Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2.[Br:16]Br.Cl>ClC(Cl)C.C(OCC)C>[Br:16][C:7]1[C:6]([F:5])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:15]
Reactant: O=C1CCc2cc(F)ccc21
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: O=C1CCc2c1ccc(F)c2Br
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
A solution of aluminum trichloride (11.10 g, 83.00 mmol) in dichloroethane (100 mL) was slowly added a solution of 5-fluoro-2,3-dihydro-1H-inden-1-one (5 g, 33.3 mmol) in dichloroethane (10 mL) at ambient temperature and stirred for 5 minutes, followed with the addition of bromine (2.57 mL, 50.0 mmol). The resulting dark red mixture was heated at 70° C. for 2 hours. The reaction mixture was cooled to ambient temperature and poured into a mixture of ice and HCl (1N, 50 mL). Diethyl ether (300 mL) was added and the mixture was partitioned. The organic portion was washed with water (75 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel (gradient elution: 0-10% EtOAc/hexanes) to provide the title compound mixed with inseparable bisbrominated side product (4,7-dibromo-5-fluoro-2,3-dihydro-1H-inden-1-one). MS (DCI) m/z 246 (M+NH4)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[N-:30]=[C:31]=[O:32].N[C:34]1[C:39]2[O:40][CH2:41][C:42](=[O:44])[NH:43][C:38]=2[CH:37]=[CH:36][CH:35]=1>CCOC(C)=O.CN(C=O)C>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:31]([NH:30][C:34]2[C:39]3[O:40][CH2:41][C:42](=[O:44])[NH:43][C:38]=3[CH:37]=[CH:36][CH:35]=2)=[O:32])=[C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1
Reactant: NCc1ccc(C(F)(F)F)cc1N1CCCC1
Reactant: [N-]=C=O
Reactant: Nc1cccc2c1OCC(=O)N2
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1COc2c(cccc2NC(=O)NCc2ccc(C(F)(F)F)cc2N2CCCC2)N1
Temperature: 80 °C
Yield: 9 %

Procedure:
Amine 2b (750 mg, 3.1 mmol) (Scheme 7) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (920 mg, 3.1 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 5 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1f (620 mg, 3.1 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 1/petroleum ether 1). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 120 mg of a white solid. Yield=9% 1HNMR (DMSO, 200 MHz) δ 1.89 (4H, m), 3.20 (4H, m), 4.33 (2H, d, J=5.6 Hz), 4.60 (2H, s), 6.45 (1H, dd, J=8 Hz, J′=1.2 Hz), 6.79 (1H, t, J=8.4 Hz), 7.04 (1H, bs), 7.16 (1H, d), 7.23 (1H, t), 7.35 (1H, d), 7.72 (1H, dd, J=8.2 Hz, J′=1.4 Hz), 8.16 (1H, bs), 10.63 (1H, bs); [M+1] 435.1 (C21H21F3N4O3 requires 434.41).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][C@H:19]1[CH2:24][O:23][CH2:22][CH2:21][NH:20]1>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][C@@H:19]2[CH3:18])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[C@H]1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H]1COCCN1c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 2,4-dichloropyrimidine (5.00 g, 0.034 mol) and DIPEA (8.00 mL, 0.046 mol) in 2-propanol (60 mL) at 0° C. was added (S)-3-methylmorpholine (3.73 g, 0.037 mol) dropwise. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to RT and stirred for a further 16 h. Solvent was removed in vacuo and the residue was then partitioned between water and EtOAc. The phases were separated and the organic layer washed with brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield a yellow oil (6.54 g, 91%).
Reaction SMILES: NC1C=C[C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=CC=1.C([N:16](CC)CC)C.CN(C1C=CC=CN=1)C.[CH2:30]([OH:34])[CH:31](O)[CH3:32]>O>[C:30]1(=[O:34])[NH:16][C:11](=[O:13])[C:10]2=[CH:9][CH:8]=[CH:5][CH:32]=[C:31]12
Reactant: CC(O)CO
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccccn1
Solvent: O
Product: O=C1NC(=O)c2ccccc21
Temperature: 140 °C
Reaction time: 5.5 h

