Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#N)=[C:4]([F:11])[CH:3]=1.S(=O)(=O)(O)O.[OH2:17].[OH-:18].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]([OH:18])=[O:17])=[C:4]([F:11])[CH:3]=1
Reactant: N#Cc1cc(F)c(N)cc1F
Reactant: O
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1cc(F)c(C(=O)O)cc1F
Temperature: 80 °C
Reaction time: 96 h
Yield: 42 %

Procedure:
To a solution of 4-amino-2,5-difluorobenzonitrile (6.21 g, 38.28 mmol) in dioxane (32.5 mL) was added 52.2 mL of sulphuric acid 73% p/p. The reaction mixture was stirred at 80° C. for 96 hours. The crude was poured into 250 mL of water and basified by sodium hydroxide 32% until basic pH and washed with methylen chloride. The aqueous phase was neutralized with hydrochloric acid 5N and the crude was extracted with ethyl acetate, washed with brine, dried and the solvent was removed under reduced pressure to give the title compound as a white solid (42%), which was used in the next step without further purification.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:38][N:37]=[N:36][N:35]=2)=[CH:30][CH:29]=1.N1CCCCC1.O>CN(C=O)C>[NH:38]1[C:34]([C:31]2[CH:32]=[CH:33][C:28]([NH:27]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:29][CH:30]=2)=[N:35][N:36]=[N:37]1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCNCC1
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(-c2nnn[nH]2)cc1)c1ccccc1

Procedure:
Prepared by reacting 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone with 1.3 equivalents of 5-(4-amino-phenyl)-1H-tetrazole in DMF (125° C., for 2 hours), subsequent treatment with 6.7 equivalents of piperidine (20° C., 1 hour) and precipitation with water.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][O:27][CH3:28])=[CH:22][CH:23]=3)[O:18][CH2:17][C:16]2([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][O:38][CH3:39])=[CH:32][CH:31]=2)[CH3:29])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.O>O1CCCC1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][O:27][CH3:28])=[CH:22][CH:23]=3)[O:18][CH2:17][C:16]2([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][O:38][CH3:39])=[CH:34][CH:35]=2)[CH3:29])=[CH:11][CH:10]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of (3RS,4RS)-4-[4-(t-butyldimethylsilyloxy)phenyl]-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]-3-methylchroman (1.1 g, 1.99 mmol) in tetrabydrofuran (10 ml) was added 1N-tetrabutylainmoniumfluoride (3.99 ml, 3.99 mmol) in tetrahydrofuran and stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was treated with water and extracted with ethyl acetate. The extract was dried over, anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give (3RS,4RS)-4-(4-hydroxyphenyl)-7-(methoxymethoxy)-3-[4-(methoxymethoxy)pheny]-3-methylchroman (0.84 g, 96.4%) as a foamy oil. To a solution of (3RS,4RS)-4-(4-hydroxyphenyl)-7-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl-]-3-methylchroman (0.31 g, 0.71 mmol) in dimethylformamide (6 ml) was added potassium carbonate (0.39 g, 2.84 mmol) and 5,5-di-(ethoxycarbonyl)-1-iodo-5(4,4,5,5,5-pentafluoropentyl)butane (0.54 g, 1.07 mmol) and stirred at 80° C. for 3 hours. After the reaction was completed, the reaction mixture was treated with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (0.552 g, 96%) as a foamy oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]=[O:13])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C([O-])(O)=O.[Na+].O.ClC(OCC)=O>[CH2:18]([O:17][C:15]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]=[O:13])[C:5]([O:7][CH3:8])=[O:6])=[O:16])[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1ccc(C=O)c(N)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(C(=O)OC)ccc1C=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 41.4 %

