Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)C=CC=CC=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@H:23]2[CH2:22]1.C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[F:33][C:16]([F:15])([F:34])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH:29][C:12]([CH:7]3[CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:27][CH2:28][C@H:23]2[CH2:22]1
Reactant: N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C1CCCC1

Procedure:
The title compound was prepared by substituting cyclopentanecarboxylic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.82 (d, J=6.9, 1H), 7.71 (s, 1H), 7.61 (d, J=7.7, 1H), 7.55 (d, J=7.7, 1H), 7.46 (t, J=7.7, 1H), 4.48-4.41 (m, 1H), 4.07 (q, J=7.1, 1H), 2.82 (ddd, J=2.9, 7.8, 16.7, 1H), 2.72 (dd, J=2.9, 9.5, 1H), 2.66 (p, J=7.9, 1H), 2.50-2.42 (m, 1H), 2.37 (dd, J=2.9, 9.0, 1H), 2.34-2.29 (m, 1H), 2.21 (dd, J=7.5, 9.4, 1H), 2.03 (dt, J=7.0, 15.3, 1H), 1.86 (dddd, J=7.4, 12.3, 20.5, 23.4, 3H), 1.75-1.60 (m, 5H), 1.53-1.41 (m, 2H), 1.30 (td, J=4.7, 11.1, 1H), 1.11 (t, J=7.1, 1H); MS (ESI+) m/z 381 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:23])[NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.C(O)C(N)(CO)CO>ClCCl.CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][C:27]4[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=4)[CH2:32][CH2:33]3)=[O:19])=[CH:21][CH:22]=2)=[O:23])[N:8]([CH3:10])[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: c1cc(CN2CCNCC2)ccn1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccncc3)CC2)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-ureido]benzoic acid (0.08 g, 0.26 mmol) in a mixture of dichloromethane (4 mL) and DMF (0.20 mL) is added 1-(4-pyridinylmethyl)piperazine (0.046 g, 0.26 mmol), PS-DCC (0.41 g, 0.52 mmol) and HOBT (0.035 g, 0.26 mmol). The mixture is stirred overnight at 45° C. in a closed tube (orbital stirring). Then PS-Trisamine is added (0.52 mmol) and the mixture is stirred for 4 hr at room temperature, filtrated, and washed three times with dichloromethane. The solvents are evaporated under reduced pressure and the residue is purified by biotage column chromatography (eluent: ethyl acetate/methanol 10:1) to give 0.020 g (0.04 mmol), 16% as white solid. ES+(m/z)=476 [M+H].
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH:17]([CH3:19])[CH3:18].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCC(C)C)nc1Cl
Yield: 86.7 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-isobutoxypiperidine-1-carboxylate obtained in Example (117d) (1.26 g, 4.6 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 1.02 g, 5 mmol), WSC hydrochloride (2.88 g, 15 mmol), HOBt (1.01 g, 7.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 1.71 g of the title compound as a colorless solid (87%).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2=[N:12][CH:13]=[C:14]([NH:16]C(=O)OC(C)(C)C)[CH:15]=[C:10]2[CH:9]=[N:8]1>Cl.O1CCOCC1>[NH:7]1[C:11]2=[N:12][CH:13]=[C:14]([NH2:16])[CH:15]=[C:10]2[CH:9]=[N:8]1
Reactant: CC(C)(C)OC(=O)Nc1cnc2c(cnn2COCC[Si](C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cnc2[nH]ncc2c1
Reaction time: 8 h
Yield: 97.9 %

