Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH:6]([N:14]([CH2:21][C:22]1[N:23]=[C:24]2[C:29](=[N:30][CH:31]=1)[N:28]=[C:27]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[NH:26][C:25]2=[O:38])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[C:7]([O:9]C(C)(C)C)=[O:8]>C(O)(C(F)(F)F)=O.ClCCl>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH:6]([N:14]([CH2:21][C:22]1[N:23]=[C:24]2[C:29](=[N:30][CH:31]=1)[N:28]=[C:27]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[NH:26][C:25]2=[O:38])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)CCC(C(=O)OC(C)(C)C)N(Cc1cnc2nc(NC(=O)C(C)C)[nH]c(=O)c2n1)C(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCC(C(=O)O)N(Cc1cnc2nc(NC(=O)C(C)C)[nH]c(=O)c2n1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.8 %

Procedure:
The ester 143 (2 g, 2.9 mmol) was dissolved in 20 mL of 50% TFA in dichloromethane and the solution was stirred at room temperature for 30 min. after which the TLC showed the complete disappearance of the starting ester. The reaction mixture was concentrated and the residue was crystallized from CH2Cl2:Hexanes (2:3) and crystallized product was filtered off and dried to obtain the pure product 144 (1.76 g, 96%) as off white powder. 1H NMR (DMSO-d6, 400 MHz) δ=12.32 (bs, 1H), 11.94 (s, 1H), 8.88 (s, 1H), 8.84 (d, J=7.4 Hz, 1H), 7.90 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 5.22 (s, 2H), 4.45-4.41 (m, 1H), 3.62 (s, 3H), 2.78-2.75 (m, 1H), 2.35 (t, J=7.4 Hz, 2H) 2.07-1.92 (m, 2H), 1.12 (d, J=6.8 Hz, 6H). 13C NMR DMSO-d6) δ=180.77, 173.70, 172.19, 165.70, 159.21, 155.54, 149.93, 149.84, 147.75, 141.78, 134.18, 130.53, 128.71, 128.49, 117.51, 114.64, 53.98, 52.06, 51.93, 34.97, 30.11, 25.68, 18.73. MS. Molecular weight calculated for C26H26F3N7O8, Cal. 621.18, Found 620.18 (M−H−).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccccc2F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To an N,N-dimethylformamide (30.0 mL) solution of 2-fluorophenol (5.43 g, 48.4 mmol) and 4-fluorobenzaldehyde (3.00 g, 24.2 mmol) was added potassium carbonate (10.1 g, 72.5 mmol) under nitrogen atmosphere, which was stirred for 16 hours at 80° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15→1:10) to obtain the title compound (5.20 g, 99.4%).
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:5]=[C:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[NH:7][C:8]=1[CH3:9])[CH3:3].C[O-].[Na+].[C:22](OC)(=[O:25])[C:23]#[CH:24]>>[C:11]([C:10]1[CH:24]=[CH:23][C:22](=[O:25])[N:7]2[C:8]([CH3:9])=[C:4]([CH2:2][CH3:3])[NH:5][C:6]=12)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#CC(=O)OC
Reactant: CCc1nc(CC(=O)c2ccccc2)[nH]c1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCc1[nH]c2c(C(=O)c3ccccc3)ccc(=O)n2c1C

Procedure:
The compound is prepared as described in example 20 with 200 mg (0.76 mmol) of 2-(4-Ethyl-5-methyl-1H-imidazol-2-yl)-1-phenylethanone hydrochloride (example XVII), 50 mg (0.92 mmol) of sodium methylate and 63.5 mg (0.76 mmol) methyl propiolate.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34]>>[C:24]1([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[O:2])=[CH:5][CH:6]=4)[CH:14]=3)=[C:19]([C:20]([F:21])([F:23])[F:22])[O:18][N:17]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Product: O=C(NCC(F)(F)F)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 49 %

Procedure:
As described for Example 10, 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (70 mg, 0.17 mmol) was converted, using 2,2,2-trifluoroethylamine instead of cyclopropanemethylamine, to the title compound (40 mg, 49%) which was obtained as a white solid. MS: m/e=481.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:12]3[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]3)[S:3][C:4]=2[CH:10]=1
Reactant: O[C@H]1CCNC1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O[C@H]1CCN(c2nc3ccc(Cl)cc3s2)C1
Temperature: 150 °C

