Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:4]=1[NH2:5].[Cl:13][CH2:14][CH:15]([CH3:19])[C:16](Cl)=[O:17]>C1C=CC=CC=1.O>[Cl:13][CH2:14][CH:15]([CH3:19])[C:16]([NH:5][C:4]1[CH:6]=[C:7]([C:10](=[O:12])[CH3:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:17]
Reactant: CC(CCl)C(=O)Cl
Reactant: COc1ccc(C(C)=O)cc1N
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C(C)=O)cc1NC(=O)C(C)CCl
Reaction time: 2 h
Yield: 77 %

Procedure:
24.8 g of 2-methoxy 5-acetyl aniline [obtained according to Oelschager Arzneimit. Forschung 8 532-539 (1958)] dissolved in 150 ml benzene are added with 10.6 g of 3-chloro isobutyric acid chloride in 40 ml benzene. The mixture is kept at room temperature for 2 hours under stirring then diluted with 250 ml water. The benzenic phase is separated. The aqueous phase is extracted twice with benzene. The benzenic solutions are united, washed with 2N hydrochloric acid and then with water, dried on sodium sulphate, filtered and evaporated to dryness. The residue is recrystallised from isopropyl ether from which 15.5 g or pure compound are recovered (yield = 77%) -1-(β-chloroα-methyl propionylamino) 2-methoxy 5-acetylbenzene melts at 92-97°.
Reaction SMILES: [Mg].[CH3:2][CH2:3][O:4][C:5]([C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].O.Br[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29]>O1CCCC1>[C:16]([O:15][C:13]([NH:8][C@H:7]([CH2:11][CH2:10][C:9]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])=[O:12])[C:5]([O:4][CH2:3][CH3:2])=[O:6])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Fc1ccc(F)c(Br)c1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)ccc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium (0.569 g) in tetrahydrofuran (20 mL), 1-bromo-2,5-difluorobenzene (2.64 mL) was added dropwise at 55° C. over 15 minutes, and the reaction solution was stirred at room temperature for one hour. This solution was added dropwise to a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (5.0 g) in tetrahydrofuran (25 mL) at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 5.7 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[CH:16]([CH2:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH2:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25](O)=[O:26].C1(OC)C=CC=CC=1>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([NH2:8])=[O:26].[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH2:14]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C1CC=CC=C12
Reactant: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: NC(=O)C(F)(F)F
Product: O=C1CC2(CCNCC2)c2ccccc21
Reaction time: 1 h

Procedure:
A solution of the intermediate from Step A in a 1:1:0.5 mixture of trifluoroacetic acid, dichloromethane and anisole was stirred for 1 hour and then concentrated and azeotroped from toluene to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:29]=2)[CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:28]2[N:29]=[CH:30][C:31]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)=[CH:32][CH:33]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2ccc(N3CCC3)nc2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(N5CCC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 2-azetidin-1-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 5.1.1, 39 mg, 0.150 mmol) to give the title compound as a white solid. (HPLC: tR 2.24 min (Method A); M+H=426 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.25-8.18 (m, 1H), 8.14-8.09 (m, 1H), 8.06-8.02 (m, 1H), 7.89-7.81 (m, 1H), 7.62-7.53 (m, 1H), 7.42 (s, 1H), 6.48-6.42 (m, 1H), 4.01-3.93 (m, 4H), 3.91 (s, 3H), 3.56 (s, 3H), 2.36-2.28 (m, 2H), 1.96 (s, 3H))
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[N:24][C:23]([O:27][CH3:28])=[CH:22][CH:21]=3)[CH2:10][CH2:9]1)(C)(C)C.[Cl:30][C:31]1[C:41](C(O)=O)=[CH:40][C:34]2[NH:35][C:36](=[O:39])[CH2:37][S:38][C:33]=2[CH:32]=1>>[CH3:28][O:27][C:23]1[N:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:6]([C:41]3[C:31]([Cl:30])=[CH:32][C:33]4[S:38][CH2:37][C:36](=[O:39])[NH:35][C:34]=4[CH:40]=3)=[O:5])[CH2:9][CH2:10]1)=[CH:26]2
Reactant: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)cc2n1
Reactant: O=C1CSc2cc(Cl)c(C(=O)O)cc2N1
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)c4cc5c(cc4Cl)SCC(=O)N5)CC3)cc2n1

