Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[CH2:49][C:50]([CH3:53])([OH:52])[CH3:51])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:49][C:50]([OH:52])([CH3:53])[CH3:51])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CC(C)(O)CCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.2 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 825 mg, 2.50 mmol) was suspended in methylene chloride (12.5 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (1.25 mL, 2.5 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (582 μL, 5.00 mmol) was added. The reaction continued to stir at 0° C. for 10 min. 4-(3-Amino-pyrazol-1-yl)-2-methyl-butan-2-ol (424 mg, 2.50 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to the reaction. The reaction continued to stir at 0° C. for 10 min. The reaction was diluted with methylene chloride (50 mL), washed with water (15 mL), saturated aqueous brine solution (10 mL), 1.0 M aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 35% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-hydroxy-3-methyl-butyl)-1H-pyrazol-3-yl]-propionamide (653 mg, 54%) as a white foamy solid: ESI-LRMS m/e calcd for C23H32ClN3O4S [M+] 481.18, found 482.35 [M+H+], 464.22 [M−H2O+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.09-1.23 (m, 2H, CH2), 1.29 (s, 6H, 2×CH3), 1.46-1.94 (m, 8H, 4×CH2), 1.94-2.04 (m, 2 H, CH2), 2.18-2.29 (m, 1H, CH), 3.28 (s, 3H, SO2CH3), 3.55 (t, J=7.5 Hz, 1H, CH), 3.00-4.25 (m, 2H, NCH2), 6.65 (d, J=2.3 Hz, 1H, Ar), 7.29 (d, J=2.3 Hz, 1H, Ar), 7.47 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.61 (d, Jm=1.7 Hz, 1H, Ar), 8.10 (d, Jo=8.2 Hz, 1H, Ar), 8.12 (s, 1H, NH).
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].CCN(C(C)C)C(C)C.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[C:25]([N:1]1[C:5]2([CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[CH2:4][CH2:3][CH:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:27])[CH3:26]
Reactant: CCOC(=O)C1CCC2(CCOCC2)N1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCC2(CCOCC2)N1C(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.4 %

Procedure:
To a solution of ethyl 8-oxa-1-azaspiro[4.5]decane-2-carboxylate (166) (135 mg, 0.63 mmol) in anhydrous dichloromethane (2 mL) was added Hunig's base (0.22 mL, 1.3 mmol) followed by acetyl chloride (0.05 mL, 0.76 mmol) and the reaction stirred at room temperature under nitrogen for 1.5 h. The reaction was diluted with dichloromethane and washed with 0.1 N HCl and the organic layer dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 60-100% hexanes/EtOAc to afford the title compound as a yellow oil (94 mg, 58% yield).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Br:21]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH:11](/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC/C=C\C(Br)/C=C\CCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Linoleic acid (7 g, 25 mmol, Aldrich) was dissolved in 25 ml of carbon tetrachloride dried over P2O5. N-bromosuccinimide (4.425 g, 25 mmol, desiccated overnight over P2O5) and 0.05 g AIBN were added, and the reaction mixture in a flask with a reversed condenser was stirred with gentle heating till the reaction was initiated as manifested by an intense boiling (if the reflux is too intense the heating should be decreased). When succinimide stopped accumulating on the surface, the heating was continued for another 15 min (about 1 h in total). The reaction mixture was cooled to RT and the precipitate filtered off and washed with CCl4 (2×5 ml). The combined organic fractions were evaporated and the 11-Bromolinoleic acid obtained was gradually added to a solution of NaBD4 (390 mg, 10 mmol) in 30 ml of isopropanol. After an overnight stirring, a diluted solution of HCl was slowly added till there was no more deuterium gas produced. Upon a standard workup, the mono-deuterated acid was brominated and reduced again to yield a target di-deutero derivative (bp 230-231° C./15 mm, 4.4 g, 63%). MALDI-TOF MS: mono-bromo derivative, found: 358.202, 360.191 (doublet, approx 1:1, MI); di-deutero delivative, found: 282.251 (MI).
Reaction SMILES: C[N:2]([CH3:13])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Br:14][C:15]1[CH:16]=C([CH:19]=[CH:20][CH:21]=1)N>CCO.O>[Br:14][C:15]1[CH:16]=[C:13]([NH:2][CH2:3][CH2:4][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(Br)c1
Reactant: CN(C)CCC(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(CCNc1cccc(Br)c1)c1ccccc1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
A mixture of 3-(dimethylamino)-1-phenylpropan-1-one (0.1 mol) and 3-bromoaniline (0.1 mol) in 1:1 EtOH/H2O (100 mL) was heated at 80° C. overnight. The resulting mixture was concentrated and the residue was washed with H2O and then EtOH several times to give to give 3-(3-bromophenylamino)-1-phenylpropan-1-one (27 g, 90%). 1H NMR (400 MHz, CDCl3): δ=3.52 (m, 2H), 4.33 (m, 2H), 4.51 (m, 1H), 6.8 (m, 1H), 7.05 (m, 2H), 7.28 (m, 1H), 7.72 (m, 2H), 7.80 (m, 1H), 8.2 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][O:34][C:35]1[CH:41]=[CH:40][C:38]([OH:39])=[CH:37][CH:36]=1.CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:39][C:38]3[CH:40]=[CH:41][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.43 g (11.5 mmol) of hydroquinone monomethyl ether and 20 ml of dry dimethylformamide is stirred at room temperature for 16 hours, then poured into 60 ml of water and extracted three times with methylene chloride. The organic extracts are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. After chromatography on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there is obtained p-methoxyphenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 210°-211°.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22](I)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1(B(O)O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([C:34]5[C:35]6[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:31]=[CH:32][CH:33]=5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(I)cc32)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: C[C@H](Nc1nccc(-n2cnc3ccc(-c4cccc5ccccc45)cc32)n1)c1ccccc1
Yield: 87.9 %

