Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][CH:4]1[N:7]([CH:8](O)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH2:5]1)[CH3:2].CC1C=CC=C(C)N=1.S(Cl)([Cl:34])=O>O1CCCC1>[CH2:1]([S:3][CH:4]1[N:7]([CH:8]([Cl:34])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:6](=[O:23])[CH2:5]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCSC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6.8 g. of p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-2-hydroxyacetate in 200 ml. of tetrahydrofuran at 0°-5° C. was added 2.98 ml. of 2,6-dimethylpyridine. This was followed by dropwise addition of a solution of 1.73 ml. of thionyl chloride in 20 ml. of tetrahydrofuran, over a 5-minute period. Stirring was continued at 0°-5° C. for 15 minutes, and then the reaction mixture was filtered. The filtrate was evaporated to dryness in vacuo, and the residue was dissolved in 200 ml. of dichloromethane. The resulting solution was washed successively with dilute hydrochloric acid and water, and dried with anhydrous sodium sulfate. Evaporation in vacuo gave the title compound as a yellow, viscous liquid (yield: 7.12 g). The IR spectrum (CHCl3) of the product showed an absorption at 5.63 microns. The NMR spectrum (CDCl3) of the product showed absorptions at 1.3(t,3H); 2.47-3.7(m,4H); 4.9-5.3(m, 1H); 5.4(s,4H); 6.06 and 6.18(ss,1H); 7.58 (d,2H); and 8.22(d,2H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:24]([CH2:31][CH3:32])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:8].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[CH:43][C:44]([CH:47]=[O:48])=[N:45][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH2:31]([N:24]([CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:4]1[C:5]([CH3:23])=[C:6]([CH:22]=[C:2]([C:41]2[CH:46]=[N:45][C:44]([CH:47]=[O:48])=[CH:43][CH:42]=2)[CH:3]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:8])[CH3:32]
Reactant: CC1(C)OB(c2ccc(C=O)nc2)OC1(C)C
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc(N(CC)C2CCOCC2)c1C
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: C1COCCO1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(C=O)nc2)cc(N(CC)C2CCOCC2)c1C
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A solution of 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)benzamide (0.5 g, 0.99 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinaldehyde (0.346 g, 1.48 mmol), and tetrakis (0.114 g, 0.99 mmol) in dioxane (10 mL) was purged with argon for 10 min. To this, aq. Na2CO3 (0.378 g, 3.56 mmol, 1.8 mL) was added and again degassed for 10 min. Reaction mixture was heated at 100° C. for 16 h. On completion, it was concentrated to obtain crude material which was column purified to afford the title compound (0.40 g, 76.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:14]1([CH2:20][C:21](=O)[CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:12][C:6]1([CH3:13])[C:7](=[O:11])[NH:8][C:9]2[CH:10]=[C:2]3[C:3](=[CH:4][C:5]1=2)[C:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:21]([CH3:22])[NH:1]3
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Reactant: CC(=O)Cc1ccccc1
Solvent: ClCCl
Product: Cc1[nH]c2cc3c(cc2c1-c1ccccc1)C(C)(C)C(=O)N3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Analogously to Example 5, 4 g. (22.7 mmole) 6-amino-3,3-dimethylindolin-2-one are diazotised and reduced. Subsequently, 3 g. (22.3 mole) phenylacetone are added thereto and the reaction mixture further stirred for 18 hours at 25° C. The oil which separates out is shaken out several times with methylene chloride, evaporated and the residue worked up with cyclohexane and filtered off with suction. The solid residue is again dissolved in methylene chloride, washed twice with aqueous sodium hydrogen carbonate solution and once with water, dried with anhydrous sodium sulphate with the addition of charcoal and crystallised from methylene chloride. Yield 1.25 g. (19% of theory); m.p. 233°-235° C.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([NH:11][C@@H:12]([CH3:28])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([Cl:27])[CH:20]=3)=[N:15]2)=[O:10])[N:8]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O.Cl>C(O)C>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:9]([C:7]3[N:8]=[C:4]([CH:1]([OH:3])[CH3:2])[S:5][CH:6]=3)=[O:10])[CH3:28])[N:15]=2)[CH:24]=[CH:23][C:22]=1[C:25]#[N:26]
Reactant: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
Into a flask containing (S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide (1 g, 2.416 mmol) dissolved in ethanol (10 ml), sodium borohydride (0.137 g, 3.62 mmol) was added in small parts under nitrogen atmosphere. The following mixture was stirred overnight in RT. Next morning water (1 ml) was added dropwise and the pH of the mixture was adjusted to under 7 with 1 M HCl and the mixture was evaporated. 30 ml of ethyl acetate was added and stirred for 30 min, filtered and the filtrate was evaporated and dried in vacuum at 40° C. The product was purified by recrystallizing it twice from diethyl ether/ethanol to yield 41.6% of the title compound. 1H-NMR (400 MHz; DMSO-d6): δ 1.10-1.16 (m, 3H), 1.44-1.48 (m, 3H), 4.29-4.52 (m, 3H), 4.94-4.02 (m, 3H), 6.22-6.26 (m, 1H), 6.95-6.99 (m, 1H), 7.83-7.88 (m, 1H), 7.93-8.00 (m, 2H), 8.07-8.10 (m, 1H), 8.11 (d, 1H), 8.33-4.39 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[OH:12])=[CH:4][N:3]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br)#[N:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:18][C:17]3[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=3)[C:13]#[N:14])[C:9]2=[O:12])=[CH:4][N:3]=1
Reactant: Oc1nccc2cnc(Br)cc12
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cn2ccc3cnc(Br)cc3c2=O)c1

