Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:19]([O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[N:15]=[CH:16][N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]cn1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1cn(Cc2ccccc2)cn1)C(=O)OCc1ccccc1
Yield: 30273.2 %

Procedure:
2-tert-Butoxycarbonylamino-3-(1H-imidazol-4-yl)-propionic acid (25 g, 97.92 mmol), benzyl bromide (17.59 g, 12.2 mL, 0.103 mmol) and potassium carbonate (16.9 g, 0.122 mol) in DMF (250 mL) were stirred overnight under argon. The solvent was removed and the residue taken up into water and CH2Cl2. The organic layer was washed with water and brine, dried and filtered. The solvent was removed and the residue subject to column chromatography (silica gel, 75% EA/PE to afford 3-(1-benzyl-1H-imidazol-4-yl)-2-tert-butoxycarbonylamino-propionic acid benzyl ester (6.79 g, 16%) Rf 0.6, followed by 10% MeOH/EA to afford the title compound (15.832 g, 47%) Rf 0.1). ESMS 346 (M+H+) Mpt 100.5-101.7° C. 1H NMR (500 MHz, CDCl3) δ 1.42 (9H, s), 3.02 (2H, m), 4.51 (1H, m), 5.19 (1H, d, J=12.1 Hz), 5.08 (1H, d, J=12.1 Hz), 5.81 (1H, m), 7.35 (5H, m), 7.47 (1H, s). 13C NMR (CDCl3) δ 28.22, 29.48, 53.67, 66.88, 79.88, 116.23, 126.63, 128.26, 128.45, 133.61, 135.19, 135.39, 155.59, 171.97.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:29]=[O:30])C>C1COCC1.CCCCCC>[CH:29]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1)=[O:30]
Reactant: CN(C)C=O
Reactant: Brc1ccc(CCOC2CCCCO2)c2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(CCOC2CCCCO2)c2ccccc12
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 1-bromo-4-(2-tetrahydropyranyloxyethyl)naphthalene in anhydrous THF (15 mL) under nitrogen was cooled to −78° C. n-Butyl lithium (1.4 mL of a 2.5 M solution in hexane) was added via syringe, and the mixture was stirred at the same temperature for 30 min. DMF (1.1 mL) was added, and the mixture was allowed to reach room temperature. It was diluted with satd. NH4Cl solution (10 mL), extracted with ether (3×10 ml), dried (MgSO4) and concentrated. Flash chromatography using hexane/ethyl acetate 5:1 as eluent provided 408 mg (54%) of a colorless oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>ClCCl.CN(C1C=CN=CC=1)C>[CH3:16][C:13]1([CH3:17])[N:12]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1C(=O)c1ccccc1
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
A solution of 2-(adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one (33.6 mg, 0.140 mmol) prepared in Process 3 of Example 12 in dichloromethane (2 mL) was added sequentially with benzoyl chloride (40.0 mg, 0.280 mmol), triethylamine (56.6 mg, 0.560 mmol), and DMAP (catalyst amount) at room temperature, and the resultant was stirred at the same temperature for 1.5 hours. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=3:1), and the title compound (40.4 mg, 85.3%) was obtained as a white crystalline powder.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:34]1([C:39]2[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>O.CCO.C1(C)C=CC=CC=1.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.CCCCCC>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:41]3[CH:42]=[CH:43][CH:44]=[C:39]([N:34]4[CH2:35][CH2:36][CH2:37][CH2:38]4)[CH:40]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1cccc(N2CCCC2)c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
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: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cccc(N2CCCC2)c1