Procedure:
2-[(S)-1-Phenylethylamino]-4-[6-iodobenzimidazol-1-yl]pyrimidine (EXAMPLE 415) (50 mg), 1-naphthyl boronic acid (22 mg), potassium carbonate (31 mg), and tetrakis(triphenylphosphine)palladium(0) (5 mg) were dissolved in degassed n-propanol (2.6 mL) and water (0.4 mL) and stirred at 80° C. under argon atmosphere for 15 hours. Upon cooling, the reaction mixture was filtered through Celite® (the ppt was washed with 10 mL of EtOAc) and evaporated. The residue was purified by preparative thin layer chromatoraphy eluted with 5% MeOH/CH2Cl2) giving 44 mg of the title compound. 1H NMR (500 MHz, CDCl3), δ 8.82 (br s, 1H), 8.38 (s, 1H), 7.97-7.75 (m, 4H), 7.54-7.29 (m, 9H), 7.19 (t, 1 H, J=7.5 Hz), 7.01 (d, 1H, J=Hz), 5.7 (s, 1H), 1.67 (d, 3H, J=7.0 Hz); Mass spectrum (ESI) 442.3 (M+1).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH2:35][C:36]1[CH:37]=[C:38]([CH:51]=[CH:52][C:53]=1[N:54]1[CH2:59][CH2:58][N:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[CH3:66])[CH2:56][CH2:55]1)[C:39]([NH:41][CH2:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C:46]1=[O:50])=[O:40].Br[C:68]1[N:73]=[CH:72][CH:71]=[CH:70][N:69]=1>CC(O)(C)C.C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:50]=[C:46]1[CH2:47][CH2:48][CH2:49][N:45]1[CH2:44][CH2:43][CH2:42][NH:41][C:39](=[O:40])[C:38]1[CH:51]=[CH:52][C:53]([N:54]2[CH2:59][CH2:58][N:57]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[CH3:66])[CH2:56][CH2:55]2)=[C:36]([NH:35][C:68]2[N:73]=[CH:72][CH:71]=[CH:70][N:69]=2)[CH:37]=1
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reactant: Brc1ncccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2Nc2ncccn2)CC1

Procedure:
N-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-3-(pyrimidin-2-ylamino)-4-(4-o-tolyl-piperazin-1-yl)-benzamide (compound no. 242) was prepared as follows: In a microwavable glass tube, Pd(OAc)2 (0.0025 g, 0.0115 mmol) and X—PHOS (5.4 mg, 0.0115 mmol) were taken in a mixture of t-BuOH:toluene (1:5) (2.0 mL) and stirred. This solution was evacuated for 5 min and purged with nitrogen. 3-Amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide (0.05 g, 0.115 mmol) and 2-bromo-pyrimidine (2.7 mg, 0.172 mmol) were added to this, evacuated and nitrogen purged. This mixture was stirred at 140° C. under MW for 30 min. LC-MS indicated the product formation along with some other by-products. The reaction mixture was concentrated, dissolved in methanol and purified on preparative HPLC using water/methanol as eluent to give desire product (10.0 mg, 17%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:28][NH2:29])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[C:30](OCC)(OCC)(OCC)[CH3:31].CS(O)(=O)=O.O1CCCC1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]3[O:27][C:30]([CH3:31])=[N:29][N:28]=3)=[CH:23][CH:24]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)NN)cc2)c1-c1ccc(F)cc1
Reactant: CCOC(C)(OCC)OCC
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nnc(Cc2ccc(NC(=O)/C=C/c3cnn(C)c3-c3ccc(F)cc3)cc2)o1
Yield: 47.1 %

