Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].F[C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25].Cl>CS(C)=O.C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([O:10][C:19]3[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=3)[C:24]([OH:26])=[O:25])=[N:7][C:6]=2[CH:11]=1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(O)c1cc(Oc2nc3cc(Cl)ccc3o2)ccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A reactor is charged with 1.69 grams (0.01 mole) of 5-chlorobenzoxazol-2-one (Formula II Compound), 10 milliliters of dimethylsulfoxide, and 2.76 grams (0.02 mole) of anhydrous potassium carbonate. To this mixture is added 1.85 grams (0.01 mole) of 5-fluoro-2-nitrobenzoic acid (Formula III Compound) in 4 milliliters of dimethylsulfoxide. After stirring at about 75° C. to 80° C. for about 18 hours, the reaction mixture is stripped of solvent and the residue is dissolved in a mixture of methylene chloride and water. The mixture is acidified to pH 2 to 3 with 5 normal hydrochloric acid and the aqueous phase is extracted with methylene chloride. The combined organic phases are washed with water and saturated sodium chloride solution. Filtration and removal of solvent affords 5-(5-chloro-2-benzoxazolyloxy)-2nitrobenzoic acid. (Formula IV Compound);
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9](=[O:14])[C:10](=[O:13])OC)=[O:4].[CH3:15][C:16]([Mg]Cl)([CH3:19])[CH2:17][CH3:18].[Cl-].[NH4+].CCOCC>O1CCCC1.CCCCC>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9](=[O:14])[C:10](=[O:13])[C:16]([CH3:19])([CH3:15])[CH2:17][CH3:18])=[O:4]
Reactant: COC(=O)C(=O)N1CC[C@H]1C(=O)OC
Reactant: CCC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: CCC(C)(C)C(=O)C(=O)N1CC[C@H]1C(=O)OC
Temperature: -78 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a cooled (about −78° C.) solution of (2S)-Methyl-1-(1,2-dioxo-2-methoxyethyl)-azetidine-2-carboxylate from Reference Example 2 (0.98 g, 4.86 mmol, 1.0 eq) in dry tetrahydrofuran (15 mL) under an argon atmosphere was added 1,1-dimethylpropylmagnesium chloride in THF (6.30 mL of 1M solution, 6.30 mmol, 1.3 eq) over about 15 minutes. After stirring the resulting homogeneous mixture at about −78° C. for about 3 hours, the mixture was poured into chilled saturated ammonium chloride and extracted into ethyl acetate (2×50 mL). The organic phase was washed with water, dried over sodium sulfate and concentrated. Flash chromatography of the residue (2:3 ether:pentane) produced 0.90 g (77% yield) of the product as a colorless oil. 1H NMR (CDCl3) δ 0.77-0.98 (m, 3H); 1.20-1.30 (series of s, 6H); 1.68-2.01 (m, 2H); 2.24-2.40 (m, 1H); 2.60-2.80 (m, 1H); 3.80-3.82 (series of s, 3H); 3.99-4.43 (series of m, 2H); 4.84 and 5.26 (series of dd, 1H, J=6.9, 9.4).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:60][NH:61][CH2:62][CH2:63][OH:64]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[OH:64][CH2:63][CH2:62][N:61]([CH3:60])[C:34](=[O:35])[CH2:33][CH:30]1[S:29][C:28]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:20][C:19]=3[O:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[N:32][CH2:31]1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: CNCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CN(CCO)C(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.4 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), and 2-(methylamino)ethanol (42 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (102 mg, yield 60%) as a pale-yellow amorphous solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[C:65]2[O:64][C:63]([CH3:67])([CH3:66])[CH2:62][C:61]=2[CH:60]=[CH:59][CH:58]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[C:65]3[O:64][C:63]([CH3:67])([CH3:66])[CH2:62][C:61]=3[CH:60]=[CH:59][CH:58]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: CC1(C)Cc2cccc(N=C=O)c2O1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cccc(NC(=O)N3CCC(CCOc4ccc5cc4CCc4cncc(c4)Nc4ncc(Cl)c(n4)N5)CC3)c2O1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 7-isocyanato-2,2-dimethyl-2,3-dihydro-1-benzofuran as the starting materials in 60% yield. LCMS for C35H39ClN7O3 (M+H)+: m/z=640.1.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[CH3:21][C@H:22]([NH:31][CH3:32])[C@@H:23]([OH:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1>>[CH3:21][C@@H:22]([NH:31][CH3:32])[C@H:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CN[C@H](C)[C@H](O)c1ccccc1
Temperature: 28 °C
Reaction time: 48 h

