Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:4]=1[CH2:5][CH:6]1[O:8][CH:7]1[CH2:9]2.[N-:14]=[N+:15]=[N-:16].[Na+].S(=O)(=O)(O)O.C(Cl)Cl>CS(C)=O>[N:14]([C@@H:6]1[CH2:5][C:4]2[C:10](=[CH:11][CH:12]=[CH:13][C:3]=2[O:2][CH3:1])[CH2:9][C@H:7]1[OH:8])=[N+:15]=[N-:16].[N:14]([C@@H:7]1[CH2:9][C:10]2[C:4](=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][CH:11]=2)[CH2:5][C@H:6]1[OH:8])=[N+:15]=[N-:16]
Reactant: COc1cccc2c1CC1OC1C2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cccc2c1C[C@@H](N=[N+]=[N-])[C@H](O)C2
Product: COc1cccc2c1C[C@@H](O)[C@H](N=[N+]=[N-])C2
Reaction time: 15 h

Procedure:
30.0 g (0.170M) of 1a,2,7,7a-tetrahydro-3-methoxynaphth[2,3-b]oxirane are dissolved in dimethyl sulphoxide. Furthermore, 90.0 g (1.384M) of sodium azide are suspended in DMSO and 19.5 g (0.200M) of concentrated sulphuric acid are dissolved in DMSO. The total quantity of DMSO is 1000 ml. The solutions and supensions are combined. Stirring subsequently takes place for 15 hours at 60°. 1500 ml of methylene chloride are then added to the reaction mixture. A suspension is obtained, which is filtered over Hyflo. The rose solution is concentrated by evaporation at 60° (10 torr), then at 80° (high vacuum 1/100 torr). Trans-3-azido-1,2,3,4-tetrahydro-5-methoxy-2-naphthalinol (m.p. 83°-84°) and its structural isomer trans-3-azido-1,2,3,4-tetrahydro-8-methoxy-2-naphthalinol (m.p. 145°-147°) are obtained in a ratio of 1:1. The structural isomers are separated by fractional crystallisation (methylene chloride/hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.CN.[CH3:14][N:15](C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>ClCCl.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:15][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CN(C)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)Cc1cccc(Br)c1
Yield: 81.6 %

Procedure:
A solution of 3-bromophenyl acetic acid (2.15 g), a tetrahydrofuran solution of methyl amine (6 ml, 2M), dimethylaminopyridine (1.32 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.06 g) in dichloromethane was stirred at room temperature for 16 hrs. The organic solution was washed thrice with 2M hydrochloric acid solution, dried over magnesium sulphate, filtered and evaporated to afford a solid (1.86 g).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.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>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:17]1
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1ccccc1Br
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: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1-c1ccsc1
Temperature: 25 °C

Procedure:
To a mixture of 2-bromobenzaldehyde (0.32 mL, 2.70 mmol) and 3 mL of 2 M aqueous sodium carbonate in 15 mL of toluene was added thiophene-3-boronic acid (384 mg, 3.00 mmol) in ethanol (3 mL). The mixture was stirred and then treated with tetrakis(triphenylphosphine)palladium (0) (93.0 mg, 3 mole %) and heated to reflux under nitrogen atmosphere for 4.5 hr. The resulting solution was cooled to room temperature, the dark brown reaction mixture was diluted with ethyl acetate (75 mL) and washed with water (2×75 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to yield 2-(3-thienyl)benzaldehyde as a brown oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:19][C:9]1([CH3:20])[CH:8]([N:7]2[C:3]([CH:2]=[O:1])=[CH:4][N:5]=[CH:6]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[O:10]1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=O
Temperature: 60 °C