Procedure:
The alkylation of 7-bromo-1-hydroxy-6-azaisoquinoline (1.00 g, 4.40 mmol) using 3-cyanobenzyl bromide (1.31 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 3-[1-oxo-7-(3-Phenyl-prop-1-ynyl)-1H-6-azaisoquinolin-2-ylmethyl]benzonitrile
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.C([O-])([O-])=O.[K+].[K+].[F:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[OH:34].CO.CCOC(C)=O>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[O:34][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=C(c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1)N1CCCC1
Yield: 93.8 %

Procedure:
A mixture of 21 (2.4 g, 8.89 mmol), K2CO3 (4.97 g, 35.96 mmol) and 2-fluoro-4-nitrophenol (1.55 g, 9.89 mmol) were heated at 150° C. in diphenyl ether (40 mL) for 2 days. The mixture was purified by column chromatography (eluents EtOAc-hexane 5:95, 2:8, then MeOH-EtOAc 2:98, 5:95) to give the title compound 22 as a yellow solid (3.23 g, 93% yield). MS (m/z): 388.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:14])=[C:8]([CH2:12]O)[CH:9]=[CH:10][CH:11]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:21][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:2]([CH3:1])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[C:7]=1[CH3:14]
Reactant: Cc1cccc(C)c1COc1cccc(CO)c1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(C)c1COc1cccc(CBr)c1C
Reaction time: 4 h

Procedure:
To a solution of (3-(2,6-dimethylbenzyloxy)-2-methylphenyl)methanol (Step C, 3.68 g, 14.37 mmol) and CBr4 (5.25 g, 15.8 mmol) in dry CH2Cl2 (20 ml) was added portion wise triphenylphosphine (4.14 g, 15.8 mmol) at 0° C. The reaction mixture was stirred for 4 hours, filtered, concentrated and purified by flash chromatography on a silica gel column (hex: ethyl acetate 4:1) to give the title compound. The solid was further kept under vacuum for 6 hours to dry.
Reaction SMILES: BrC1C(=O)C(C(O)=O)=CN(C(C)C)C=1C.[Br:16][C:17]1[C:18](=[O:31])[C:19]([C:28]([OH:30])=O)=[CH:20][N:21]([C@H:24]([CH2:26][CH3:27])[CH3:25])[C:22]=1[CH3:23].Cl.CS(C1C=CC(CN)=CC=1)(=O)=O.[CH3:45][C:46]1[O:50][C:49]([CH2:51][NH2:52])=[N:48][N:47]=1.BrBr>>[CH3:45][C:46]1[O:50][C:49]([CH2:51][NH:52][C:28]([C:19]2[C:18](=[O:31])[C:17]([Br:16])=[C:22]([CH3:23])[N:21]([C@H:24]([CH2:26][CH3:27])[CH3:25])[CH:20]=2)=[O:30])=[N:48][N:47]=1
Reactant: CC[C@H](C)n1cc(C(=O)O)c(=O)c(Br)c1C
Reactant: Cc1nnc(CN)o1
Agent: BrBr
Agent: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Product: CC[C@H](C)n1cc(C(=O)NCc2nnc(C)o2)c(=O)c(Br)c1C