Procedure:
To a mixture of methyl 3-amino-4-formylbenzoate (110 mg, 0.614 mmol) in 6 mL THF plus 4 mL saturated NaHCO3 and 1 mL H2O at rt was added ethyl chloroformate (0.070 mL, 0.737 mmol) at the reaction stirred at rt. After 50 min, an additional 0.5 mL saturated NaHCO3 and 5 drops ethyl chloroformate was added. At 17.5 hours the mixture was heated to 60° C., 1 mL saturated Na2CO3 added, and 5 drops ethyl chloroformate added. Then to push reaction to completion, a small scoop of solid Na2CO3 was added and additional ethyl chloroformate added drop-wise until the reaction was approximately 80% complete (45 hours total reaction time). The reaction was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with brine, dried with Na2SO4, and evaporated. The solid was crystallized from hexane/EtOAc and the filtrate chromatographed eluting with 2.5% MeOH/CHCl3. The impure products from crystallization and chromatography were combined and then recrystallized from hexane/EtOAc to give the title compound as a light yellow solid (63.8 mg, 41%). 1H NMR (CDCl3) δ: 10.53 (br. s, 1H), 10.00 (d, J=0.6 Hz, 1H), 9.11-9.12 (m, 1H), 7.80-7.84 (m, 1H), 7.72-7.76 (m, 1H), 4.28 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N+](C1C=CC([C:10]2[C:18]([CH2:19][C@H:20]3[C@@H:25]([OH:26])[C:24]4[CH:27]=[C:28]([O:31][CH2:32][C:33]5[S:34][C:35]6[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:36]=6[N:37]=5)[CH:29]=[CH:30][C:23]=4[O:22][CH2:21]3)=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O-])=[O:13])=CC=1)([O-])=O.[CH3:43][S:44]([NH2:47])(=[O:46])=[O:45].[H-].[Na+]>>[F:42][C:39]1[CH:40]=[CH:41][C:35]2[S:34][C:33]([CH2:32][O:31][C:28]3[CH:29]=[CH:30][C:23]4[O:22][CH2:21][C@@H:20]([CH2:19][C:18]5[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=5)[C:12]([NH:47][S:44]([CH3:43])(=[O:46])=[O:45])=[O:13])[C@@H:25]([OH:26])[C:24]=4[CH:27]=3)=[N:37][C:36]=2[CH:38]=1
Reactant: CS(N)(=O)=O
Reactant: O=C([O-])c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1-c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)NC(=O)c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1

Procedure:
Synthesis was carried out as in example 1, but using 460 milligrams optically pure (-)cis-4-nitrophenyl-3-[[6-[(5-fluoro-2-benzothiazolyl)methoxy]-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-yl]methyl]benzoate, 1.18 grams methane sulfonamide and 324 milligrams sodium hydride. 260 milligrams of product was obtained. αD =-35.9°; c=0.005 in tetrahydrofuran.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:17][CH2:16]3)=[O:14])[N:38]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:39]2=[O:40])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3Cc3ccccc3)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and benzyl isocyanate to give the title compound as a colorless solid. MS: 532.9 ([M+H]+)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[N:18](CC4C=CC=CC=4)[CH:19]([CH3:21])[CH2:20][C:10]=3[C:9]2=[O:29])[CH:5]=[CH:6][CH:7]=1.Cl[C:31]1[CH:32]=[C:33]([N:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][N:45]=3)[C:40]([OH:47])=[C:39]([CH2:48][CH:49]([OH:51])[CH3:50])[C:38]2=[O:52])[CH:34]=[CH:35][CH:36]=1.C1(N2C3C(=CC=CN=3)[C:62]([OH:69])=C(CCO)C2=O)C=CC=CC=1>>[CH3:40][O:47][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[N:18]([OH:69])[CH:19]([CH3:21])[CH2:20][C:10]=3[C:9]2=[O:29])[CH:5]=[CH:6][CH:7]=1.[OH:47][C:40]1[C:41]2[C:46](=[N:45][CH:44]=[CH:43][CH:42]=2)[N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:69][CH3:62])[CH:32]=2)[C:38](=[O:52])[C:39]=1[CH2:48][CH:49]([OH:51])[CH3:50]
Reactant: CC(O)Cc1c(O)c2cccnc2n(-c2cccc(Cl)c2)c1=O
Reactant: CC1Cc2c(c3cccnc3n(-c3cccc(Cl)c3)c2=O)N1Cc1ccccc1
Reactant: O=c1c(CCO)c(O)c2cccnc2n1-c1ccccc1
Product: COc1cccc(-n2c(=O)c(CC(C)O)c(O)c3cccnc32)c1
Product: COc1cccc(-n2c(=O)c3c(c4cccnc42)N(O)C(C)C3)c1