Procedure:
To a solution of 4-(5-hydroxymethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (0.500 g, 1.84 mmol) (Example 6d) in dioxane (10 mL) is added manganese dioxide (2.4 g, 27.6 mmol) and the reaction mixture is heated to 60° C. overnight. Filtration through celite and concentration in vacuo afforded 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde, which is used in the next step without further purification; MS (ESI) m/z 271.1 (M+H).
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[C:9]1([CH2:15][C:16]#[N:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>C(O)C.C(OCC)C>[OH:2]/[N:1]=[C:15](\[C:16]#[N:17])/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CCc1ccccc1
Reactant: CC(C)CCON=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: N#C/C(=N\O)c1ccccc1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A solution of isopentyl nitrite (16.00 g, 137 mmol) in ethyl alcohol (30 mL) was added dropwise to a solution of 2-phenylacetonitrile (16 g, 137 mmol) and sodium hydroxide (5.46 g, 137 mmol) in ethyl alcohol (30 mL) at 0° C. Once the addition was complete, the mixture was allowed to warm to room temperature. After stirring for 2h, the reaction mixture was diluted with diethyl ether and the resultant solid was collected by filtration and washed with diethyl ether. The solid was vacuum dried to yield (Z)—N-hydroxybenzimidoyl cyanide (10 g, 68.9 mmol, 50.4% yield) as a light yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][NH2:22])[CH:19]=2)[NH:14][C:13]=1[CH3:23])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:24](=O)[CH3:25].[C:27](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:28].[Na+]>ClC(Cl)C>[CH2:2]([O:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][N:22]([CH2:24][CH3:25])[CH2:27][CH3:28])[CH:19]=2)[NH:14][C:13]=1[CH3:23])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC=O
Reactant: Cc1[nH]c2ccc(CN)cc2c1C(=O)OCc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN(CC)Cc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a mixture of 5-aminomethyl-2-methyl-1H-indole-3-carboxylic acid benzyl ester, hydrochloride (300 mg, 0.91 mmol, Example 63, Step E) and in dichloroethane (40 mL) was added acetaldehyde (0.1 mL, 1.82 mmol). The mixture was stirred for 0.5 hour and then sodium triacetoxyborohydride (289 mg, 1.37 mmol) was added. The mixture was stirred at room temperature overnight and then partitioned between methylene chloride and water. The organic phase was washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a solid residue, which was purified by chromatography (5%-15% methanol in methylene chloride) to give 107 mg (34%) of the desired product as a white solid: mp 106-108° C.; MS(APCI+): m/z 351.1 (MH+); Anal. Calcd for C22H26N2O2.0.25H2O: C, 74.44; H, 7.52; N, 7.89. Found: C, 74.30; H, 7.51; N, 7.79.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(NCC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1Br
Agent: O=C1CC(=O)N(c2ccc(CNC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3Br)cc2)c2ccc3ccccc3c2N1
Yield: 21 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-bromobenzoyl chloride (0.143 mmol), the title compound (10 mg, yield 21%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][NH:18][CH2:19]3)=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[F:22][C:23]1[CH:28]=[C:27]([N:29]=[C:30]=[O:31])[CH:26]=[CH:25][C:24]=1[CH3:32].O>CN(C=O)C>[F:22][C:23]1[CH:28]=[C:27]([NH:29][C:30]([N:18]2[CH2:17][CH2:16][C:15]3[C:20](=[CH:21][C:12]([O:11][C:9]4[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:10]=4)=[CH:13][CH:14]=3)[CH2:19]2)=[O:31])[CH:26]=[CH:25][C:24]=1[CH3:32]
Reactant: Cc1ccc(N=C=O)cc1F
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)CNCC3)ccn1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc3c(c2)CN(C(=O)Nc2ccc(C)c(F)c2)CC3)ccn1
Reaction time: 24 h

Procedure:
To a solution of N-methyl-4-(1,2,3,4-tetrahydroisoquinolin-7-yloxy)pyridine-2-carboxamide (34 mg, 0.12 mmol) in DMF (1 mL) was added to 2-fluoro-4isocyanato-1-methylbenzene (21.8 mg, 0.144 mmol). The reaction mixture was allowed to stir for 24 h. Water added and the resulting solid was separated and purified by reverse phase HPLC to N-(3-fluoro-4-methylphenyl)-7-({2-[(methylamino)carbonyl]-pyridin-4-yl}oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide (32 mg, 61%). LCMS: (AA) ES+) 435.5.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:18]C(OC(Cl)C)=O>ClCCl>[ClH:18].[CH3:17][S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCNCC1
Product: Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To dichloromethane (70 ml) was added the compound (9.58 g, 37.66 mmol) obtained in step A and 1-chloroethyl chloroformate (4.53 ml, 41.43 mmol) was added under ice-cooling with stirring, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (70 ml), and the mixture was heated under reflux for 30 min. The reaction mixture was cooled to room temperature, and the precipitated solid was filtered and washed with a small amount of methanol. The filtrate was concentrated under reduced pressure, and the precipitated solid was filtered, and washed with a small amount of methanol. The obtained solid was combined, and the mixture was washed with diethyl ether to give the title compound (6.65 g, yield 88%) as a colorless solid.
Reaction SMILES: N1([C@@H](C)[C@@H](C)[OH:12])C2C=CC=CC=2N=C1.[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N+:34]([C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=1)([O-:36])=[O:35].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N+:34]([C:37]1[CH:38]=[CH:39][C:40]([C:41]([O-:43])=[O:42])=[CH:44][CH:45]=1)([O-:36])=[O:35].[C:28]1([P:21](=[O:12])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C[C@@H](O)[C@H](C)n1cnc2ccccc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: O=C([O-])c1ccc([N+](=O)[O-])cc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 12 h