Procedure:
The title compound is prepared as an off-white lyophilizated powder following Scheme 1 and in analogy to Example 1 using {1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester and 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: I[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+].[O:16]=[C:17]1[O:23][C@H:22]([C@H](CO)O)[C:20]([O-])=[C:18]1O.[Na+].C(OC)(=O)CC>CS(C)=O.[O-]S([O-])(=O)=O.[Cu+2].O>[O:7]1[C:6]2[CH:10]=[CH:11][C:3]([CH2:2][N:12]3[CH:20]=[C:18]([C:17]([O:23][CH3:22])=[O:16])[N:14]=[N:13]3)=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: [N-]=[N+]=[N-]
Reactant: ICc1ccc2c(c1)OCO2
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCC(=O)OC
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cn(Cc2ccc3c(c2)OCO3)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 611.8 %

Procedure:
Compound 419 (1.72 g, 6.57 mmo) was dissolved in a 0.5 M solution of sodium azide 13.1 mL, 6.57 mmol) in DMSO (2 mL), stirred at room temperature overnight and quenched by pouring into a saturated solution of sodium thiosulfate. The compound was extracted with AcOEt, washed with brine, dried over MgSO4 and filtered to give a yellow solution. Water (2.5 mL) was then added followed by solid sodium ascorbate (130 mg, 0.657 mmol), methyl propionate (553 mg, 0.657 mmol) and 1M aq. CuSO4 solution (0.2 mL) to give a yellow solution. The reaction mixture was stirred overnight at room temperature to give a mustard-colored suspension. Water was added until a suspension formed, filtered, washed with water, and dried to generate the title compound 420 (1.05 g, 63% yield) as a mustard-colored solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1.C(NC(N)=[S:26])(=O)C.C(OCC)(=O)C>C(O)C>[SH:26][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CCBr)cc2)cs1
Reactant: CC(=O)NC(N)=S
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(CCS)cc2)cs1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a suspension of N-(4-{2-[4-(2-bromoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (353.3 mg, 1.000 mmol) in ethanol (4 ml) was added 1-acetyl-2-thiourea (177.4 mg, 1.501 mmol), and the mixture was heated under reflux for 7 hr. 1-Acetyl-2-thiourea (176.6 mg, 1.495 mmol) was added, and the mixture was heated under reflux for 17 hr. The mixture was cooled to room temperature, ethyl acetate (10 ml) was added, and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure, and purified twice by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. DM-2035 21 g, ethyl acetate:hexane=2:3→1:1) to give N-(4-{2-[4-(2-sulfanylethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (210.4 mg, 0.687 mmol, 68.7%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:2]1=[O:15].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)=[O:24])[CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:25]1([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:12]3[CH2:11][CH2:10][C:3]4([C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:1][C:2]4=[O:15])[CH2:14][CH2:13]3)[CH:18]=2)=[O:24])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1
Reactant: O=C1Nc2ncccc2C12CCNCC2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(N2CCC3(CC2)C(=O)Nc2ncccc23)ncn1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
43 mg (0.21 mmol) spiro[piperidine-4,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one were added to 50 mg (0.19 mmol) (6-chloro-pyrimidin-4-yl)-(2,3-dihydro-indol-1-yl)-methanone and 52 μL (0.58 mmol) DIPEA in 5 mL DMF. The reaction mixture was stirred for 2 h at RT. The reaction mixture was evaporated down using the rotary evaporator and the residue was mixed with 20 mL water and stirred for 30 min at RT. The product precipitated was suction filtered, stirred with diisopropylether and isopropanol, suction filtered and dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13](=[O:15])[NH:49][CH2:48][CH2:47][N:46]([CH3:50])[CH3:45])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)CCN
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (116 mg, 0.38 mmol), HATU (218 mg, 0.46 mmol), N,N-dimethylethylenediamine (40 mg, 0.46 mmol) and DIPEA (0.2 mL, 1.1 mmol) in DMF (2 mL). MS (LC-MS): 374.2 [M]+; tR (HPLC conditions c): 3.87 min.
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:16][N:17]1[C:21]([NH2:22])=[N:20][N:19]=[N:18]1.C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[CH:7][C:3]=1[C:4]([NH:22][C:21]1[N:17]([CH3:16])[N:18]=[N:19][N:20]=1)=[O:5]
Reactant: COc1c([N+](=O)[O-])ccc(C(=O)O)c1Br
Reactant: Cn1nnnc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: COc1c([N+](=O)[O-])ccc(C(=O)Nc2nnnn2C)c1Br
Temperature: 65 °C
Yield: 48 %