Procedure:
A stirred mixture of 2,6-dichlorobenzo[d]thiazole (CAS #3622-23-9, 0.314 g, 3.00 mmol), (S)-pyrrolidin-3-ol (0.314 g, 3.60 mmol), and potassium carbonate (1.24 g, 9.00 mmol) in water/ethanol (10 mL/8 mL) was heated at 150° C. under microwave irradiation for 5 minutes. The reaction mixture was cooled to room temperature then partitioned between dichloromethane and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a crude solid that was purified by crystallization from ethyl acetate/hexane. Crystals were collected by filtration, then dried under vacuum to provide (S)-1-(6-chlorobenzo[d]thiazol-2-yl)pyrrolidin-3-ol. 1H NMR (300 MHz, CD3OD) δ ppm 2.04-2.14 (m, 1H), 2.16-2.29 (m, 1H), 3.48-3.55 (m, 1H), 3.59-3.75 (m, 3H), 4.54-4.59 (m, 1H), 7.26 (dd, J=2, 8 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.67 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 255 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]([CH3:24])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:5].[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:19]2[CH2:20][CH:16]([CH2:15][CH2:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][C:4]([CH3:24])([CH3:5])[C:3]([OH:25])=[O:2])=[C:8]([CH3:23])[CH:9]=3)[N:17]([CH3:22])[C:18]2=[O:21])=[CH:29][CH:28]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCC2CNC(=O)N2C)cc1C
Reactant: BrCc1ccc(Br)cc1
Product: Cc1cc(CCCC2CN(Cc3ccc(Br)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)O

Procedure:
The titled compound was prepared using 2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid methyl Ester (0.100 g, 0.287 mmole) and 4-bromo benzyl bromide (0.108 g, 0.431 mmole) to produce an oil (0.058 g, 40%). Mass [EI+] 503, 505 (M+H)+, [EI−] 501, 503 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.NC(N)=[S:17]>C(O)C>[N+:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2](=[S:17])[CH:3]=[CH:4][NH:5]2)=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: NC(N)=S
Reactant: O=[N+]([O-])c1ccc2c(Cl)ccnc2c1
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(=S)cc[nH]c2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-7-nitroquinoline (100 mg, 0.48 mmol) and thiourea (100 mg, 1.3 mmol) were added to ethanol (50 ml) and stirred at 80° C. for 30 minutes. After allowing to cool to room temperature, ethanol was removed under reduced pressure. The residue was chromatographed by silica gel column chromatography and eluted with mixed solution of methylene chloride with methanol (19 : 1) for collection of yellow bands. The solvent was removed to obtain 7 mg (7%) of the titled yellow compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([OH:24])[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.C=O.[C:27](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:27][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[N:15]=[C:16]([OH:24])[C:17]=2[CH2:23]1
Reactant: Cc1nccn1-c1ccc(Nc2nc(O)c3c(n2)CCNC3)cc1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nccn1-c1ccc(Nc2nc(O)c3c(n2)CCN(C)C3)cc1
Reaction time: 0.17 h
Yield: 345.7 %

Procedure:
A suspension of 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol (1.4 g, 4.34 mmol, Example 9c), formaldehyde (0.423 g, 5.21 mmol) and acetic acid (0.025 mL, 0.43 mmol) in MeOH (25 mL) was stirred for 10 min. Sodium cyanoborohydride (0.273 g, 4.34 mmol) was added and the reaction was stirred for an additional 10 min after which water (2 mL) was added. Solvent was evaporated and EtOAc (2 mL) was added followed by the addition of potassium carbonate solution (sat. aq., 1 mL). The solution was stirred and the formed precipitate was filtered off to give 6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol (0.500 g, 34.2%).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: BrCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 849.9 %