Procedure:
Coprinus rhizophorus IFO 30197 was inoculated to a medium containing 1% glucose, 0.5% peptone and 0.3% yeast extract, and culturing was aerobically carried out at 30° C. for 48 hours. After this cultured solution (5 ml) was centrifuged to give bacterial cells, the cells were dried in the air and the resulting dried bacterial cells were suspended in 1 ml of 0.05 M Tris hydrochloric acid buffer (pH 7.5). To this were added glucose (50 mg), glucose dehydrogenase (0.2 mg), NADP (0.6 mg), NAD (0.6 mg) and dl-2-methylamino-1-phenyl-1-propanone hydrochloride (10 mg). Reaction was allowed to take place by carrying out reciprocation-shaking at 28° C. and at 300 rpm for 48 hours. The reaction solution was analyzed on HPLC (Column Sumichiral AGP manufactured by Sumika Chemical Analysis Service; diameter of 4 mm; length of 150 mm; 0.03 M sodium phosphate buffer; pH 7.0; flow rate of 0.5 ml/min; detection wavelength at UV 220 nm). The produced amounts and the optical activities of pseudoephedrine were determined. Consequently, only l-pseudoephedrine was obtained selectively, as shown in Table 6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25]I>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][N:16]1[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:15]1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: ClCCCCI
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCCl)CC1

Procedure:
In analogy to the procedure described in example 5A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 1-chloro-4-iodobutane gave the title compound as orange solid. MS: 403.2 (MH+, 3Cl).
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:14]([C:16]1[N:21]=[C:20]([NH2:22])[CH:19]=[CH:18][CH:17]=1)#[CH:15].[CH2:23]([N:30]=[N+:31]=[N-:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O.C(O)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:23]([N:30]1[CH:15]=[C:14]([C:16]2[N:21]=[C:20]([NH2:22])[CH:19]=[CH:18][CH:17]=2)[N:32]=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1cccc(N)n1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2cn(Cc3ccccc3)nn2)n1
Reaction time: 14 h

Procedure:
Sodium ascorbate (34 mg, 0.17 mmol) and copper (II) sulfate pentahydrate (11 mg, 0.042 mmol) were added to a solution of 6-ethynylpyridine-2-amine (100 mg, 0.85 mmol) and benzyl azide (113 mg, 0.846 mmol) in water (5 mL) and ethanol (5 mL). The reaction mixture was stirred vigorously in the absence of light for 14 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-100% ethyl acetate/hexanes, linear gradient) to afford 6-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridin-2-amine. MS ESI calc'd. for C14H14N5 [M+H]+ 252. found 252. 1H NMR (500 MHz, CD3OD) δ 8.21 (s, 1H), 7.49-7.44 (m, 1H), 7.37-7.26 (m, 5H), 7.22 (d, J=7.4 Hz, 1H), 6.49 (d, J=8.2 Hz, 1H), 5.58 (s, 2H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)C.[Cl:7][C:8]1[N:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C>O>[Cl:7][C:8]1[N:13]=[C:12]([N:2]([CH3:3])[CH3:1])[CH:11]=[CH:10][N:9]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CN(C)c1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a 20% dimethylamine-ethanol solution (15.4 g) of 2,4-dichloropyrimidine (3.0 g) was added triethylamine (3 ml) under ice-cooling, and the mixture was stirred for 30 min. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml). The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:1) to give the title compound (1.90 g) as white crystals, m.p.=77-79° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][CH:36]=[N:37]2)=[CH:32][CH:31]=1.[OH-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:5]=[CH:4][N:3]=[C:2]2[O:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[CH:35][CH:36]=[N:37]2)=[CH:32][CH:31]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCCCC1
Reactant: Oc1ccc2cccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cccnc4c3)ncnc2cc1OCCN1CCCCC1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a suspension of 4-chloro-6-methoxy-7-(2-piperidinoethoxy)quinazoline (250 mg, 0.78 mmol), (prepared as described for the starting material in Example 180), in DMF (10 ml) was added anhydrous potassium carbonate (320 mg, 2.30 mmol) and 7-hydroxyquinoline (135 mg, 0.94 mmol), and the reaction heated under reflux at 90C for 1 hour. The reaction was cooled to ambient temperature and 1N aqueous sodium hydroxide added. The resulting precipitate was filtered, washed with water and acetone, and dried under suction to give 6-methoxy-7-(2-piperidinoethoxy)-4-(quinolin-7-yloxy)quinazoline (248 mg, 0.58 mmol, 75%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15].[C:16]([Cu])#[N:17]>CN1CCCC1=O.O.C(OCC)(=O)C>[OH:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:16]#[N:17])=[C:13]([O:14][CH3:15])[C:6]=2[C:7]=1[CH3:12]
Reactant: COc1c(Br)ccc2oc(CO)c(C)c12
Reactant: N#C[Cu]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1c(C#N)ccc2oc(CO)c(C)c12
Yield: 71.1 %

