of dicyclohexylcarbodiimide dissolved in 6 ml of dimethylformamide are added dropwise at 0° to 1.0 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid and 1.03 g of 94.7% cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine dissolved in 20 ml of dimethylformamide. The mixture is left to stir at room temperature for 4 days, treated with 0.23 g of ion-free water and evaporated in a water-jet vacuum. The residue is treated five times with toluene and in each case again evaporated. The constituents of the residue which are soluble in chloroform are chromatographed on 60 g of aluminum oxide (activity grade III, neutral). The alcohol eluate is again chromatographed on 15 g of aluminum oxide (activity grade III, neutral). The fractions which are eluted with acetonitrile and ethanol contain, according to the gas chromatogram and mass spectrum, (R/S)-cis-N-[2-(2,6-dimethyl-1piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Br:12])=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].Cl>>[NH2:1][C:2]1[C:11]([Br:12])=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7]
Reactant: CCNCc1cc(C(=O)OC)cc(Br)c1N
Agent: Cl
Product: CCNCc1cc(C(=O)O)cc(Br)c1N
Temperature: -15 °C

Procedure:
2.7 gm of 2-amino-3-bromo-5-carbomethoxy-N-ethyl-benzylamine were boiled for 35 minutes with 65 ml of 6 N hydrochloric acid. Thereafter, upon cooling the reaction solution to -15° C, N-ethyl-2-amino-3-bromo-5-carboxy-benzylamine hydrochloride crystallized out and was recrystallized from ethanol/ether, whereupon it had a melting point of 261° C (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:30][CH:31]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: ClCc1ccc(OCc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (415 mg), 3-(4-chloromethylphenoxymethyl)pyridine (554 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 80.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (340 mg, yield: 55%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)CSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
6-Amino-9-benzyl-2-(isobutylthio)purine (60 mg, 0.19 mmol) and bromine (0.4 ml) were dissolved in 85 ml of methylene chloride and the solution was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (chloroform) to give the subject compound (20 mg, yield 27%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[N:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)[N:14]=[C:13]([C:23](OCC)=[O:24])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[N:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)[N:14]=[C:13]([CH2:23][OH:24])[CH:12]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2cccc(Br)c2)n(-c2cccnc2F)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(Br)c1)c1cc(CO)nn1-c1cccnc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A solution of ethyl 5-[(3-bromophenyl)sulfonyl]-1-(2-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylate (467 mg) in tetrahydrofuran (5 mL) was cooled to −78° C., and a 1.5 mol/L solution (2.7 mL) of diisobutylaluminum hydride in toluene was added dropwise. The reaction mixture was stirred at 0° C. for 2 hr, treated with 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 371 mg, yield 88%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]\[CH2:39]O)=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:39]/[CH:38]=[CH:37]\[C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:36][CH:35]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OC/C=C\c1ccc(Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C\c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 215 mg (1 mM) of (Z)-3-[4-(1-imidazolylmethyl)phenyl]-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylamino-pyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 528 mg (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:7][C:6]2=[O:16].[CH3:17][CH:18](O)[CH:19]=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:17]([CH:7]1[C:6](=[O:16])[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]21[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:18]=[CH:19][CH3:20]
Reactant: COc1ccc2c(c1)C(=O)CC21CCCC1
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(OC)ccc2C12CCCC2
Yield: 51 %

Procedure:
A solution of 9.73 g of 5'-methoxy-2',3'-dihydro-spiro[cyclo-pentane-1,1'-[1H]indene]-3'-one, 9.3 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxy-propane was boiled under reflux for 90 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 7:1). In addition to 4.0 g of educt, there were obtained 6.24 g (51%) of (RS)-2'-(2-buten-1-yl)-5'-methoxy-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one as a yellow oil.
Reaction SMILES: [NH2:1][CH:2]([CH:8]([F:10])[F:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>ClCCl>[CH2:15]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH:2]([NH2:1])[CH:8]([F:10])[F:9])[CH3:16]
Reactant: CCO
Reactant: NC(CCC(=O)O)C(F)F
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCC(N)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2 mmole of 4-amino-4-difluoromethylbutyric acid in 15 ml of dichloromethane is treated with 2 mmole of thionyl chloride at 25° C. for one hour after which 20 ml of ethanol is added. The solution is stirred at 25° C. for one hour, washed with water, dried and concentrated to afford 4-amino-4-difluoromethylbutyric acid ethyl ester.
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[Na].C([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=C>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)CC(C)=O
Reactant: C=Cc1ccccn1
Agent: [Na]
Product: CC(=O)CCCc1ccccn1
Yield: 14.6 %

Procedure:
According to reference F. Noel, Albertson J. Am. Chem. Soc. 1950, 72, 2594-99, a reaction mixture comprising 50 g of acetyl acetone, 1.5 g of sodium and 108 g of 2-vinylpyridine is refluxed for 7 hours. The produced may be distilled as a yellow oil at 1.5. 102 Pa (1.1 Torr) (b.p.: 90-127° C.). Fractional distillation of this oil yields 11.9 g of 5-(2-pyridyl)-2-pentanone (4a) with a boiling point of 88-105° C. and 1.3·102 Pa (1.0 Torr).