Procedure:
Preparation 26 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 12b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methyl-[1,3,4]oxadiazol-2-yl)-methylamine. ESI mass spectrum: [M+H]+=383 (bromine isotope pattern); Retention time HPLC: 0.83 min (Z018_S04).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([CH3:21])[N:8]=2)[CH:6]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3,4-dichlorophenyl)-6-methyl-pyrimidine (example E.61) (0.16 g, 0.42 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.12 g, 0.54 mmol) according to the general procedure VI. Obtained as a yellow solid (0.043 g, 26%). MS (ISP) 398.1 [(M+H)+]; mp 255.5° C.
Reaction SMILES: [Mg].Br[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][N:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]1=[O:19].[NH4+].[Cl-]>C1COCC1>[CH3:11][N:12]1[C:13](=[O:19])[CH2:14][CH2:15][CH2:16][C:17]1([CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:18]
Reactant: CN1C(=O)CCCC1=O
Reactant: BrC=Cc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)CCCC1(O)C=Cc1ccccc1

Procedure:
The Grignard reagent prepared in 300 ml of THF from 24 g (1.0 mole) of magnesium and 42 g (0.30 mole) of β-bromostyrene is decanted from excess metal and added dropwise under nitrogen to a solution of 27 g (0.21 moles) of N-methyl glutarimide at 3°-5°. After 1 1/2 hrs. at room temperature, the mixture is treated with 250 ml of saturated NH4Cl solution with cooling. The separated aqueous layer is reextracted and the combined THF extracts washed with salt, dried over MgSO4 and freed of solvent. Product is extracted into hot ether and crystallized on cooling to yield white crystals, mp 108°-112°C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][N:32]([S:40]([CH3:43])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:38]=1)[S:40]([CH3:43])(=[O:42])=[O:41]
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine Rf value: 0.6 (silica gel, methylene chloride/methanol=5:1) C28H30N4O5S
Reaction SMILES: CO.Cl.Cl.[Cl:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:9][NH:10][C:11]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[NH:15])=[NH:12].[CH3:29][C:30]([CH3:32])=O>>[ClH:5].[CH2:17]([NH:16][C:14]1[NH:13][C:11]([NH:10][CH2:9][C:8]2[CH:25]=[CH:26][C:27]([Cl:28])=[C:6]([Cl:5])[CH:7]=2)=[N:12][C:30]([CH3:32])([CH3:29])[N:15]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCNC(=N)NC(=N)NCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(Cl)c(Cl)c2)N1

Procedure:
25 ml of methanol, 40 ml of acetone and 0.1 ml of concentrated hydrochloric acid were added to 1.8 g (4.4 mmol) of N1-(3′,4′-dichlorobenzyl)-N5-octyl-biguanide hydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled of f under reduced pressure, and the residue was dissolved in 80% aqueous acetonitrile. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.5 g of a colorless resinous solid (1) from the first main elution fraction with a mixture of chloroform and methanol (95:5), and 0.7 g of a colorless resinous solid (2) from the second main elution fraction.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([N:18]1[C:22]([C:23](=[O:25])[CH3:24])=[CH:21][N:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O1CCCC1>[CH2:11]([N:18]1[C:22]([C:23]([OH:25])([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:24])=[CH:21][N:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrCCc1ccccc1
Reactant: CC(=O)c1cncn1Cc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(O)(CCc1ccccc1)c1cncn1Cc1ccccc1
Temperature: 25 °C