Procedure:
Dihydropyran (5.20 g, 6.11 mmol) was added to a stirring 0° C. solution of 7-bromoheptane-1-ol (2) (11.0 g, 56.7 mmol) and a catalytic amount of PTSA in CH2Cl2. After stirring at rt for 12 h, the reaction mixture was diluted with CH2Cl2 (200 mL), washed with water (100 mL×2), brine (100 mL×3), dried over anhydrous sodium sulphate, and evaporated. The residue was purified by silica gel column chromatography using a gradient of 10-20% ethyl acetate/hexane as eluent to give 2-(7-bromoheptyloxyl)tetrahydro-2H-pyran (3) (14.50 g, 92%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf˜0.55; 1H NMR (400 MHz, CDCl3) δ 4.58-4.56 (m, 1H), 3.84-3.88 (m, 1H), 3.68-3.77 (m, 1H), 3.46-3.51 (m, 1H), 3.33-3.43 (m, 3H), 1.80-1.81 (m, 2H), 1.30-1.62 (m, 14H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.NC1C=CC=CC=1.[CH3:35][N:36]([CH3:50])[CH2:37][CH2:38][CH2:39][N:40]([CH2:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1)[CH3:41]>>[CH3:50][N:36]([CH3:35])[CH2:37][CH2:38][CH2:39][N:40]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([NH:47]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:48][CH:49]=1)[CH3:41]
Reactant: CN(C)CCCN(C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Solvent: Nc1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)CCCN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-(3-dimethylamino-propyl)-N-methyl-amino)-methyl)-aniline aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C30H34N4O3
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[C:19](OCC)=[O:20])=[CH:4][CH:3]=1.[CH3:26][NH2:27]>>[OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[C:19]([NH:27][CH3:26])=[O:20])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Product: CNC(=O)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 4',5,7-trihydroxy-2-isoflavonecarboxylate (100 mg) and 30% methanolic solution of methylamine (5 ml) was stirred at room temperature for 30 minutes, the solvent was distilled off under reduced pressure, and the solid residue was recrystallized from methanol, affording 50 mg of 4',5,7-trihydroxy-N-methyl-2-isoflavonecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH:11]2[C:13]#[N:14])=[O:9])=[CH:4][CH:3]=1.[CH3:15][Mg]Br>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:12][CH:11]2[C:13]#[N:14])([OH:9])[CH3:15])=[CH:6][CH:7]=1
Reactant: N#CC1CC1C(=O)c1ccc(Cl)cc1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(O)(c1ccc(Cl)cc1)C1CC1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
714 mg of the compound from Example 74A with a purity of 54% (1.89 mmol) were introduced into 7 ml of diethyl ether at RT, 0.94 ml (2.83 mmol) of a 3N solution of methylmagnesium bromide in diethyl ether was added, and the mixture was stirred at RT overnight. The reaction mixture was added to a saturated, ice-cold aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile-water gradient) to result in 257 mg (55% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[C:3](=[O:14])[NH:4][C:5](=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1NC(=O)C(c2ccccc2)=C1Cl
Solvent: CN(C)C=O
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)NC2=O)cc1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
To a solution of 3-chloro-4-phenyl-1H-pyrrole-2,5-dione (4.84 mmol, 1.0 g) in dry DMF (5 mL) was added 4-methoxyaniline (4.87 mmol, 600 mg) and the reaction mixture was subjected to microwave heating single node 150° C., 15 min, followed by 150° C., 10 min. The solvent was evaporated, and the crude mixture was partitioned between dichloromethane and water. The organic phase was dried over anhydrous Na2SO4, concentrated and the residue was purified on SiO2 (Heptane:EtOAc, 3:1→2:1) to give 457 mg (32%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.27 (s, 1H), 7.09-6.99 (m, 3H), 6.87-6.83 (m, 2H), 6.65-6.60 (m, 2H), 6.52-6.47 (m, 2H), 3.58 (s, 3H).
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[N:19]=[C:18]1[NH2:32])=[NH:6]>[Ni].CO.O>[ClH:1].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[N:19]=[C:18]1[NH2:32])(=[NH:4])[NH2:6]
Reactant: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccc3ccccc3c2)nc1N
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: O
Product: N=C(N)c1cccc2c1CCC2=Nn1cc(-c2ccc3ccccc3c2)nc1N

Procedure:
Analogously to Example 2, 0.3 g of Raney nickel is added to a mixture of 1.0 g (2.13 mmol) of 1-[4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-4-(2-naphthyl)-imidazole dihydrochloride in 120 ml of methanol/water (1:1), and hydrogenation is carried out at room temperature and under normal pressure until the absorption of hydrogen has ceased. The reaction mixture is then filtered, the filtrate is acidified to pH 3 with 3N methanolic hydrochloric acid, and concentration is carried out by evaporation in vacuo. Recrystallization of the residue from ethanol with the addition of a small amount of methanol yields the title compound, m.p. >280° C., 1H-NMR (DMSO/D2O): δ=8.31 (d, 1H); 8.18 (s, 1H); 8.05 (s, 1H); 7.92-8.03 (m, 3H); 7.79-7.86 (m, 2H); 7.52-7.69 (m, 3H); 3.35 (s, 4H).
Reaction SMILES: [H-].[Na+].CS([O:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)(=O)=O.S([O-])(=O)(=O)C.C1(C)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:40]2[CH2:39][CH2:38][CH2:37][C:36]=2[C:35]=1O>CN(C)C=O>[CH3:32][O:33][C:34]1[C:35]([O:7][C@H:8]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9]2)=[C:36]2[C:40](=[CH:41][CH:42]=1)[CH2:39][CH2:38][CH2:37]2
Reactant: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: COc1ccc2c(c1O)CCC2
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1O[C@H]1CCN(Cc3ccccc3)C1)CCC2
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
In 540 ml of anhydrous dimethylformamide 5 g of 2,3-dihydro-5-methoxy-1H-inden-4-ol were dissolved. The solution was stirred, placed under a steam of nitrogen and 1.5 g of a 60% dispersion of sodium hydride in oil was added. The reaction mixture was stirred at room temperature for half an hour. The temperature was raised to 100° C. and a solution of 7.78 g of (R)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine in 78 ml of anhydrous dimethylformamide was added dropwise over 1 hour. Another 3,0 g of mesylate in 30 ml of anhydrous dimethylformamide were added dropwise over 0.5 hours and the reaction continued for another 1.5 hours at 100° C. Evaporation in vacuo gave a semi solid that was partitioned between water and ethyl acetate. The ethyl acetate extract was dried and evaporated in vacuo. The derived product was isolated by chromatography over silica using toluene/-ethanol as the eluent giving 9.45 g of (S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl)-pyrrolidine as an oil. M.S. (C.I.) (M/Z): 324 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[O:9][C:10]=1[CH3:11])=[O:5])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:32]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[O:9][C:10]=1[CH2:11][Br:32])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1CBr
Yield: 135.7 %