Procedure:
To (1R,2S)-2-benzimidazol-1-yl-1-methyl-propanol (1.27 g, 6.68 mmol), triphenylphosphine (1.19 g, 1.1 equiv), and 4-nitrobenzoic acid (1.22 g, 1.1 equiv) in THF (20 mL) was added diethyl azodicarboxylate (1.15 mL, 1.1 equiv). After stirring 12 h, the solvent was removed, and chromatographed on silica gel eluting with ethyl acetate to give the intermediate 4-nitrobenzoate and triphenylphosphine oxide as a mixture. This mixture was directly hydrolyzed with 1.0N sodium hydroxide (20 mL) in THF/methanol for 3 h. The solvent was partially removed and the reaction diluted with water and extracted with ethyl acetate. The crude product was chromatographed on silica gel eluting with 7%(8:1, ethanol/ammonium hydroxide) in dichloromethane. (1S,2S)-2-benzimidazol-1-yl-1-methyl-propanol was isolated as a colorless solid 552 mg (44%). 1H NMR (CDCl3) 8.00(s,1H), 7.69(d,1H), 7.43(d,1H), 7.24(M, 2H), 4.36(m,1H), 4.27(m,1H), 1.33(d,3H), 1.22(d,3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].O.CO>C(OCC)(=O)C>[CH:25]1([C:23]([C@H:14]2[CH2:13][CH2:12][C@H:11]3[C@H:10]4[C@H:19]([CH2:18][CH2:17][C@:15]23[CH3:16])[C:20]2[CH:21]=[CH:22][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH2:8][CH2:9]4)=[O:24])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)C3CCCCC3)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)C1CCCCC1
Yield: 8200 %

Procedure:
A mixture of methyl-17β-cyclohexylcarbonyl-estra-1,3,5(10)-triene-3-carboxylate (0.14 g, 0.34 mmol), K2CO3 (0.2 g, 1.45 mmol), water (3.0 mL) and methanol (30 mL) was heated at reflux overnight. The reaction mixture was then concentrated. The residue was diluted with water, acidified with dilute HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried, and concentrated. The resulting solid was washed with CH3CN and isolated by filtration from boiling ethyl acetate to give, 0. 11 g of the title compound. mp 280°-285° C. (softened at 260° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:6][C:5]=1[O:18][CH3:19])([O-])=O.[H][H]>O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:6][C:5]=1[O:18][CH3:19]
Reactant: [H][H]
Reactant: COc1cc(Oc2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1COCCO1
Product: COc1cc(Oc2ccc(Cl)cc2)ccc1N
Yield: 100 %

Procedure:
220 g of 2-nitro-5-(4-chlorophenoxy)-anisole are dissolved in 2000 ml of dioxane and, after addition of 20 g of Raney nickel, the solution is hydrogenated at room temperature and under normal pressure. The theoretical amount of hydrogen is taken up after 12 hours, whereupon the catalyst is filtered off and the solvent evaporated, affording as residue 196.5 g of 2-amino-5-(4-chlorophenoxy)-anisole in the form of a dark brown oil, which is further processed direct.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].CS(C)=O.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][N:52]=[C:51]([CH2:54][NH2:55])[N:50]=2)=[CH:45][CH:44]=1>C(#N)C>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:55][CH2:54][C:51]4[N:50]=[C:49]([C:46]5[CH:45]=[CH:44][C:43]([O:42][CH3:41])=[CH:48][CH:47]=5)[O:53][N:52]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: COc1ccc(-c2nc(CN)no2)cc1
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1ccc(-c2nc(CNC(=O)c3ccc4n3Cc3ccccc3N(C(=O)c3ccc(-c5ccccc5C)c(C)c3)C4)no2)cc1
Temperature: 85 °C