Procedure:
tert-Butyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-ylcarbamate (0.100 g, 0.274 mmol) was dissolved in 4N HCl in dioxane (8 mL), and the reaction mixture was left at room temperature overnight. The reaction mixture was concentrated. The resulting solids were suspended in DCM and neutralized with triethylamine. The crude product was purified by column chromatography, eluting with ethyl acetate to give 1H-pyrazolo[3,4-b]pyridin-5-amine (0.036 g, 95%) as an oil.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[C:11]([CH3:13])[C:8]([CH:9]=[O:10])=[C:7]([CH3:14])[CH:6]=1)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>C(OCC)(=O)C.CC(O)=O.CC(O)=O.[Pd]>[CH3:13][C:11]1[CH:12]=[C:5]([OH:4])[CH:6]=[C:7]([CH3:14])[C:8]=1[CH:9]=[O:10]
Reactant: C=CCOc1cc(C)c(C=O)c(C)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O=CO
Product: Cc1cc(O)cc(C)c1C=O
Reaction time: 0 h
Yield: 51 %

Procedure:
4-Allyloxy-2,6-dimethyl-benzaldehyde, 9.67 g (50.9 mmole), 1.14 g (5.09 mmole) of palladium II acetate, and 8.00 g (30.5 mmole)of triphenylphosphine was mixed in a flask. Formic acid, 2.11 ml (56 mmole), was added and the mixture was swirled in a 80° oil bath. Within 15 seconds the reaction exothermed and turned very dark. The gum was dissolved in ethyl acetate, washed once in sodium bicarbonate, once in water, and once in brine then chromatographed on 350 ml silica, using 20%, then 40% ethyl acetate/hexane. Fractions were bulked and crystallize from methylene chloride/hexane to give 3.90 g (51%) of subtitled product which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([CH2:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:11](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].S(=O)(=O)(O)[OH:31]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([CH2:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:11]([OH:12])=[O:31])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc([C@@H](CC2CCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1Cl
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc([C@@H](CC2CCC2)C(=O)O)cc1Cl
Temperature: 110 °C
Yield: 71 %

Procedure:
A solution of (R)-2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclobutyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (330 mg, 0.76 mmol) in dioxane (4 mL) was treated with a 9 N aqueous sulfuric acid solution (2 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (75 mL) and extracted with a chloroform/methanol solution (3:2, 2×50 mL) and then concentrated. The resulting residue was then dissolved in acetonitrile and concentrated with silica gel (3 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes) to afford (R)-2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclobutyl-propionic acid (154 mg, 71%) as a yellow viscous oil: [α]30589=−48.3° (c=0.18, methylene chloride); ES-HRMS m/e calcd for C14H17O2SCl (M+Na)+ 307.0530, observed 307.0530; 1H NMR (300 MHz, DMSO-d6) δ 1.47-2.16 (m, 9H, CH and 4×CH2), 2.47 (s, 3H, SCH3), 3.40 (t, J=7.3 Hz, 1H, ArCHCO), 7.25 (s, 2H, Ar), 7.34 (s, 1H, Ar), 12.41 (s, 1H, CO2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]#[N:7])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(#N)C>[CH2:19]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:1][CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(C#N)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(C#N)cc(C)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
3-Ethyl-4-hydroxy-5-methyl-benzonitrile (6.0 g, 37 mmol) is dissolved in acetonitrile (80 mL) and K2CO3 (10.1 g, 73 mmol) and benzyl bromide (6.56 g, 38 mmol) are added. The resulting suspension is stirred at 60° C. for 18 h, then water is added (100 mL) and the org. phase is collected. The aq. phase is extracted with EtOAc (100 mL) and the combined org. extracts are washed with water followed by brine, dried over MgSO4, filtered, evaporated and purified by CC (eluting with Heptane/EtOAc 9:1) to give 4-benzyloxy-3-ethyl-5-methyl-benzonitrile as a yellow oil (7.02 g); LC-MS: tR=1.11 min, [M+H]+=293.16.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@@H:11]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][N:24]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ncc(B(O)O)cn1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@@H](N5CCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 30A for the product of Example 1E and substituting 2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR (400 MHz, CDCl3) δ ppm 8.77 (s, 2H) 8.04 (d, J=8.90 Hz, 1H) 7.98 (d, J=1.23 Hz, 1H) 7.58 (dd, J=8.44, 1.99 Hz, 1H) 4.08 (s, 3H) 3.60-3.72 (m, 1H) 3.04-3.14 (m, 1H) 2.65-2.78 (m, 2H) 2.51-2.63 (m, 4H) 2.38-2.51 (m, 2H) 1.84 (s, 4H). MS: (M+H)+=367.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[NH:23][CH:24]=[C:25]([CH2:27][CH2:28][OH:29])[N:26]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:23]2[CH:24]=[C:25]([CH2:27][CH2:28][OH:29])[N:26]=[C:22]2[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nc(CCO)c[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(CCO)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
Triphenylmethyl chloride (24.5 g, 88 mmol) in DMF (100 ml) was added dropwise over 1 hr to a solution of 2-methyl-4-(2-hydroxyethyl)imidazole (10 g, 80 mmol) and triethylamine in DMF (100 ml). The reaction mixture was stirred at ambient temperature for 18 hours and then the volatiles were removed by evaporation. The resultant solid was triturated with water (3×500 ml) and ether (200 ml), collected by filtration and dried under vacuum at 60° C. to give the title compound (23.7 g, 80%) as a pale yellow solid. NMR 1.43 (d, 3H), 1.62 (s, 3H), 2.53 (s, 1H), 4.80 (q, 1H), 6.59 (s, 1H), 7.13 (m, 6H), 7.37 (m, 9H); m/z 369.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH3:7])=[NH:5])#[N:2].Cl.[NH2:9][C:10]1[CH:14]=[C:13]([CH3:15])[O:12][N:11]=1.N>O>[CH3:7][NH:6][C:4]([NH:3][C:1]([NH:9][C:10]1[CH:14]=[C:13]([CH3:15])[O:12][N:11]=1)=[NH:2])=[NH:5]
Reactant: CNC(=N)NC#N
Reactant: Cc1cc(N)no1
Agent: Cl
Agent: N
Solvent: O
Product: CNC(=N)NC(=N)Nc1cc(C)on1
Yield: 27.6 %