Procedure:
1.0 g of magnesium turnings are covered with 5 ml of dry tetrahydrofuran. To the mixture is added 7.8 g of (2-bromoethyl)benzene in 30 ml of dry tetrahydrofuran at such a rate that a smooth reaction is maintained. The mixture is then heated under reflux for one hour. After being cooled to room temperature, 3.0 g of 1-(3-benzyl-3H-imidazol-4-yl)-ethanone in 20 ml of tetrahyrofuran is added dropwise to the Grignard reagent and the reaction mixture is refluxed for one hour. The cooled reaction mixture is poured into a cold dilute hydrochloric acid solution. Work-up of the mixture gives the crude product, which is recrystallized from ethyl acetate. The yield is 3.3 g.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:51]=[CH:50][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]56[CH2:40][CH:35]7[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]7)[CH2:32]5)[CH2:38]6)=[CH:27][CH:26]=4)=[CH:20][C:19]=3[N:41]([CH3:49])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:52].O1CCOCC1>>[ClH:52].[C:31]12([C:28]3[CH:29]=[CH:30][C:25]([O:24][C:21]4[CH:22]=[CH:23][C:18]5[N:17]=[C:15]([CH2:14][O:13][C:12]6[CH:11]=[CH:10][C:9]([CH2:8][CH:4]7[S:3][C:2](=[O:1])[NH:6][C:5]7=[O:7])=[CH:51][CH:50]=6)[N:41]([CH3:49])[C:19]=5[CH:20]=4)=[CH:26][CH:27]=3)[CH2:38][CH:37]3[CH2:39][CH:33]([CH2:34][CH:35]([CH2:36]3)[CH2:40]1)[CH2:32]2
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)cc21
Temperature: 25 °C
Reaction time: 29 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-[4-(1-adamantyl)phenoxy]phenyl}-N-methylcarbamate (1.82 g) and 4N hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 29 hours. The solvent of the reaction mixture was evaporated to dryness and to the residue was added ether and the insoluble product was filtered and washed with ether to give the title compound (1.35 g).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25].Cl>C(Cl)Cl.O1CCOCC1>[C:24]([O:16][CH2:15][C:13]1[C:12]2[C:7]([CH:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:26])[CH3:25]
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)OCc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 61 %

Procedure:
A solution of 9-anthracenemethanol (15.0 g, 72 mmole) and triethylamine (7.3 g, 72 mmole) in methylene chloride (100 ml) and 1,4-dioxane (120 ml) was cooled. Acetyl chloride (6.8 g, 86.4 mmole) was added dropwise to the solution at 5°-10° C. and reacted with stirring for 2.5 hours at same temperature. After reaction, the reaction mixture was poured into ice-cold H2O (350 ml), acidified with 10% aqueous HCl, extracted with methylene chloride (100 ml). The resulting organic layer was washed with H2O (100 ml×1), saturated aqueous sodium bicarbonate (100 ml×1) and H2O (100 ml×1), dried over anhydrous MgSO4 and evaporated. The residual crude solid (17.7 g) was recrystallized from n-hexane to give 11.0 g of 9-anthrylmethyl acetate as yellow needles having a melting point of 110.0°-111.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[CH:4][C:3]=1[S:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[CH2:22]2)=[CH:17][CH:16]=1)(=[O:13])=[O:12]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[S:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[CH2:22]2)=[CH:17][CH:16]=1)(=[O:12])=[O:13]
Reactant: C=C(C)c1ccc(S(=O)(=O)Nc2ccc([C@@H]3CCN(CCC)C3)cc2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3F)cc2)C1
Reaction time: 3 h
Yield: 73.5 %