Procedure:
A suspension of (5-bromo-4-methoxy-3-methyl benzofuran-2-yl)-methanol (0.31 g; 1.1 mmol, Example 136, Step 1) and CuCN (0.21 g; 2.3 mmol; 2 eq) in N-methylpyrrolidinone (1.5 mL) was subjected to microwave radiation at 200° C. for 10 minutes. The reaction was diluted with water and ethyl acetate (10 mL each) and filtered. The layers were separated and the aqueous phase was washed with a second portion of ethyl acetate. The combined organic layers were washed twice with water and once with brine. After drying over magnesium sulfate, filtration and concentration in vacuo gave the crude product. Chromatography on silica gel, eluting with 20% to 30% ethyl acetate/hexanes gave pure 2-hydroxymethyl-4-methoxy-3-methyl benzofuran-5-carbonitrile (0.17 g; 67% yield).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:6]2.[Cl:20][CH2:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[ClH:20].[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:6]2
Reactant: ClCc1nc2ccccc2s1
Reactant: Oc1ccc2c(c1)CCC(CN1CCCCC1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2sc(COc3ccc4c(c3)CCC(CN3CCCCC3)C4)nc2c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 50.6 %

Procedure:
To a solution of 6-hydroxy-2-piperidinomethyltetralin hydrochloride (205 mg, Reference Example 19) and 2-chloromethylbenzothiazole (183 mg) in DMF (10 ml) was added potassium carbonate (327 mg) and the reaction mixture was stirred at room temperature for 4 days and further at 60° C. for 7 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate:methanol=10:1), alumina column chromatography (eluent: ethyl acetate:hexane=1:4) and converted into its hydrochloride, which was recrystallized from methanol-ethyl acetate to obtain the titled compound (158 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][NH:16][CH2:15][CH:14]([C:18]([O:20][CH3:21])=[O:19])[CH2:13]1.C(N(CC)CC)C.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][N:16]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:31])[CH2:15][CH:14]([C:18]([O:20][CH3:21])=[O:19])[CH2:13]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1CNCC(c2ccc(C(F)(F)F)cc2F)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2F)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
938 mg (3.07 mmol) of the compound from Example 87A were initially charged in 40 ml of dichloromethane and cooled to 0° C., and admixed with 1.28 ml (0.93 g, 9.22 mmol) of triethylamine and 0.62 g (3.07 mmol) of 4-nitrophenyl chloroformate. The reaction mixture was allowed to warm up slowly to RT and stirred at RT for 16 h. It was washed repeatedly with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. This gave 1.21 g of crude product in 85% purity (LC-MS), which was reacted without any further purification steps.
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[N:16]3[N:17]=[N:18][N:19]=[C:15]3[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:13]([CH3:30])=[C:12]2[C:31]([O:33]CC)=[O:32])=[CH:7][CH:6]=1)#[N:4].Cl>C(O)C.C1COCC1.O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[N:16]3[N:17]=[N:18][N:19]=[C:15]3[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=3)[C:13]([CH3:30])=[C:12]2[C:31]([OH:33])=[O:32])=[CH:9][CH:10]=1)#[N:4]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nnnn2[C@@H]1c1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2)n2nnnc2N1c1cccc(C(F)(F)F)c1
Temperature: 55 °C