Procedure:
2-bromo-3-methoxy-4-nitrobenzoic acid (95 mg, 0.344 mmol) and 1-methyl-1H-tetrazol-5-amine (44 mg, 0.447 mmol) are dissolved in pyridine (6 ml). Oxalyl chloride (41 μl, 0.465 mmol) is slowly added dropwise, and the reaction mixture is subsequently warmed to 65° C. for 2 hours. The solvent is stripped off and the residue is separated by preparative HPLC. This gives 59 mg (0.165 mmol, yield 48%) of 2-bromo-3-methoxy-N-(1-methyl-1H-tetrazol-5-yl)-4-nitrobenzamide.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOCCOC1.Cl[CH:22](Cl)[C:23]([OH:25])=[O:24].[CH:27]1([C:33]([CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)([OH:46])[C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH:44]=[CH:43][CH:42]=[CH:41]3)=[CH:36][C:35]=2[OH:45])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCOCC1>[CH:47]1([C:33]2([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH:44]=[CH:43][CH:42]=[CH:41]4)=[CH:36][C:35]=3[O:45][CH:22]([C:23]([OH:25])=[O:24])[O:46]2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: Oc1cc(-n2cccc2)ccc1C(O)(C1CCCCC1)C1CCCCC1
Reactant: O=C(O)C(Cl)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C1Oc2cc(-n3cccc3)ccc2C(C2CCCCC2)(C2CCCCC2)O1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a suspension of 228 mg of NaH (60% dispersion in mineral oil) and 18 mg of 18-crown-6 ether in 8 ml of anhydrous dioxane, a solution of 2.3 ml of a solution of dichloroacetic acid (1 M) in anhydrous dioxane was slowly added at room temperature. The reaction mixture was heated to 60° C. and a solution of 504 mg of 2-(Dicyclohexyl-hydroxy-methyl)-5-pyrrol-1-yl-phenol in 6 mL anhydrous dioxane was added and stirred at 95° C. for 6 h. After cooling to 0° C., the reaction mixture was quenched with 2 ml of isopropanol and poured on ice. The aqueous phase was extracted with ether, then acidified with HCl (2 M, to pH 1), and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 118 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:34][C:35](OC(C)=O)=[O:36].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[N:12]([CH:8]2[CH2:9][C:10]3[CH:11]=[C:2]([NH:1][C:35](=[O:36])[CH3:34])[CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7]2)[CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(N)cc3C2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2c(c1)CC(N(CCCN1CCN(C)CC1)C(=O)Nc1ccc(F)c(Cl)c1)CC2
Reaction time: 16 h
Yield: 83 %

Procedure:
To a solution of 1-(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-urea (from Preparative Example 27, 0.033 g, 0.070 mmol) in CH2Cl2 (0.2 mL) at 0° C. were added Ac2O (0.0066 mL, 0.070 mmol) and DIEA (0.036 mL, 0.21 mmol). The mixture was stirred from 0° C. to room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 0.030 g (83%) of N-(7-{3-(3-chloro-4-fluoro-phenyl)-1-[3-(4methyl-piperazin-1-yl)-propyl]-ureido}-5,6,7,8-tetrahydro-naphthalen-2yl)-acetam ide as a light yellow gum. 1H NMR (300 MHz, CD3OD): δ 7.60 (dd, 1H, J=6.9, 2.4 Hz), 7.38 (d, 1H, J=2.1 Hz), 7.30 (ddd, 1H, J=9.0, 4.2, 2.4 Hz), 7.20 (dd, 1H, J=8.4, 2.1 Hz), 7.15 (t, 1H, J=9.0 Hz), 7.05 (d, 1H, J=8.4 Hz), 4.31 (m, 1H), 3.60 (m, 8H), 3.47 (m, 2H), 3.24 (t, 2H, J=7.2 Hz), 2.97 (m, 7H), 2.14-2.00 (m, 7H). MS-ESI: 516.1 (M+H+).
Reaction SMILES: CCCCCC.C([Al](CC(C)C)CC(C)C)C(C)C.C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.C(O)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:56]([Cl:65])[C:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:58]>C1(C)C=CC=CC=1>[Cl:65][CH2:56][C@H:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[OH:58]
Reactant: O=C(CCl)c1ccccc1
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Agent: OC(c1ccccc1)c1ccccc1
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O[C@H](CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.5 ml (0.5 mmol) of hexane solution of triisobutylaluminum (1.0 M) was added a slurry solution of 143 mg (0.5 mmol) of (R)-1,1′-bi-2-naphthol in 10 ml of toluene at room temperature, and the mixture was stirred at room temperature for 30 minutes. Thereto 1.84 g (20 mmol) of benzhydrol was added and the mixture was stirred further at room temperature for 30 minutes. Thereto 1.55 g (10 mmol) of phenacyl chloride was added and the mixture was stirred further at room temperature for 2 hours. The after-treatment and the analysis of the product were then carried out in the same manner as described in Example 2.
Reaction SMILES: [O-2].[Gd+3:2].[O-2].[O-2].[Gd+3].[N+:6]([O-:9])([OH:8])=[O:7]>>[N+:6]([O-:9])([O-:8])=[O:7].[Gd+3:2].[N+:6]([O-:9])([O-:8])=[O:7].[N+:6]([O-:9])([O-:8])=[O:7]
Reactant: O=[N+]([O-])O
Agent: [Gd+3]
Agent: [O-2]
Product: O=[N+]([O-])[O-]
Reaction time: 1 h
Yield: 62 %