Procedure:
A suspension of 2.40 g (16.3 mmol) and 2.80 g (15.6 mmol) of 4-(4aminophenyl)butyric acid in 20 mL of propylene glycol, 2.40 mL (1.74 g, 17.3 mmol) of triethylamine and 10 mg (0.08 mmol) of dimethylaminopyridine was heated to 140° C. The mixture became a clear solution after 5 min at 140° C. After stirring for 330 min, the reaction mixture was cooled to 25° C. and diluted with 20 mL of water. The solid phthalimide which had formed was filtered off. The filtrate was acidified with 3% HCl solution. The resulting solid was filtered off and was recrystallized from 2-propanol and water to give 0.62 g of compound 133 as a tan solid.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.ClC1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:24][C:11]1[O:12][C:13]([C:15]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[CH:14][C:10]=1[CH2:9][OH:8]
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
Reactant: FC(F)(F)c1ccc(Cl)nc1
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: O
Solvent: COCCOC
Product: Cc1oc(-c2ccc(C(F)(F)F)cn2)cc1CO
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (2.4 g), 2-chloro-5-trifluoromethylpyridine (1.8 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (7 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, purified by silica gel chromatography (10% ethyl acetate/hexane to 100% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.1 g, 62%) as a yellow crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:30][C:31](O)=[O:32])(=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)CCl.CI>>[C:1]([O:5][C:6](=[O:12])[CH2:7][N:8]([CH2:9][CH2:10][OH:11])[C:31](=[O:32])[CH2:30][C@H:29]([O:28][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNCCO
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Solvent: ClCCCl
Solvent: CI
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N(CCO)CC(=O)OC(C)(C)C
Yield: 52.6 %

Procedure:
In the same manner as described in Example 2-(5), N-(2-hydroxyethyl)glycine t-butyl ester (0.25 g, 1.43 mmol) was acylated with (R)-3-tetradecanoyloxytetradecanoic acid (0.714 g, 1.57 mmol) in the presence of EDC-MeI (0.466 g, 1.57 mmol) to give 0.46 g (51%) of N-(2-hydroxyethyl)-N-[(R)-3-tetradecanoyloxytetradecanoyl]glycine t-butyl ester as an amorphous solid: 1H NMR (CDCl3) δ0.88 (t, 6 H, J=~6.5 Hz), 1.15-1.7 (m, 51 H), 2.26 (t, 2 H, J=7.5 Hz), 2.60 (dd, 1 H, J=6.5, 15 Hz), 2.86 (dd, 1 H, J=6.7, 15 Hz), 3.40-4.15 (m, 7 H), 5.25 (m, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:5][CH2:6]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CC(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[N:18][CH:19]=1>C(Cl)(Cl)Cl>[Cl:8][CH2:9][C:10]([NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1ccc(N)cn1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(NC(=O)CCl)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Triethylamine (0.50 g, 4.9 mmol) and chloroacetyl chloride (0.56 g, 4.9 mmol) were added dropwise at 0° C. to a stirred suspension of 5-Amino-2-cyanopyridine (0.27 g, 2.25 mmol) in chloroform (10 mL). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with chloroform (50 mL) and washed with water (2×50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and the crude product obtained was crystallized from chloroform:petroleum ether (1:2) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C@H:35]([CH:38]([CH3:40])[CH3:39])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C@@H:35]([CH2:36][OH:37])[CH:38]([CH3:40])[CH3:39])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC(C)[C@@H](N)CO
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@@H](CO)C(C)C)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and (R)-2-amino-3-methyl-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C25H37N6O5SF2[(M+H)+] 571.2509, observed 571.2514.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:16]=2)[N:3]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1cncc(Oc2cccc(-c3ccccc3)c2)n1
Yield: 98 %

Procedure:
Using Method DD (reaction time: 20 hours) with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 3-phenyl-phenol (268 mg, 1.49 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:2), the title compound was obtained (370 mg). Yield: 98%. 1H NMR (250 MHz, DMSO-d6) δ 7.35-7.72 (m, 9H, Harom), 8.53 (s, 1H, HPz 5), 8.59 (s, 1H, HPz 3). m/z: 283.1 [(M+H)+, calcd for C16H11ClN2O 282.1].
Reaction SMILES: C1COCC1.[CH:6]1[CH:11]=[C:10]([CH:12]=[O:13])[C:9]([N+:14]([O-])=O)=[CH:8][CH:7]=1.O.C(=O)=O>CO>[CH:6]1[CH:11]=[C:10]([CH:12]=[O:13])[C:9]([NH2:14])=[CH:8][CH:7]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccccc1C=O
Yield: 94.9 %