Procedure:
This procedure will also produce 1,2,3,5-tetrahydro-5-(3-chlorophenyl)-2-methyl-1-(phenylmethyl)-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-one when 1-(3-chlorophenyl)-3-(2-hydroxypropyl)-4-hydroxy-[1,8]naphthyridin-2-one is substituted for 1-phenyl-3-(2-hydroxyethyl)-4-hydroxy-[1,8]naphthyridin-2-one. Furthermore, 1,2,3,5-tetrahydro-5-(3-methoxyphenyl)-1-hydroxy-2-methyl-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-one is produced by this procedure when 4-hydroxy-1-(3-methoxyphenyl)-3-(2-hydroxypropyl)-[1,8]naphthyridin-2-one is substituted for 1-phenyl-3-(2-hydroxyethyl)-4-hydroxy-[1,8]naphthyridin-2-one and hydroxylamine hydrochloride is substituted for benzylamine hydrochloride.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][C:14]32[CH2:21][CH2:20][CH2:19][N:18]2[CH:22]=[N:23][CH:24]=[C:17]32)=[CH:9][CH:8]=1)(=O)=O.[CH3:27][N:28](C)C=O>[C-]#N.[Zn+2].[C-]#N.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:14]12([CH2:21][CH2:20][CH2:19][N:18]3[CH:22]=[N:23][CH:24]=[C:17]13)[C:15]1[C:10](=[CH:9][CH:8]=[C:7]([C:27]#[N:28])[CH:16]=1)[CH2:11][CH2:12][CH2:13]2
Reactant: O=S(=O)(Oc1ccc2c(c1)C1(CCC2)CCCn2cncc21)C(F)(F)F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)C1(CCC2)CCCn2cncc21
Temperature: 120 °C
Reaction time: 20 h

Procedure:
An apparatus purified by baking is charged under argon with 1.160 mmol of 3′,4′,6,7-tetrahydro-2′H,5H-spiro[imidazo[1,5-a]pyridine-8,1′-naphthalen]-7′-yl trifluoromethanesulphonate together with 2.320 mmol zinc(II) cyanide in 15 ml of degassed N,N-dimethylformamide. 0.093 mmol of tetrakis(triphenylphosphine)palladium is added and the reaction mixture is stirred at 120° C. for 20 hours. The reaction mixture is cooled and poured into 100 ml of ice-water. It is extracted with ethyl acetate (3×). The combined organic phases are dried over magnesium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60F) as a white solid. Rf=0.165 (dichloromethane-2M ammonia in EtOH=95:5); Rt=5.64.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH2:14]1[C:19](=O)[CH2:18][C:16](=[O:17])[CH2:15]1.[NH2:21][C:22]1[N:26]([CH3:27])[NH:25][C:24](=[O:28])[CH:23]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[C:23]3[C:24](=[O:28])[NH:25][N:26]([CH3:27])[C:22]=3[NH:21][C:19]3[CH2:14][CH2:15][C:16](=[O:17])[C:18]2=3)=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: O=C1CCC(=O)C1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: Cn1[nH]c(=O)cc1N
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(F)c(C(F)(F)F)c1
Yield: 63.5 %

Procedure:
4-Fluoro-3-trifluoromethylbenzaldehyde (0.28 g, 1.5 mmol), 1,3-cyclopentadione (0.15 g, 1.5 mmol), and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.17 g, 1.5 mmol) were processed as described in Example 1 to provide 0.35 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.21 (m, 2H), 2.7 (m, 2H), 3.51 (s, 3H), 4.8 (s, 1H), 7.35 (t, 1H), 7.45 (m, 1H), 7.55 (d, 1H), 9.6 (bs, 1H), 10.48 (s, 1H); MS (ESI−) m/z 366 (M−H)−; Anal. calcd for C17H13N3F4O2: C, 55.59; H, 3.51; N, 11.44. Found: C, 55.41; H, 3.37; N, 11.21.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[CH3:12][CH:13]([NH2:15])[CH3:14]>C(O)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:15][CH:13]([CH3:14])[CH3:12])[C:5]=2[S:4][CH:3]=1
Reactant: CC(C)N
Reactant: Clc1ncnc2c(Br)csc12
Solvent: CCO
Product: CC(C)Nc1ncnc2c(Br)csc12
Yield: 95.5 %