Procedure:
In a reactor are added 4.9 g of 1-cyano-3-methyl-guanidine, 6.7 g of 3-amino-5-methyl-isoxazole hydrochloride and 1.3 ml of water. The reaction mixture is heated until dissolution is complete, after which the reaction is exothermal. After cooling, the reaction mixture is taken up into 30 ml water followed by 3 ml ammonia (d = 0.89). It is then extracted with 30 ml methylene chloride. After drying, treatment with carbon black and evaporation of the solvent, the residue is crystallized from absolute ethanol, to give 2.7 g of 1-methyl-5-(5-methyl-isoxazol-3-yl)-biguanide. M.p. (cap.) = 140° C. followed by resolidification, then 150°-151° C. with introduction at 140° C. and heating at a rate of 2° C./minute.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:14][NH2:15]>C(O)C>[CH3:10][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:15][N:14]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2ccccc2)[nH]n1
Yield: 80 %

Procedure:
To a solution of 1-phenylbutane-1,3-dione (5.0 g, 30.8 mmol) in ethanol (50 mL), was added hydrazine hydrate (1.54 g, 30.8 mmol) at ambient temperature. The reaction was refluxed for 5 h. After cooling, the reaction was concentrated under reduced pressure and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated under reduced pressure. The residue was added 10% ethyl acetate in hexane. The precipitate was filtered and washed with hexane. The white solid was dried in air to give the title compound (3.9 g). LCMS m/z=159.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H), 6.65 (s, 1H), 7.34 (m, 1H), 7.42 (m, 2H), 7.82 (m, 2H).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[O:27][CH3:28])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[NH2:25][C@@H:24]1[C:23](=[O:26])[N:22]2[C:17]([C:15]([OH:16])=[O:14])=[C:18]([O:27][CH3:28])[CH2:19][S:20][C@H:21]12
Reactant: COC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
A suspension of 1.65 g of 7β-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester and 2 ml of anisole is mixed with 20 ml of pre-cooled trifluoroacetic acid and stirred for 15 minutes in an ice bath. It is diluted with 100 ml of cold toluene and the reaction mixture is evaporated under reduced pressure. The dark brown residue is dried under a high vacuum and stirred with diethyl ether; the precipitate is filtered off, washed with acetone and diethyl ether and dried. The salt, thus obtainable, of 7β-amino-3-methoxy-3-cephem-4-carboxylic acid and of trifluoroacetic acid is dissolved in 10 ml of water; the aqueous solution is twice washed with 10 ml of ethyl acetate at a time and brought to a pH of 4.5 by adding a 10% strength solution of triethylamine in methanol. The mixture is diluted with 10 ml of acetone and stirred for one hour at 0° C. The precipitate is filtered off, washed with a 1:2 mixture of acetone and diethyl ether and dried in a high vacuum and yields 7β-amino-3-methoxy-3-cephem-4-carboxylic acid in the form of the internal salt, thin layer chromatogram (silica gel): Rf~0.16 (system: n-butanol/acetic acid/water, 67:10:23); ultraviolet absorption spectrum (in 0.1 N hydrochloric acid): λmax =261 mμ (ε=5,400).
Reaction SMILES: [CH:1]1([C:5]2[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=2[C:12]([F:15])([F:14])[F:13])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[I:21]Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O.CO>[CH:1]1([C:5]2[C:6]([C:12]([F:13])([F:14])[F:15])=[CH:7][C:8]([NH2:9])=[C:10]([I:21])[CH:11]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Nc1ccc(C2CCC2)c(C(F)(F)F)c1