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)-benzyl]-4-methyl-1,3-oxazolidin-2-one (0.05 g, 0.084 mmol), 3-(pyrrolidino)phenyl boronic acid (0.032 g, 0.167 mmol), tetrakis(triphenylphosphine)palladium (5% mol) and sodium carbonate (0.019 g, 0.18 mmol) in 7 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 4 h. TLC (EtOAc:hexane/1:1) showed that the reaction was over. The solvents were removed. Water (10 ml) was added. The organic was extracted with methylene chloride (3×10 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/6:4 as the eluant. LC-MS (M+1): 617.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.C(O)(=O)C.[CH2:18]([NH2:21])[CH2:19][CH3:20].[BH3-]C#N.[Na+]>ClC(Cl)C.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:21][CH2:18][CH2:19][CH3:20])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCCNC1CCc2ccc(OC)cc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-Methoxy-2-tetralone (6.21 g, 35.2 mmol) and acetic acid (5.3 ml, 105.6 mmol) were dissolved in dichloroethane (100 ml) and cooled to 0° C. Propyl amine (5.7 ml, 70.4 mmol) was added and the mixture was stirred under a N2 atmosphere for 30 min. NaCNBH3 (5.5 g, 80.8 mmol) in anhydrous MeOH (15 ml) was then added to the mixture and allowed to stir overnight at ambient temperature. The volatiles were then evaporated and the mixture was partioned between ethyl acetate and 1 M NaOH. The organic layer was separated, dried (Na2SO2), filtered, and concentrated. The crude residue was then taken up in EtOAc, at which time ethereal HCl was added, and the material evaporated to dryness. The crude salt was dissolved in a minimum volume of MeOH, and precipitated by the gradual addition of diethyl ether. The salt was collected via filtration and dried to yield 5.09 g (64%, free base) and used in the subsequent transformations. 1H NMR (free base) (400 MHz, CDCl3) 0.91-0.95 (t, 3H, J=7.6 Hz), 1.38 (bs, 1H), 1.48-1.60 (m, 3H), 2.04-2.09 (m, 1H), 2.54-2.62 (m, 2H), 2.67-2.71 (t, 3H, J=7.6 Hz), 2.88-2.92 (m, 2H), 2.97-3.04 (m, 1H), 3.81 (s, 3H), 6.60-6.61 (dd, 1H, J=1.6 Hz), 6.65-6.78 (m, 1H), 6.95-6.98 (d, 1H, J=8.8 Hz).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([N:22]3[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[C:17]([F:29])[CH:16]=2)[CH2:10]1)(C)(C)C.C1(C(C2C=CC=CC=2)CCO[C:41](=[S:45])[CH:42]([F:44])[F:43])C=CC=CC=1>>[F:21][C:19]1[CH:20]=[C:15]([N:11]2[CH2:10][CH:9]([CH2:8][NH:7][C:41](=[S:45])[CH:42]([F:44])[F:43])[O:13][C:12]2=[O:14])[CH:16]=[C:17]([F:29])[C:18]=1[N:22]1[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][CH2:23]1
Reactant: FC(F)C(=S)OCCC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Product: O=C1C=CN(c2c(F)cc(N3CC(CNC(=S)C(F)F)OC3=O)cc2F)CC1

Procedure:
The title compound compound is prepared from {3-[3,5-difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (250 mg, 0.59 mmol) and difluorothioacetic acid-O-(3,3-diphenyl-propyl) ester (420 mg, 1.25 mmol) following the method described for Example 10. The crude product is purified by silica gel column chromatography (gradient 50 to 100% EtOAc in hexanes). MS (m/z): 418 [M+1]+. 1H NMR (300 MHz, CDCl3) δ11.13 (br. s, 1H), 7.46–7.38 (m, 3H), 6.49 (t, J=55.2 Hz, 1H), 5.07–4.98 (m, 2H), 4.19 (t, J=9.1 Hz), 1H), 4.02–3.76 (m, 5H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:8][C:9]([F:13])=[C:10]([F:12])[Cl:11]>C1(C=CC(O)=CC=1)O>[CH3:3][C:2]1([C:1]([O:6][CH3:7])=[O:5])[CH2:4][C:9]([F:13])([F:8])[C:10]1([Cl:11])[F:12]
Reactant: FC(F)=C(F)Cl
Reactant: C=C(C)C(=O)OC
Agent: Oc1ccc(O)cc1
Product: COC(=O)C1(C)CC(F)(F)C1(F)Cl
Temperature: 140 °C
Yield: 53.9 %