Procedure:
A mixture of (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-[4-(2-hydrazino-2-oxoethyl)phenyl]acrylamide (0.50 g), triethyl orthoacetate (0.63 g), methanesulfonic acid (0.025 g), and tetrahydrofuran (10 mL) was heated under reflux for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-{4-[(5-methyl-1,3,4-oxadiazol-2-yl) methyl]phenyl}acrylamide as pale-yellow crystals (0.25 g, yield 46%) from a fraction eluted with ethyl acetate-methanol (100:0-20:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 151-152° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[NH:10][C:9]2=[N:11][C:12]([CH2:14][CH3:15])=[CH:13][C:8]2=[C:7]([Cl:16])[N:6]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>O1CCCC1.C(Cl)Cl>[CH3:3][S:4][C:5]1[N:6]=[C:7]([Cl:16])[C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[N:11]([CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[CH:19]=3)[C:9]=2[N:10]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CCc1cc2c(Cl)nc(SC)[nH]c-2n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a suspension of 48 mg (2.00 mmol) of sodium hydride in 4.0 mL of tetrahydrofuran was added 227 mg (1.00 mmol) of 2-(methylthio)-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine and 410 mg (2.00 mmol) of 3-chlorobenzyl bromide. The reaction was stirred at ambient temperature for 18 hours then diluted with 30 mL of methylene chloride and washed with 20 mL of saturated sodium bicarbonate solution. The organic phase was dried with sodium sulfate and concentrated. The crude product was purified by flash chromatography (25 g silica, methylene chloride-heptane gradient 1:1 to 100:0) to provide 350 mg (99%) of 2-(methylthio)-4-chloro-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidine as a white solid. nmr (500 MHz, CDCl3) δ1.33 (t, J=7.4 Hz, 3H), 2.58 (s, 3H), 2.59 (q, J=7.4 Hz, 2H), 5.30 (s, 2H), 6.29 (s, 1H), 6.92 (d, J=7.4 Hz, 1H), 7.09 (s, 1H), 7.23 (m, 2H)
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:29]2[CH2:31][O:30]2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:29]([OH:30])[CH2:31][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(C2CO2)cc1OC
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CCN(C)CC3)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.4 %

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (500 mg, 2.33 mmol) was dissolved in DMF (6 ml). A solution of sodium hydride (50%) (168 mg, 7.00 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(3,4-dimethoxyphenyl)oxirane (630 mg, 3.50 mmol) in DMF (4 ml) was added dropwise for 10 min and stirred for 14 h at RT. Reaction was monitored by LCMS. The reaction mixture was quenched with ice water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to get 50 mg of pure product. 1H NMR (CDCl3, Oxalate salt) δ (ppm): 7.40-7.30 (m, 2H), 7.10-7.00 (m, 1H), 6.90-6.80 (t, 2H), 6.80-6.60 (t, 1H), 5.00-4.80 (t, 2H), 4.30-4.20 (m, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 3.00-2.90 (m, 4H), 2.80 (s, 3H), 2.75-2.70 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13]C(=O)C.[OH-].[K+]>CCO.O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH2:13]
Reactant: COc1cc(OC)c(Cl)c(NC(C)=O)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c(Cl)c(N)c1Cl
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a suspension of N-(2,6-dichloro-3,5-dimethoxy-phenyl)-acetamide (f) (6.50 g, 24.61 mmol) in a mixture of EtOH (80 mL) and water (30 mL), KOH (20 g) is added, and the mixture is stirred 2 days at 80° C. After the solvent (EtOH) is removed under vacuum, water (˜15 mL) is added, and a white solid is collected by filtration and washed with water and dried to give final product g: 1H NMR 600 MHz (CDCl3) δ 6.03 (s, 1H), 4.55 (s, 2H), 3.88 (s, 6H); MS m/z 222.00 (M+1).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH:13]=O.[BH4-].[Na+].O>CO>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:13][NH:2][CH3:1]
Reactant: CN
Reactant: Cc1c(C=O)[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1[nH]c2ccccc2c1C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
Methylamine (0.34 mL, 8.4 mmol, 33% in ethanol) was added to a solution of 3-methylindole-2-carboxaldehyde (447 mg, 2.8 mmol) in methanol (10 mL) and stirred for 5 hours. Sodium borohydride (104 mg, 2.8 mmol) was slowly added at 0° C. The resultant mixture was warmed to room temperature and stirred overnight. Water (2 mL) was added slowly at 0° C. and the mixture was evaporated to a paste. The paste was partitioned between water (2 mL) and dichloromethane (15 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic phases were dried and evaporated to afford title compound (348 mg, 71%). NMR (400 MHz, DMSO-d6): 10.63 (s, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.92 (t, J=6.6 Hz, 1H), 3.73 (s, 2H), 2.25 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C(O)=O.[CH2:19]([NH:21][NH2:22])[CH3:20]>C(O)(=O)C>[CH2:19]([N:21]1[C:9]([CH2:10][CH3:11])=[CH:8][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:22]1)[CH3:20]
Reactant: CCOC(=O)C(=O)CC(=O)CC
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)n(CC)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
Ethyl 2,4-dioxohexanoate (21.5 g) in glacial acetic acid (125 ml) was cooled in an ice-bath and treated with N-ethylhydrazine oxalate (18.75 g) over 15 minutes. After addition was complete the mixture was stirred for 3 hours at room temperature. The acetic acid was then removed by evaporation in vacuo. The orange oily residue was dissolved in EtOAc and the solution washed repeatedly with saturated aqueous NaHCO3 and once with brine. Following drying over MgSO4 the solvent was evaporated in vacuo to give ethyl 1,5-diethylpyrazole-3-carboxylate as an oil (20.7 g); δ(CDCl3) 1.25-1.45 (9H, 3×3H,t, J 7 Hz), 2.62 (2H, q, J 7 Hz), 4.17 (2H, q, J 7 Hz), 4.38 (2H, q, J 7 Hz), 6.57 (1H, s) ppm.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C([O-])(=O)C.[Na+].O>CO>[CH3:16][O:15][C:13](=[O:14])[CH2:12][NH:8][C:7]1[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: COC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CNc1ccc(C(C)C)cc1