Procedure:
Under nitrogen, 12.3 g (13.6 mmol) lithium cobalt (I) phthalocyanine x 4.5 THF and 322 mg (2 mmol) O-nitrobenzaldehyde are agitated in 65 ml methanol for 90 hours at 20° C. The green reaction mixture is mixed with 10 ml water; CO2 and air are passed in for 5 min., and the blue precipitate is centrifuged which is washed with ethanol. The centrifugate collected is concentrated, and the residue separated into ether and water. Concentration of the ether phase, dried with sodium sulfate, produces 230 mg (96%) O-amino benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13]1.C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)O
Reactant: c1ccc(C2CCCNC2)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(N2CCCC(c3ccccn3)C2)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-6-chloronicotinic acid (1.6 g, 9.248 mmol) in N,N-dimethylformamide (41 mL) was added 2-(piperidin-3-yl)pyridine (1.82 g, 11.098 mmol) and triethylamine (25.455 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified via column chromatography to afford 2-amino-6-(3-(pyridin-2-yl)piperidin-1-yl)nicotinic acid
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[OH:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Reactant: COc1cccc(B(O)O)c1O
Product: COc1cccc(-c2cccc(-c3cccc(-c4ccc(C)cc4O)n3)n2)c1O
Yield: 33 %

Procedure:
6-(2-Hydroxy-3-methoxyphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 2-hydroxy-3-methoxyphenylboronic acid in 33% yield using method F; δH [2H6]-DMSO 13.52,(2H, b), 8.31,(2H, dd), 8.26,(1H, d), 8.21,(1H, d), 8.12,(1H, d), 8.02,(1H, d), 7.70,(1H, d), 7.09,(1H, d), 6.92, (1H, t), 6.82,(1H, d), 3.86,(3H, s), 2.32,(3H, s); MS 385 (MH)+; HPLC retention time (system 1) 4.21 minutes.
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15](Br)[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCCN=C1CCCCC2.[C:34]1([C@H:40]([NH2:43])[CH2:41][CH3:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:44](=O)([O-])[OH:45].[Na+]>O1CCCC1>[C:34]1([C@H:40]([NH:43][C:44]([C:15]2[N:16]3[C:17]([CH2:18][O:19][CH2:20][CH2:21]3)=[C:13]([C:11]([NH:10][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH3:9])=[O:12])[CH:14]=2)=[O:45])[CH2:41][CH3:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC[C@@H](NC(=O)c1cc(Br)n2c1COCC2)c1ccccc1
Reactant: CC[C@@H](N)c1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC[C@@H](NC(=O)c1cc(C(=O)N[C@H](CC)c2ccccc2)n2c1COCC2)c1ccccc1
Yield: 35 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 12a) (200 mg, 0.551 mmol), molybdenum(0) hexacarbonyl (44 mg, 0.165 mmol), trans-di-(μ-acetato)bis[2-(di-o-tolylphosphino)benzyl]dipalladium(II) (52 mg, 0.055 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (500 mg, 3.31 mmol) and (R)-1-phenyl-propylamine (745 mg, 5.51 mmol) in dry tetrahydrofuran (5 ml) was heated for 30 min at 130° C. in a microwave reactor, then aqueous sodium hydrogencarbonate was added and the mixture was extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate, evaporated to dryness and the crude product was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 86 mg (35%) of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6,8-dicarboxylic acid bis-[((R)-1-phenyl-propyl)-amide] as white solid. LC/MS (method 4): Rt=1.28 min; m/z=446.38 (M+H+). 1H-NMR: δ (ppm)=8.44 (1H, d), 8.15 (1H, d), 7.25-7.40 (9H, m), 7.22 (2H, q), 4.80-5.00 (4H, m), 4.15 (2H, m), 3.87 (2H, m), 1.73-1.80 (4H, m), 0.85-0.90 (6H, m).
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:18])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([N:13]1[C:14]2[C:9](=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10][NH:11][C:12]1=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCc2c(cccc2Oc2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCc2c(Oc3ccccc3)cccc2N1Cc1ccccc1
Temperature: 25 °C

Procedure:
The product of 2c above, 5-phenoxy-3,4-dihydro-(1H)-quinazolin-2-one (0.08 g, 0.33 mmol) was dissolved in dimethylformamide (3 mL) and stirred at room temperature under argon. Sodium hydride (0.0084 g, 0.35 mmol) was added and the mixture heated to 55° C. in an oil bath. Gas evolution occurred and a clear solution resulted. Benzyl bromide (0.060 g, 0.35 mmol) was added and the reaction mixture was heated at 55° C. for 1 hour. The solvent was evaporated in vacuo, to give the crude product which was flash chromatographed on silica gel eluted with 0–4% methanol in methylene chloride to give a white amorphous solid. Recrystallization from ethyl acetate hexane gave the title compound as a white crystalline compound. mp 171–173° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O=C(Cl)[O:23][C:24](Cl)(Cl)Cl.[CH2:29]([NH:33][CH3:34])[CH2:30][CH2:31][CH3:32]>>[CH2:29]([N:33]([CH3:34])[C:24]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][CH2:16]1)=[O:23])[CH2:30][CH2:31][CH3:32]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCCNC
Reactant: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Product: CCCCN(C)C(=O)N1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-Cyclopropyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and butyl-methyl-amine. MS (ESI): 384.4 (MH+).
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].[Cl:11][C:12]1[C:21]([NH2:22])=[C:20]([NH:23][CH2:24][C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:11][C:12]1[C:21]2[N:22]=[C:1]([CH2:2][CH2:3][CH3:4])[N:23]([CH2:24][C:25]3[O:29][N:28]=[C:27]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[CH:26]=3)[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cc(-c2ccc(F)cc2)no1
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 110 °C
Yield: 20.2 %