Procedure:
174 g (1.74 mol) of methyl methacrylate and 1.5 g of hydroquinone are initially introduced into an autoclave, and 200 g (1.74 mol) of trifluorochloroethylene are added at -70° C. 7 bar of nitrogen are injected, and the mixture is then heated to 140° C. The pressure which is established at this temperature is increased to 28 bar by injecting more nitrogen. The mixture is maintained at 140° C. for 17 hours and then allowed to cool, the pressure is released, and the mixture is distilled. In this process, 203 g (54% of theory) of methyl 1-methyl-2-chloro-2,3,3-trifluoro-cyclobutane-1-carboxylate are obtained in form of a liquid of boiling point 57° C. at 17 mbar.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:9][C:10]([C:12]#[C:13][C:14](OCC)=[O:15])=[O:11])[CH3:8]>C(O)C>[CH2:7]([O:9][C:10]([C:12]1[N:6]2[CH:5]=[CH:4][S:3][C:2]2=[N:1][C:14](=[O:15])[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Nc1nccs1
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sccn12
Reaction time: 8 h

Procedure:
5 g of 2-aminothiazole are dissolved in 50 ml of ethanol and 8.5 g of acetylene dicarboxylic acid diethyl ester are added to the resulting solution. The mixture increases in temperature and a solid substance begins to precipitate. After standing overnight, it is filtered off, washed with a little ethanol and dried. 7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 173° to 175° C. is thus obtained in a yield of 8.2 g (85.4% of the theoretical).
Reaction SMILES: O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(C)C(=C(C)C(=O)CC1)CC3.C(OC)=O.[OH:27][C@@:28]1(C)[CH2:33][CH2:32][C@H:31]2[C@H:34]3[C@H:44]([CH2:45][CH2:46][C@:29]12[CH3:30])[C@:42]1([CH3:43])[C:37](=[C:38]([CH3:50])[C:39](=[O:49])[C:40](=[CH:47][OH:48])[CH2:41]1)[CH2:36][CH2:35]3.[H-].[Na+]>>[OH:48][CH:47]=[C:40]1[CH2:41][C@@:42]2([CH3:43])[C:37]([CH2:36][CH2:35][C@@H:34]3[C@@H:44]2[CH2:45][CH2:46][C@@:29]2([CH3:30])[C@H:31]3[CH2:32][CH2:33][C@@H:28]2[OH:27])=[C:38]([CH3:50])[C:39]1=[O:49]
Reactant: CC1=C2CC[C@@H]3[C@H](CC[C@@]4(C)[C@H]3CC[C@]4(C)O)[C@@]2(C)CC(=CO)C1=O
Agent: CC1=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: COC=O
Product: CC1=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC(=CO)C1=O