Procedure:
0.161 g of 2-fluoro-4-isopropenyl-N-[4-((S)-1-propyl-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide (0.37 mmol) were dissolved in 20 ml methanol, a tip of a spatula 10% Pd/C added, and the reaction mixture hydrogenated for 3 h at 50° C. The reaction mixture was filtered over celite, washed with methanol, and the filtrate evaporated to dryness under reduced pressure. The residue was purified via silica gel chromatography on a chromabond column with ethyl acetate and ethyl acetate/methanol (10%). Fractions containing the product were combined, the solvent evaporated to yield 0.11 g of the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:23]3[NH:27][N:26]=[CH:25][CH:24]=3)=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[C:12]=2[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.C(Cl)Cl.[C:37](OC(=O)C)(=[O:39])[CH3:38].CO.O.C(=O)(O)[O-].[Na+]>>[C:13]([C:12]1[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[C:10]([C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[S:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:37](=[O:39])[CH3:38])[CH:7]=1)#[N:14]
Reactant: N#Cc1c(-c2ccnc(N)c2)sc(-c2ccn[nH]2)c1-c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2sc(-c3ccn[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Reaction time: 8 h
Yield: 44 %

Procedure:
To a mixture of 2-(2-aminopyridin-4-yl)-4-(2,4-dichlorophenyl)-5-(1H-pyrazol-5-yl)thiophene-3-carbonitrile (0.10 g, 0.12 mmol) and Pyridine (0.3923 mL, 4.851 mmol) in DCM (0.2 mL, 3 mmol) was added Acetic anhydride (0.114 mL, 1.21 mmol) at 0° C. The ice bath was removed after 2 h and stirring was continued at rt overnight. The solvent was evaporated and the residue was stirred in MeOH (5 mL, 100 mmol) and Water (1 g, 60 mmol) containing Sodium bicarbonate (0.6112 g, 7.276 mmol). The mixture was concentrated and the residue was collected with EtOAc. The mixture was washed with brine and dried. The solvent was evaporated and the residue was purified by column chromatography to afford the title compound (0.024 g, 41%). LC/MS (FA) ES+ 454, 456. 1H NMR (400 MHz, DMSO-d6) δ: 13.28 (1H, s), 10.78 (1H, s), 8.58 (1H, s), 8.50 (1H, dd, J=5.27, 0.63 Hz), 7.93 (1H, d, J=1.71 Hz), 7.71 (1H, d, J=2.37 Hz), 7.63 (2H, dd, J=5.25, 1.77 Hz), 7.53 (1H, dd, J=5.25, 1.77 Hz), 5.49 (1H, d, J=2.38 Hz), 2.13 (3H, s)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([CH3:14])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH:10]([CH3:29])C1)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[NH:8]1[CH2:13][CH:12]([N:11]([CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:40][CH2:39][CH2:38][C:33]4[CH:34]=[C:35]([F:37])[CH:36]=[C:31]([F:30])[CH:32]=4)[N:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH3:29])[CH2:14]1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3cc(F)cc(F)c3)n2)c1)C1CNC1

Procedure:
Intermediate 114 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 425. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.74 (s, 1H), 8.38 (d, 2H), 7.97 (d, 1H), 7.71 (m, 2H), 7.90 (d, 2H), 6.74 (s, 1H), 4.58 (m, 5H), 4.07 (m, 4H), 3.25 (q, 2H), 3.07 (t, 2H), 1.39 (t, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[OH:10].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12]>C1COCC1>[Br:9][C:7]1[CH:6]=[CH:5][C:4]2[O:10][C:11](=[O:12])[NH:1][CH2:2][C:3]=2[CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1cc(Br)ccc1O
Solvent: C1CCOC1
Product: O=C1NCc2cc(Br)ccc2O1

Procedure:
A solution of 2-(aminomethyl)-4-bromophenol (I) (1.16 g, 5.7 mmol), triethylamthylamine (III) and carbonyldiimidazole (II) (1.86 g, 11.5 mmol) in anhydrous THF (100 ml) is refluxed for 4 hours. The solvent is evaporated and the residue dissolved in dichloromethane (DCM) (100 ml). The organic solution is washed with 1N HCl (20 ml×3) and then with brine (50 ml). The solvent is then evaporated and the resulting residue is purified by chromatography to give 6-bromo-3,4-dihydrobenzo[e][1,3]oxazin-2-one as a white powder.