Procedure:
Slightly excess gadolinium oxide was dissolved in concentrated nitric acid under heating to effect the reaction. After 1 hour, the reaction liquid was filtered and the filtrate was cooled to precipitate crystalline gadolinium nitrate. Yield: 62%.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[S:32]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:38][CH2:37][C:34]5[CH:35]=[CH:36][S:32][CH:33]=5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: NCc1ccsc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCc5ccsc5)c4)cc23)CC1
Yield: 10.1 %

Procedure:
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), 1-(3-thienyl)methanamine (9.83 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (4.7 mg, 7.8%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[C:13]([C:18](=[N:24][O:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:12]=1.Cl>CN(C)C=O.O>[NH2:10][C:11]1[CH:16]=[C:15]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:14]=[C:13]([C:18](=[N:24][O:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:12]=1
Reactant: CCOC(=O)C(=NOC)c1nc(N)cc(Cl)n1
Reactant: Sc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=NOC)c1nc(N)cc(Sc2ccccc2)n1
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
To a solution of thiophenol (2.55 g) in N,N-dimethylformamide (20 ml) was added 50% sodium hydride (1.1 g) under cooling in an ice bath and the mixture was stirred for 20 minutes at 0° C. to 5° C. To the mixture was added ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (2.0 g) and the mixture was stirred for 6 hours at ambient temperature. The resultant mixture was poured into cold water, adjusted to pH7 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was subjected to column chromatography on silica gel (50 g) using a mixture of chloroform and ethyl acetate (3:1 by valume) as an eluent. The fractions containing the object product were collected and evaporated to give ethyl 2-(4-amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (460 mg), mp 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[N:13]([CH3:18])[C:14]([C:15]([OH:17])=O)=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[OH-].[NH4+:35].C(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[N:13]([CH3:18])[C:14]([C:15]([NH2:35])=[O:17])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1
Reactant: [NH4+]
Reactant: Cn1c(C(=O)O)c2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1c(C(N)=O)c2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 0.5 h

Procedure:
A stirred suspension of 3 g (0.0075 mole) of 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-2-methyl-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylic acid in 90 ml of methylene chloride was cooled in an ice bath and treated with 1.9 g (0.009 mole) of phosphorus pentachloride in portions. Stirring in the cold under a drying tube was continued for 30 min. Ammonia was then bubbled into the cold solution for 5 min and stirring in the cold was continued 30 min. longer. Evaporation at reduced pressure gave a tan solid. The solid was stirred with 3N ammonium hydroxide and extracted with methylene chloride. An emulsion formed but was destroyed by filtering to remove some high melting solid. The methylene chloride layer was dried over sodium sulfate and evaporated to give a yellow solid which was recrystallized from benzene to give off-white needles with mp 158°-160°. Uv λ sh 215 mμ (ε=43000) max 272 (15500) sh 330 (2500); ir (CHCl3); ir (CHCl3) 3510, 3400 cm-1 (NH2) 1703 (CO) 1685 (CONH2).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([OH:20])[C@@H:10]([NH:12]C(=O)OC(C)(C)C)[CH3:11])=[CH:5][CH:4]=1)[CH3:2].Cl>C(#N)C.O>[NH2:12][C@@H:10]([CH3:11])[C@@H:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[OH:20]
Reactant: CCc1ccc([C@@H](O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CCc1ccc([C@@H](O)[C@H](C)N)cc1
Reaction time: 3.5 h

Procedure:
To a stirred solution of tert-butyl [(1S,2R)-2-(4-ethylphenyl)-2-hydroxy-1-methylethyl]carbamate (450 mg, 1.51 mmol) in acetonitrile (10 ml) was added aq. HCl (6 N, 3 ml), and stirring was continued for 3.5 h. Then the mixture was diluted with water (10 ml), and acetonitrile was removed in vacuo. The mixture was washed with dichloromethane (20 ml). The aqueous layer was then made alkaline (pH≈10) by addition of aq. NaOH (10 N), and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried with Na2SO4, the solvent was removed in vacuo to afford white solid, 280 mg (97%).