Procedure:
A mixture of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 9 (0.26 mmol), dimethylsulfoxide (100 uL) and [5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methylamine of Step A (0.546 mmol) in acetonitrile (2.5 mL) was heated to 85° C. for 16 hours. After cooling the solvent was evaporated and the residue was taken up in dichloromethane (10 mL). This was washed with water (2×), dried over anhydrous sodium sulfate, and evaporated. The residue was purified by HPLC (Normal phase, Luna CN bonded packing) and crystallized from ethyl acetate/hexane, m.p. 133-135° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].Br[CH2:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=2[N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:29][C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]([CH2:19][N:4]3[C:5](=[O:16])[C:6]4[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=4[N:2]([CH3:1])[C:3]3=[O:17])=[N:24][C:23]=2[CH:25]=1
Reactant: Fc1ccc2sc(CBr)nc2c1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3cc(F)ccc3s1)c(=O)n2C
Yield: 98 %

Procedure:
By utilizing the well known method, 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1a (156 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (3 ml). 2-bromomethyl-5-fluoro-1,3-benzothiazole (140 mg, 0.57 mmol), potassium carbonate (118 mg, 0.79 mmol) were added to give a reaction mixture. The obtained reaction mixture was reacted overnight at room temperature and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was poured into water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1b (240 mg, off-white solid), yield: 99%.
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[CH2:40][C:41]([NH:43][C@@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42]>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:40][C:41]([NH:43][C@@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)CN)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Product: CSCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 59 %

Procedure:
Condensation of BocPro-Phe-PheNHNH2 (Example 1, 0.93 g.) and HGly-DLeu-MetNH2 (0.63 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-Gly-DLeu-MetNH2 in 59% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-Gly-DLeu-MetNH2 (0.88 g.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Gly-DLeu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt in 59% yield.
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18]3[N:21]([CH3:35])[N:22]([C:25]4[CH:34]=[N:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[C:23](=[O:24])[C:17]=3[CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[OH:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18]3[N:21]([CH3:35])[N:22]([C:25]4[CH:34]=[N:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[C:23](=[O:24])[C:17]=3[CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8]
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(c(=O)n(-c4cnc5ccccc5n4)n3C)C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nccc(N2CCc3c(c(=O)n(-c4cnc5ccccc5n4)n3C)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of (R)-1-[4-(1-methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 75, Step D, 248 mg, 0.52 mmol) in a 5:2 mixture of methanol/tetrahydrofuran (7 mL) was added potassium carbonate (218 mg, 1.57 mmol). This mixture was stirred at room temperature overnight and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5→3% methanol/chloroform) to give 150 mg (71%) of the title compound as a white solid. mp: 217-219° C. (dec); 1H NMR (CDCl3, 250 MHz) δ9.66 (s, 1H), 8.25 (d, 1H), 8.12 (dd, 1H), 7.99 (m, 1H), 7.68-7.78 (c, 2H), 6.47 (d, 1H), 4.72 (q, 12H), 4.32 (s, 2H), 4.19-4.14 (c, 3H), 3.41 (s, 3H), 2.80 (t, 2H), 1.51 (d, 3H); MS (APCI) 404 (MH+); [α]D +13.4 (c 1.5, CHCl3).
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.N[C:13]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].NC1C=CC=CC=1>CC#N>[CH2:3]([C:13]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16])[CH:1]=[CH2:2]
Reactant: CC(C)(C)ON=O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Solvent: CC#N
Solvent: C=CCBr
Solvent: Nc1ccccc1
Product: C=CCc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 2-amino-5-nitrobenzophenone (727 mg, 3.0 mmol) was added during 20 minutes while maintaining the temperature of the reaction mixture at 28-32° C. At the end of the addition of the aniline, extra t-butylnitrite (360 μl, 3 mmol) was added to the reaction mixture which then was stirred at 25° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 23:2) gave 370 mg (46%) of 2-allyl-5-nitrobenzophenone as a light yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.29, (dd, 1H, J=8.6, 2.5 Hz), 8.18, (d, 1H, J=2.4 Hz), 7.81-7.74, (m, 2H), 7.69-7.60, (m, 1H), 7.57-7.45, (m, 3H), 5.93-5.88, (m, 1H), 5.09-5.95, (m, 2H), 3.53, (m, 2H, J=6.6 Hz).
Reaction SMILES: N12CCCN=C1CCCCC2.Br[CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].CN(C)C(=O)C>O>[CH:14]([N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])=[CH2:13]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: C=CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Over a period of 2 hours, 672 g of 1,8-diazabicyclo-[5.4.0]-undec-7-ene were added dropwise to a solution of 1016 g of N-(2-bromoethyl)phthalimide in 2.81 of N,N-dimethylacetamide. During the addition, the temperature increased to 60° C. After the addition had ended, stirring was continued for 12 hours. The batch was poured into 9 l of water and filtered, and the filtration residue was dried at 50° C. This gave 621 g of product (=90% of theory) of melting point 79-80° C.