Procedure:
To a boiling solution of 6.0 g 2-(4-methoxy-phenyl)-5-methyl-oxazole-4-carboxylic acid ethyl ester in 100 ml tetrachloro-methane were added portionwise a mixture of 1.51 g 2,2′-azobis(2-methylpropionitrile) and 4.9 g N-bromosuccinimide. The reaction mixture was refluxed for three hours. The cooled reaction mixture was filtered over a celite pad and the solvent removed in vacuo to obtain 10.6 g of crude 5-bromomethyl-2-(4-methoxy-phenyl)-oxazole-4-carboxylic acid ethyl ester, which contains to some extend the dibrominated byproduct. The material was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26](O)=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([C:22]3[S:21][CH:25]=[CH:24][N:23]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1nccs1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2-thiazolecarboxylic acid as starting materials, MS (LC/MS): 414.0 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[Br:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:12]=[CH:13][C:14]=1[OH:15].C(N(C(C)C)CC)(C)C.[OH-].[Na+]>ClCCl>[Br:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: Oc1ccc(-c2cccc(F)c2)cc1Br
Reactant: COCCOCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1ccc(-c2cccc(F)c2)cc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.6 %

Procedure:
2-Methoxyethoxymethylchloride (0.67 mL, 5.83 mmol) was added dropwise to a solution of 3-bromo-3′-fluoro-[1,1′-biphenyl]-4-ol (˜5.55 mmol) and diisopropylethylamine (1.93 mL, 11.1 mmol) in dry dichloromethane (20 mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature under nitrogen for 3 days, 1.0 M aqueous sodium hydroxide (20 mL) added and the biphasic mixture stirred vigorously for 20 minutes. The reaction mixture was partitioned between ethyl acetate (100 mL) and 1.0 M aqueous sodium hydroxide solution (100 mL), the organic phase separated, washed with water (75 mL) and saturated brine (75 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give an orange oil. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 10% ethyl acetate (containing 2% methanol) in hexanes to give 3-bromo-3′-fluoro-4-((2-methoxyethoxy)methoxy)-1,1′-biphenyl (1.57 g, 80% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:23]([CH:24]=[O:25])=[CH:22][CH:21]=[C:7]3[C:8]3([CH2:14][CH2:13][N:12](C(=O)C(F)(F)F)[CH2:11][CH2:10]3)[O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:23]([CH:24]=[O:25])=[CH:22][CH:21]=[C:7]3[C:8]3([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[O:9][C:4]=2[CH:3]=1
Reactant: O=Cc1ccc2n1-c1ccc(Cl)cc1OC21CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=Cc1ccc2n1-c1ccc(Cl)cc1OC21CCNCC1

Procedure:
To 7′-chloro-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbaldehyde (510 mg, 1.28 mmol) dissolved in MeOH (5.1 mL) was added K2CO3 (371 mg, 2.69 mmol) in one portion at room temperature. Water was added (2 mL), and organic solvent was removed under vacuum. The mixture was extracted with DCM (3×10 mL). The organics were combined, dried, filtered, and concentrated to give 7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde as a yellow oil, which was used as is for the following step. ESI-MS m/z calc. 302.1. found 303.3 (M+1)+; Retention time: 1.07 minutes (3 min run).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[OH:24][C:25]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33].O>C1COCC1>[OH:24][C:25]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: NCCCCCCCC(O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(C=Cc1cccnc1)NCCCCCCCC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.4 g (23.0 mmol) 3-(3-pyridyl)-acrylic acid and 3.7 g (23.0 mmol) CDI are heated under reflux in 50 ml THF under moisture exclusion. After one hour this is cooled to RT and 6.5 g (21.9 μmmol) 8-hydroxy-8,8-diphenyloctylamine, dissolved in 20 ml THF, is added dropwise. After complete addition, stirring is carried out for a further three hours at RT and this is left to stand overnight. 50 ml water is added to the mixture and extracted three times with acetic acid ethyl ester by shaking. The combined organic phases are washed with saturated NaCl solution, dried over sodium sulfate, and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (95/5) and subsequently, crystallized twice from 200-ml and 140 ml acetic acid ethyl ester: Colorless crystals with MP. 139-140° C. in a yield of 3.7 g (39%). C28H32N2O2 (428.6)