Reactant: ClI
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1cc(C(F)(F)F)c(C2CCC2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a mixture of the compound (1.34 g) obtained in step (2) above, sodium hydrogencarbonate (628 mg), chloroform (32.0 mL) and methanol (8.00 mL), a solution of iodine monochloride (1.21 g) in chloroform (8.00 mL) was added dropwise at room temperature over a period of 30 minutes. The resulting mixture was stirred at room temperature for two hours. After adding a solution of 25% sodium metabisulfite in water (20.0 g) under cooling with ice, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with chloroform and the combined organic layers were dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give 4-cyclobutyl-2-iodo-5-(trifluoromethyl)aniline as a brown oil (2.08 g).
Reaction SMILES: [NH2:1][C:2]([C:4]([NH2:6])=[S:5])=[S:3].[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O.[OH2:16]>C(O)C.CCOCC>[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]1[S:3][C:2]2[N:1]=[C:10]([C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[OH:16])[S:5][C:4]=2[N:6]=1
Reactant: NC(=S)C(N)=S
Reactant: O
Reactant: O=Cc1ccccc1O
Solvent: CCO
Solvent: CCOCC
Product: Oc1ccccc1-c1nc2sc(-c3ccccc3O)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Into a 100 ml round bottomed flask equipped with heating mantle and magnetic stirrer, were added 2.0 g (0.017 mol) of dithiooxamide (DTO) and 21 g (0.17 mol--a tenfold excess) of o-hydroxybenzaldehyde (salicylaldehyde). The salicylaldehyde was purchased from Eastman Organic Chemicals Division of Eastman Kodak Company, Rochester, N.Y. The mixture was stirred and heated at 180°-185° C. for 2 hr. At 160° C. water began to boil off. After 2 hr, the reaction mixture was cooled to room temperature and 50 ml of ethanol/ether 1:1 were added. Stirring for 10 min was followed by filtration to remove the product. The product was washed with ethanol and dried in air overnight to afford 2.9 g (50%) of 2,5-bis(o-hydroxyphenyl)thiazolo[5,4-d]thiazole, mp 300° C. NMR and IR were in agreement with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:6]#[N:7].[NH3:13]>C(O)C.CO>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:10]=1)[C:6]([NH2:13])=[NH:7]
Reactant: N
Reactant: COc1cc(C#N)cc(OC)c1
Solvent: CO
Solvent: CCO
Product: COc1cc(OC)cc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dry HCl gas was bubbled through a cooled (−15° C.) solution of 3,5-dimethoxybenzonitrile (1.50 g, 9.20 mmol) for 30 minutes. The reaction mixture was placed in a refrigerator overnight. After evaporation of the solvent, a white solid was obtained which was dissolved in ethanol. 9.2 ml of a 2 molar solution of ammonia in Methanol was added and the reaction mixture was stirred at room temperature overnight. After evaporation of the solvent, the title compound, MS: m/e=181.2 (M+H+), (1.21 g, 71%) was obtained by chromatographic purification of the residue (silica gel, MeOH, DCM). 1H-NMR (300 MHz, d6-DMSO, 25° C.): δ(ppm)=3.80 (6H, s), 6.82 (1H, t, J=2 Hz), 7.05 (2H, t, J=2 Hz), 9.35 (3H, bs).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:17]=2)[NH:12][C:11]=1[C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[NH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:21])[N:22]([CH3:24])[CH3:23])[CH:17]=2)[NH:12][C:11]=1[C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N(C)C)cc3c2CCNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N(C)C)cc3c2CCN)c1
Yield: 96.8 %