Procedure:
A mixture of compound 65A (0.125 g, 0.5 mmol), and propan-2-amine (0.148 g, 2.5 mmol) in ethanol (10 mL) was heated under reflux for 15 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica gel eluting with 1:1 EtOAc/hexanes to give 0.13 g of the title compound: 1H NMR (DMSO-d6): δ 8.50 (s, 1H), 8.28 (s, 1H), 7.87 (d, J=7.46 Hz, 1H), 4.40-4.51 (m, 1H), 1.23 (d, J=6.78 Hz, 6H). ESI (+)/MS: 273 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:15])=[CH:12][CH:13]=[O:14].O>O1CCCC1.[Cu]Br>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([CH3:15])([CH3:10])[CH2:12][CH:13]=[O:14])=[CH:4][CH:3]=1
Reactant: CC(C)=CC=O
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cu]Br
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CC=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 21.6 grams (0.10 mole) of 4-chlorophenylmagnesium bromide (1M in diethyl ether) in 100 mL of tetrahydrofuran is cooled to -15° C., and 0.7 grams (catalyst) of copper(I) bromide is added in one portion. Upon completion of addition, 9.7 mL (0.10 mole) of 3-methyl-2-butenal is added dropwise during a 1.5 hour period, while maintaining the reaction mixture temperature below -10° C. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature, where it is stirred for about 18 hours. The reaction mixture is then poured into 300 mL of water and extracted with two 200 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using 50% petroleum ether in methylene chloride as the eluant. The appropriate product-containing fractions are combined and concentrated under reduced pressure, yielding 7.6 grams of 3-(4-chlorophenyl)-3-methylbutyraldehyde. The NMR spectrum is consistent with the proposed structure. The reaction is repeated.
Reaction SMILES: CS(O[N:6]=[C:7](Cl)[C@H:8]1[CH2:12][O:11][C:10]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:9]1)(=O)=O.N1C=CC=CC=1.[S-:25][C:26]#[N:27].[Na+].[Br:29][C:30]1[CH:31]=[C:32]([O:37][C:38]2[C:39]([CH3:44])=[N:40][CH:41]=[CH:42][CH:43]=2)[C:33]([NH2:36])=[N:34][CH:35]=1>C(#N)C>[Br:29][C:30]1[CH:31]=[C:32]([O:37][C:38]2[C:39]([CH3:44])=[N:40][CH:41]=[CH:42][CH:43]=2)[C:33]([NH:36][C:26]2[S:25][N:6]=[C:7]([C@H:8]3[CH2:12][O:11][C:10]4([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]4)[O:9]3)[N:27]=2)=[N:34][CH:35]=1
Reactant: N#C[S-]
Reactant: Cc1ncccc1Oc1cc(Br)cnc1N
Reactant: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ncccc1Oc1cc(Br)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Temperature: 40 °C
Yield: 49.9 %

Procedure:
(R)—N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (1.86 g, 6.25 mmol), pyridine (1.13 g, 14.3 mmol) and sodium thiocyanate (0.58 g, 7.14 mmol) were dissolved in acetonitrile (45 mL). The solution was heated to 40° C. for 40 minutes. 5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (1.0 g, 3.57 mmol) was added and the reaction was heated at 60° C. overnight. The solution was cooled to 0° C., filtered and the solid was dried to give (S)—N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.90 g, 1.78 mmol, 50% yield) as a white solid.
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 (57.2 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/EtOAc=20:1) to give 4-bromomethyl-1-chloro-2-methoxy-benzene (69 g, 92%). 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: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)Cl>[C:17]1([NH:16][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccccc1
Temperature: 25 °C
Yield: 9 %