Procedure:
2-Hydroxymethylene-17β-hydroxy-4-methylandrost-4-en-3-one was prepared from 32.28 g. of 17β-hydroxy-4-methylandrost-4-en-3-one and 32 ml. of methyl formate by a procedure analogous to that of Example 1, part (c) except that sodium hydride (15 g., 50%) was used in place of sodium methoxide. The 20 g. of product obtained was used directly in the next reaction.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13](O)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:37])[NH:26][C:27]([CH3:36])=[CH:28][C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([NH:22][CH2:23][C:24]3[C:25](=[O:37])[NH:26][C:27]([CH3:36])=[CH:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3]
Reactant: Cc1cc(-c2ccccc2)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21
Product: Cc1cc(-c2ccccc2)c(CNC(=O)c2cc(-c3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 11 from 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg, 0.531 mmol) and 3-(aminomethyl)-6-methyl-4-phenyl-2(1H)-pyridinone (133 mg, 0.531 mmol). The product was collected as a white solid, 0.041 g (15%). LCMS E-S (M+H)=479.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (d, J=6.82 Hz, 6H) 2.23 (s, 3H) 4.23-4.27 (m, 2H) 5.33-5.42 (m, 1H) 6.02-6.04 (m, 1H) 7.35-7.42 (m, 1H) 7.43 (s, 4H) 8.23-8.26 (m, 1H) 8.34-8.39 (m, 2H) 8.41-8.42 (m, 1H) 8.84-8.88 (m, 2H) 8.91-8.96 (m, 1H) 11.91 (s, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:20])[O:8][C:7]2[C:9]([CH:13]([C:15]3[N:16]=[CH:17][NH:18][CH:19]=3)O)=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.N.[Na].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CO.O1CCCC1>[CH3:2][C:3]1([CH3:20])[O:8][C:7]2[C:9]([CH2:13][C:15]3[N:16]=[CH:17][NH:18][CH:19]=3)=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1
Reactant: CC1(C)OCc2cccc(C(O)c3c[nH]cn3)c2O1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)OCc2cccc(Cc3c[nH]cn3)c2O1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
94.13 g (0.317 mole) of alpha-(2,2-dimethyl-4H-1,3-benzodioxin-8-yl)-1H-imidazole-4-methanol hydrochloride (prepared in Example 3.1. or 3.5.) are introduced into 1 liter of anhydrous liquid ammonia. The solubilization of the reagent is completed by the addition of 1 liter of tetrahydrofuran. 14.6 g (0.634 mole) of sodium are then added piece by piece. 5 minutes after the sodium has disappeared, 34 g of ammonium chloride are added and the reaction mixture is stirred for 30 minutes. There is then added 1.56 liter of a 10% solution of methanol in toluene. The ammonia is then evaporated on a water-bath. 780 ml of water are then added and the organic phase is separated. The aqueous phase is extracted twice with 500 ml of toluene. The organic phases are combined and washed with 1 liter of water, then dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue obtained is recrystallized from 900 ml of boiling acetone. There are thus obtained 57.8 g of 4-[(2,2-dimethyl-4H-1,3-benzodioxin-8-yl)methyl]-1H-imidazole; M.P.: 160°-170° C. Yield: 74.6% of theory.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[NH:5][C:3]1=[O:4].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[N:5]([CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])[C:3]1=[O:4]
Reactant: C=CCCCCBr
Reactant: Cn1c(=O)[nH]c2ncn(C)c2c1=O
Product: C=CCCCCn1c(=O)n(C)c(=O)c2c1ncn2C

Procedure:
is prepared analogously to Example 6 from 1,7-dimethyl-xanthine and 6-bromo-hex-1-ene.
Reaction SMILES: C1(S([C:10]2([CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:10]1([CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(c1ccccc1)C1(CCOCc2ccccc2)C=CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C1=CCCC(CCOCc2ccccc2)=C1
Temperature: 80 °C
Reaction time: 32 h

Procedure:
[2-(1-Benzenesulfonyl-cyclohex-2-enyl)-ethoxymethyl]-benzene (8) (16 g, 44.9 mmol) is dissolved in tert. butanol (450 ml) and after addition of potassium tert.-butoxide (11.1 g, 98.7 mmol) the mixture is stirred for 32 h at 80° C. Then the mixture is poured on ice and extracted with pentane. The organic layer is separated, washed with saturated NaCl-solution and dried over Na2SO4. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (1:9), silicagel).
Reaction SMILES: [Li+].[Cl-].[Cl:3][C:4]1[CH:5]=[N:6][C:7]([F:18])=[C:8]([C:16]=1[F:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[I:19]I>C1COCC1>[Cl:3][C:4]1[C:5]([I:19])=[N:6][C:7]([F:18])=[C:8]([C:16]=1[F:17])[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)c1c(F)ncc(Cl)c1F
Reactant: II
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(F)nc(I)c(Cl)c1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
Into a solution of TMPMgCl LiCl (1.0 M×2.4 mL, 2.4 mmol) in THF at −45° C. was added dropwise a solution of tert-butyl 5-chloro-2,4-difluoronicotinate (0.4 g, 1.6 mmol) in THF (3.0 mL). The mixture was stirred for 20 min then iodine (0.61 g, 2.4 mmol) was added. After 15 min at −45° C., the temperature was allowed to warm to 0° C. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified by silica chromatography (0-5% ethyl acetate in hexanes) to give tert-butyl 5-chloro-2,4-difluoro-6-iodonicotinate (0.4 g, 67%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1.Cl[C:18]1[C:23]([CH2:24][CH2:25]Cl)=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[N:21]=[C:20]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:19]=1>O1CCCC1>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([C:22]2[C:23]3[CH2:24][CH2:25][N:16]([C:14]4[CH:13]=[CH:12][N:11]=[C:10]([N:7]5[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]5)[CH:15]=4)[C:18]=3[N:19]=[C:20]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:21]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CN1CCN(c2cc(N)ccn2)CC1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccnc(N3CCN(C)CC3)c2)c1
Yield: 81.3 %