Procedure:
A solution of 4-isopropylaniline (5.05 g, 37.3 mmol), methyl bromoacetate (5.99 g, 39.2 mmol) and anhydrous sodium acetate (3.21 g) in absolute methanol (30 mL) was heated to reflux for 2 h. The solution was cooled and poured into 300 mL water. The resulting solid was collected by filtration and recrystallized from ethanol/water to afford pure product, methyl-2-(4-isopropylanilino)acetate, m.p. 35-36° C. (4.53 g, 55%). 1H NMR (CDCl3, 300 MHz): δ7.06 (2H, d, J=8.2 Hz), 6.57 (2H, d, J=8.2 Hz), 4.18 (1H, v br), 3.90 (2H, s), 3.78 (3H, s), 2.81 (1H, m, J=7.0 Hz), 1.20 (6H, d, J=7.0 Hz). Mass spectrum (ES+): m/z 209 (3), 208 (31), 148 (100).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:6]1[C:7](OC)=[O:8])=[O:4].[NH3:15]>CO>[OH:14][C@@H:11]1[CH:6]2[C:7](=[O:8])[NH:15][CH2:2][C:3](=[O:4])[N:5]2[CH2:13][CH2:12]1
Reactant: N
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)CCl
Solvent: CO
Product: O=C1NCC(=O)N2CC[C@H](O)C12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl (3S)-1-(chloroacetyl)-3-hydroxy-L-prolinate (D69, 1.48 g, 6.7 mmol) in 10 ml of MeOH and 60 ml of a saturated solution of NH3 in MeOH was stirred for 48 h at rt. The solvent was evaporated under reduced pressure, to afford a solid. Analysis indicated this to be the title compound as a pair of diastereoisomers. After a short chromatography column (CHCl3/MeOH 8/2 as eluent) the title compound was isolated as a foamy solid (1 g). Yield 88%. Reference: Khimiko-Farmatsevticheskii Zhurnal 1984, 18, 1445-8
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=O)[CH3:25].Cl.[NH2:28][OH:29].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=[N:28][OH:29])[CH3:25]
Reactant: NO
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=O)c2cc1OC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=NO)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone (compound 38) (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. Hydroxylamine hydrochloride (12 mg) and triethylamine (27 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Further, hydroxylamine hydrochloride (12 mg) and triethylamine (27 mg) were then added to the reaction solution, and the mixture was stirred at room temperature for 5 hr. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (10 mg, yield 31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](Cl)=[O:8].[CH2:13]([NH2:16])[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([NH:16][CH2:13][CH:14]=[CH2:15])=[O:8]
Reactant: O=C(Cl)C=Cc1cccc(F)c1
Reactant: C=CCN
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: C=CCNC(=O)C=Cc1cccc(F)c1
Reaction time: 72 h

Procedure:
A solution of 3-fluorocinnamoyl chloride (3.7 g) in dry toluene (35 ml) was added with stirring to allylamine (8 ml) in dry benzene (100 ml). The reaction mixture was allowed to stand at room temperature for three days. After evaporation of the solvents under reduced pressure the residue was triturated with water containing a small amount of sodium carbonate and washed with water. Recrystallization from ethanol: water gave 3-fluoro-N-allylcinnamamide (3.3 g), m.p. 84.5-87° C. as fine white needles. Elemental analysis, nmr and ir spectra were consistent with the structure assignment.