Procedure:
To a solution of 2-[N-(t-butyloxycarbonyl)]amino-cyclohexanone (0.785 g, 3.69 mmol, aniline (0.68 mL, 7.46 mmol) and glacial acetic acid (0.22 mL) in THF (10 mL) was added NaBH(OAc)3 (1.173 g, 5.53 mmol) and the mixture was stirred at 60□ C. overnight. The reaction was cooled to room temperature, diluted with CH2Cl2 (60 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous phase was washed with CH2Cl2 (2×25 mL) and the combined organic extracts dried (Na2SO4), filtered and concentrated under reduced pressure. Purification and separartion of the resultant brown oil by flash chromatography on silica gel (Hexanes/EtOAc, 9:1) afforded the low polarity cis-N-phenyl-N′-(t-butyloxycarbonyl)-cyclohexane-1,2-diamine isomer (0.095 g, 9%) and the high polarity trans-N-phenyl-N′-(t-butyloxycarbonyl)-cyclohexane-1,2-diamine isomer (0.412 g, 39%), both as pale yellow solids.
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].O>CN(C)C=O>[O:14]=[C:3]1[C:4]2[C:9](=[CH:8][C:7]([O:11][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:6]([Cl:12])[C:5]=2[Cl:13])[CH2:10][C:2]1([CH3:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (9.2 g., 0.03 mole), potassium carbonate (8.29 g., 0.06 mole) and tert-butyl bromoacetate (6.44 g., 0.033 mole) in dimethylformamide (30 ml.) is stirred at 25° C. for two hours. The reaction mixture is poured into cold water (150 ml.) and the tert-butyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetate which separates is filtered, rinsed with water and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[OH-].[K+].[Cl:15][C:16]1[CH:17]=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:19]=[C:20]([Cl:23])[C:21]=1F.O>CS(C)=O.C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:19]=[C:20]([Cl:23])[C:21]=1[N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc2c1ccn2-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-nitroindole (0.5 g, 3.0 mmol), potassium hydroxide pellets (0.7 g, 12.0 mmol) in 40.0 ml dimethylsulfoxide were stirred for 30 minutes at room temperature. Then 3,5-dichloro-4-fluorobenzotrifluoride was added and stirred at room temperature for 3 hours. Water and methylene chloride were added and the mixture was stirred for 10 minutes. The organic phase was separated, washed with water, dried and stripped under vacuum to yield 1.0 g of yellow solid of the desired product. The structure was confirmed by infrared spectroscopy, mass spectrometry and nuclear magnetic resonance spectroscopy.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([C:22]2([C:26]#N)[CH2:25][CH2:24][CH2:23]2)C)[CH:17]=[CH:18][CH:19]=1.[OH:28]S(O)(=O)=O>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:20][C:22]1([C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:28])[CH2:25][CH2:24][CH2:23]1
Reactant: O=S(=O)(O)O
Reactant: Brc1ccccn1
Reactant: CC(c1cccc(Cl)c1)C1(C#N)CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccccn1)C1(Cc2cccc(Cl)c2)CCC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromopyridine (1.1 g, 6.85 mmol) was added n-BuLi (2.7 mL, 6.85 mmol 2.5M in hexane) at −78° C. After stirring for 15 min, a solution of Example 44B (1.0 g, 4.57 mmol) in THF (20 mL) was added. The mixture was stirred at −78° C. for 15 min. followed by slow addition of 9.1 mL of 1 M H2SO4. The mixture was then heated to 50° C. and stirred for 30 min. The aqueous phase was separated and extracted with EtOAc (30 mL).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:33]([NH2:35])=[O:34])=[C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])[NH:25][CH:26]=2)=[CH:18][CH:17]=1>O1CCCC1>[CH2:31]([NH:30][C:28](=[O:29])[NH:27][C:24]1[NH:25][CH:26]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:13]([NH:12][C:3]3[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=3[F:1])=[O:14])=[CH:17][CH:18]=2)[C:23]=1[C:33]([NH2:35])=[O:34])[CH3:32]
Reactant: CCNC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: CCNC(=O)Nc1[nH]cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c1C(N)=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 200.2 %

Procedure:
0.031 cm3 (0.0213 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate is added at a temperature in the region of 25° C. to 0.056 g (0.194 mmol) of 4-(4-aminophenyl)-2-(3-ethylureido)-1H-pyrrole-3-carboxamide in solution in 20 cm3 of tetrahydrofuran. After stirring for 16 hours at a temperature in the region of 60° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is then diluted in 40 cm3 of ethyl acetate and then washed with twice 30 cm3 of water. The organic solution is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (95/2.5/2.5 by volume)]. After concentrating the fractions under reduced pressure, 0.021 g of 2-(3-ethylureido)-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-3-carboxamide is obtained in the form of a yellow solid. ES+: m/z=494 (MH+).