Procedure:
Sodium hydride (108 mg, 60% mineral oil dispersion, 2.72 mmol) was placed in a dried flask under a nitrogen atmosphere, followed by sequential addition of anhydrous tetrahydrofuran (10 ml) and 2-(4-methylpiperazin-1-yl)pyridin-4-ylamine (62 mg, 0.32 mmol) with a syringe, and the resulting mixture was heated to reflux for 2 hours. 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]morpholine (100 mg, 0.27 mmol) was added, followed by heating to reflux for 16 hours. The reaction mixture was cooled, which was subsequently added dropwise slowly onto ice water, followed by extraction twice with ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), and dried over sodium sulfate, followed by distilling off under reduced pressure, to obtain a crude product as a red oil (107 mg).
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=O)[N:9]=1)([CH3:3])[CH3:2].[S:12]1[CH2:18][C:16](=[O:17])[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:13]1=[S:14].[Cl-].[NH4+].N>C(O)C>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[C:18]2[S:12][C:13](=[S:14])[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:16]2=[O:17])[N:9]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Nc1nc(C=O)cs1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)Nc1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1

Procedure:
The reaction described in Example 1 was repeated, but using 2.7 g of 2-isopropylaminothiazole-4-carbaldehyde, 2.3 g of rhodanine-3-acetic acid, 1.7 g of ammonium chloride, 1.7 ml of 28% v/v aqueous ammonia and 50 ml of ethanol, giving the title compound as dark red needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cc(C)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1Cl
Yield: 91.6 %

Procedure:
To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol) in CCl4 (350 mL) was added NBS (57 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture was heated at reflux for 3 hours. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.33-7.31 (m, 1H), 6.95-6.91 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:28])[CH:14]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][Br:27])=[CH:22][CH:21]=1)[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:13]([OH:28])=[O:12])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(c1ccc(CBr)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.635 ml (2.420 g, 21.228 mmol) of trifluoroacetic acid were added to a solution of 500 mg (1.415 mmol) of tert-butyl[4-(bromomethyl)phenyl](cyclopentyl)acetate (Example 10A) in 5 ml of dichloromethane. The mixture was stirred at room temperature for 2 h. Saturated aqueous sodium bicarbonate solution was then added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. This gave 364 mg (87% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[O:46]1[CH2:50][CH2:49][CH2:48][C@H:47]1[CH2:51]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH:48]5[CH2:49][CH2:50][O:46][CH2:51][CH2:47]5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Reactant: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNCC5CCOCC5)c4)cc23)CC1
Yield: 68.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-(tetrahydro-2H-pyran-4-yl)methanamine (60 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 40.1 mg of the title compound (68.7%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14]([O:16]CC)=O)[C:4]1=[O:19])[CH3:2].Cl.[CH3:21][O:22][C:23](=[O:26])[CH2:24][NH2:25]>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14]([NH:25][CH2:24][C:23]([O:22][CH3:21])=[O:26])=[O:16])[C:4]1=[O:19])[CH3:2]
Reactant: COC(=O)CN
Reactant: CCOC(=O)c1c(O)c2ccccc2n(CC)c1=O
Agent: Cl
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(C(=O)NCC(=O)OC)c(O)c2ccccc21
Yield: 11 %

Procedure:
In 4 mL of toluene in a microwave vial, ethyl 1-ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (0.380 g, 1 mmol), glycine methyl ester hydrochloride (0.5 g, 4 mmol) was microwaved at 180° C. for 3 minutes and then purified by silica flash chromatography with a 1-5% MeOH/DCM gradient to afford 0.050 g. Yield: 11%