Procedure:
Under a nitrogen atmosphere, pyridine hydrochloride (0.020 g, 0.19 mmol), trimethyl orthobutyrate (2.1 g, 14 mmol), 2-chloro-N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}quinoline-3,4-diamine (3.5 g, 9.5 mmol), and toluene (50 mL) were combined and heated at 110° C. for 18 hours. The volatiles were removed under reduced pressure. The crude product was purified by column chromatography on silica gel (250 g, eluting with 20% to 40% ethyl acetate in hexane) to provide 0.806 g of 4-chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-1H-imidazo[4,5-c]quinoline as a yellow solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[CH:15]=2)[C:10]([NH:32][C:33](=[O:47])[C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)=[N:9]1)=O)(C)(C)C.C(Cl)Cl.CO>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:46][N:43]1[CH2:42][CH2:41][N:40]([C:37]2[CH:36]=[CH:35][C:34]([C:33]([NH:32][C:10]3[C:11]4[C:16](=[CH:15][C:14]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH:20]=5)=[CH:13][CH:12]=4)[NH:8][N:9]=3)=[O:47])=[CH:39][CH:38]=2)[CH2:45][CH2:44]1
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4cc(OCc5cccc(Oc6ccccc6)c5)ccc34)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4cc(OCc5cccc(Oc6ccccc6)c5)ccc34)cc2)CC1
Yield: 97.1 %

Procedure:
A solution of 3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-6-(3-phenoxy-benzyloxy)-indazole-1-carboxylic acid tert-butyl ester (87 mg, 0.137 mmol) in DCM/TFA 8:2 (5 ml) was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure and the residue purified by flash chromatography over silica gel eluting with DCM/MeOH/30% NH3 90:10:1 affording 71 mg (yield: 97%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]12[CH2:11][CH2:10][CH2:9][CH2:8]C1O[C:5]1[CH:12]=[CH:13][CH:14]=[CH:15][C:4]2=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl.[C:24](=[O:27])(O)[O-].[Na+]>C(Cl)Cl>[C:16]([N:2]([CH3:1])[C:3]12[CH2:11][CH2:10][CH2:9][CH2:8][CH:24]1[O:27][C:15]1[CH:14]=[CH:13][CH:12]=[CH:5][C:4]2=1)(=[O:18])[CH3:17]
Reactant: O=C([O-])O
Reactant: CNC12CCCCC1Oc1ccccc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N(C)C12CCCCC1Oc1ccccc12
Reaction time: 18 h

Procedure:
General procedure: A reaction mixture prepared from 8.5 g of N-methyl-6,7,8,9-tetrahydro-9a(5aH)-dibenzofuranamine, 50 ml of methylene dichloride and 4.8 g of acetic anhydride is allowed to stand at room temperature for 18 hours. The mixture is washed with one equivalent of 3 N hydrochloric acid, then with dilute sodium bicarbonate solution until slightly basic. The dried methylene chloride phase is evaporated to yield a residue of N-acetyl-N-methyl-6,7,8,9-tetrahydro-9a(5aH)-dibenzofuranamine. A solution of this residue in 30 ml of anhydrous ether is gradually added to a stirred solution of 5 g of lithium aluminum hydride in 400 ml of anhydrous ether. The mixture is stirred for 18 hours and then decomposed by the successive addition of 5 ml of water, 3.75 ml of 20% sodium hydroxide solution, and 7.5 ml water. The mixture is filtered and a slight excess of hydrogen chloride in isopropyl alcohol is added to the filtrate. The precipitated N-ethyl-N-methyl-6,7,8,9-tetrahydro-9a(SaH)-dibenzofuranamine hydrochloride is recrystallized from a mixture of methanol and ether, thereby yielding a material with mp about 138° C. to 139° C. The free base is obtained by treating an aqueous solution of the hydrochloride with sodium hydroxide and extracting with ether. A citrate is obtained by adding a solution of citric acid in methanol to a solution of the free base in methanol and concentrating.