Procedure:
{2-[2-(3,5-dimethylphenyl)-5-(3,3-dimethylureido)-1H-indol-3-yl]-ethyl}-carbamic acid tert-butyl ester (295 mg) was dissolved in a ternary solvent mixture comprising methylene chloride (6 mL), trifluoroacetic acid (2 mL) and anisole (2 mL) for 2.5 h. The volatile solvent components were removed on a rotary evaporator and the residues taken up in methanol and purified on four (20×20 cm 1000μ) preparative silica gel plates and eluted with a solvent system comprising methanol and methylene chloride in the ratio (1:9 v/v). The product (222 mg) was isolated as a foamy material.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20][C:21]1[N:26]=[C:25]([N:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]2)[C:24]([CH3:37])=[C:23]([CH3:38])[N:22]=1>CN(C)C=O>[ClH:20].[CH3:37][C:24]1[C:25]([N:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]2)=[N:26][C:21]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[N:22][C:23]=1[CH3:38]
Reactant: NCc1cccc2ccccc12
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NCc2cccc3ccccc23)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 87.7 %

Procedure:
After 1-naphthylmethylamine(0.40 ml, 2.7 mmol) and triethylamine (0.38 ml, 2.7 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 680 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][N+:14]([O-])=O)[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]>C(O)(=O)C.O.[Zn]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:13][NH2:14])[N:7]=[N:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1cc(N[N+](=O)[O-])nnc1OCC
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(NN)nnc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
N-(5,6-Diethoxypyridazin-3-yl)-N-nitroamine (W4.120; 114 mg) was dissolved in acetic acid (5 ml) and added dropwise while cooling with ice and stirring at between 10 and 20° C. to a mixture of zinc (130 mg) in water (3 ml). Thereafter, the ice bath was removed and the mixture was stirred at RT for 1 h. Then the mixture was alkalized with 10 N sodium hydroxide solution, the aqueous phase was extracted three times with DCM, and the combined DCM phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (met. A). The clean, product-containing fractions were each combined, freed of the ACN, basified with saturated potassium carbonate solution and then extracted three times with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 50 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]([CH2:21][OH:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:34][CH:35]=[CH2:36].C(OC(N[C@@H](C[C@@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C)C=O)=O)(C)(C)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]([CH2:21][O:22][CH2:36][CH:35]=[CH2:34])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC(CO)Oc2ccccc21
Reactant: C=CCBr
Agent: CC(C)[Si](OCC[C@H](C)C[C@@H](C=O)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOCC1CN(C(=O)OCc2ccccc2)c2ccccc2O1

Procedure:
The title compound is prepared starting from 3.0 g of N-benzyloxycarbonyl-2(R,S)-hydroxymethyl-3,4-dihydro-2H-1,4-benzoxazine, 2.75 g of sodium bis(trimethylsilyl)amide and 1.7 ml of 3-bromo-1-propene analogously to Example 61): Rf (D)=0.32; Rf (3:1 mixture of toluene and ethyl acetate)=0.61.