Procedure:
The reaction was carried out under argon. Solid lithium hydroxide (15.8 mg, 660 μmol, 3 eq.) was added to a solution of ethyl (7R)-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (100 mg, 220 μmol) in an ethanol/THF/water mixture (4:1:0.6, 5.6 ml). The solution was heated at 55° C. for 1.5 h. At 0° C., the mixture was then acidified with 1 N hydrochloric acid (0.66 ml) and then directly purified by preparative HPLC (Kromasil C18 column; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless amorphous solid (67 mg, 71% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:14]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)c1cc(F)cc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1cc(F)cc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-5-fluoro-benzoic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:15][C:16]#[N:17])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:10]1[CH2:11][CH2:12][CH2:13][C:8]([CH2:15][C:16]#[N:17])([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]1=[O:14]
Reactant: BrBr
Reactant: N#CCC1(c2ccc(Cl)cc2)CCCCC1=O
Solvent: ClC(Cl)Cl
Product: N#CCC1(c2ccc(Cl)cc2)CCCC(Br)C1=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
1-(4-Chloro-phenyl)-2-oxo-cyclohexyl-acetonitrile (100 mg, 0.40 mmol) was dissolved in chloroform (1 mL). To this solution bromine (67.7 mg, 0.42 mmol) in chloroform (0.5 mL) was added drop wise at −11° C. The reaction was stirred for 1½ hours at 5° C., then for 1 hours t room temperature and finally for 1 hour at 50° C. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane as eluent to yield the title compound (104 mg, 79%) as colourless oil. NMR (CDCl3, 300 MHz): δ (ppm)=7.44 (d, 2H), 7.13 (d, 2H), 4.62 (dd, 1H), 2.99 (m, 2.80 (s, 2H), 2.58 (m, 1H), 2.14 (m, 1H), 1.92 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[CH:11][N:10]=[C:9]2[CH2:25][N:26]([CH3:28])[CH3:27])=[C:4]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=O)[CH:3]=1.O.NN>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:9]([CH2:25][N:26]([CH3:28])[CH3:27])=[N:10][CH:11]=[C:12]3[CH2:13][N:14]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:4]=2[CH:3]=1
Reactant: CN(C)Cc1ncc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Br)cc1C(=O)c1ccccn1
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)Cc1ncc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 4, N-[[1-[4-bromo2-(2-pyridylcarbonyl)phenyl]-2-[(dimethylamino)methyl]-imidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 8-bromo-6-(2-pyridyl)-1-[(dimethylamino)methyl]-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:30](=[O:31])[CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: COc1cccc(CC(=O)Cl)c1
Product: COc1cccc(CC(=O)N[C@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3-(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylacetylchloride. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.: m.p. 198°-199° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][C:9](O)=[C:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][C:12]=3[OH:21])[C:4]2=[CH:3][CH:2]=1.[NH3:23]>>[NH2:23][C:9]1[CH:8]=[CH:7][C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]=1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[OH:21]
Reactant: N
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Product: Nc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Temperature: 200 °C
Yield: 91 %

Procedure:
To a 125 mL Teflon lined autoclave was added 5 g (17.5 mmol) of 1,1′-bi-2-naphthol, 23.47 g (175 mmol) of (NH4)2SO3H2O and 65 mL of concentrated aqueous ammonia. The mixture was heated in an oil-bath to 200° C. for 5 days, then cooled down to ambient temperature and filtered. The resulting solid was washed with water followed by recrystallization from benzene to afford 4.52 g (15.8 mmol, 91%) of pure 2-amino-2′-hydroxy-1,1′-binaphthyl. Enantiomerically pure NOBIN can be obtained by the resolution methods reported in the literature (Ding, K.; Wang, Y.; Yun, H.; Lin, J.; Wu, Y.; Terada, M.; Okubs, Y.; Mikami, K.; Chem. Eur. J. 1999, 5, 1734-1737).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2.[BH4-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH:6]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2
Reactant: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1O
Reaction time: 4 h

Procedure:
0.489 g (2 mmol) of 5-chloro-2-methylsulfonylindan-1-one and 0.095 g (2.5 mmol) of sodium borohydride were suspended in 10 ml of ethanol and placed in an ultrasonic bath for 4 h. The reaction mixture was then acidified with 2N HCl and stirred. The ethanol was distilled off, water and dichloromethane were added to the residue and the mixture was extracted with dichloromethane. The organic phase was separated off, dried over MgSO4, filtered and concentrated and the residue was purified chromatographically on silica gel using dichloromethane/methanol 20/1. This gave 5-chloro-2-methylsulfonylindan-1-ol of melting point 163° C.