Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[C:11]([C:9]2[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1cc(Br)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Br)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.9 %

Procedure:
To a solution of 80 mg (0.3 mmol) 5-bromo-1H-indole-7-carboxylic acid and 112 mg (0.33 mmol) (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine in 3 ml DMF, were added 0.1 ml (0.91 mmol) of N-methylmorpholine and 173 mg of TBTU (0.45 mmol) at rt. After stirring for 17 h at rt, the reaction mixture was diluted with 33 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; DCM/heptane 50:50 to 70:30) to give 152 mg white powder (90%). MS (ISP) 574.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(CCBr)c1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3cccc(Cl)c3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)-3-chlorobenzene and isolated as light-yellow gum. MS(m/e): 421.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].[F:10][C:11]([F:24])([F:23])[CH2:12][O:13][C:14]1[C:19](B(O)O)=[CH:18][CH:17]=[CH:16][N:15]=1>>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([C:19]2[C:14]([O:13][CH2:12][C:11]([F:23])([F:10])[F:24])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: OB(O)c1cccnc1OCC(F)(F)F
Product: Nc1nnc(Cl)cc1-c1cccnc1OCC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 1, intermediate b, from 4-bromo-6-chloro-pyridazin-3-ylamine (CAS RN 446273-59-2) and 2-(2,2,2-trifluoroethoxy)pyridine-3-boronic acid (CAS RN 1218790-79-4) after a reaction time of 18 hours. Brown solid (43%). MS (ESI+): m/z=305.041 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1.BrC1C=CC(Cl)=C(CC2C=CC(OCC)=CC=2)C=1.[Li]CCCC.[C:43]([Si:47]([CH3:62])([CH3:61])[O:48][C@H:49]1[C@H:56]2[C@H:52]([O:53][C:54]([CH3:58])([CH3:57])[O:55]2)[O:51][C@H:50]1C=O)([CH3:46])([CH3:45])[CH3:44]>C1COCC1>[C:43]([Si:47]([CH3:62])([CH3:61])[O:48][C@H:49]1[C@H:56]2[C@H:52]([O:53][C:54]([CH3:58])([CH3:57])[O:55]2)[O:51][C@H:50]1[C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH3:19])=[CH:15][CH:16]=2)[CH:4]=1)[OH:9])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC1(C)O[C@@H]2O[C@@H](C=O)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O1
Reactant: CCOc1ccc(Cc2cc(CO)ccc2Cl)cc1
Agent: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@H](O)[C@@H]3O[C@H]4OC(C)(C)O[C@H]4[C@@H]3O[Si](C)(C)C(C)(C)C)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Preparation of (S)-[(3aS,5S,6R,6aS)-6-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-tetrahydro-furor-2,3-d][1,3]-dioxol-5-yl]-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-methanol. To a solution of 4-bromo-1-chloro-2-(4-ethoxy-benzyl)-benzene from step C (3.6 g, 11.1 mmol) in THF (60 ml) under N2 at −78° C. was added dropwise BuLi (2.5 M in hexanes, 4.4 ml, 11.1 mmol). After 30 minutes, aldehyde from step B (2.4 g, 64% clean, 5.1 mmol) in THF (20 ml) was added dropwise, and the reaction was stirred for 30 min at −78° C., allowed to warm to room temperature and stirred for 60 minutes, quenched with sat. aq. NH4Cl, diluted with Et2O, and washed with H2O and brine. The combined aqueous washes were back extracted with Et2O, which was washed by the same sequence. The combined organic extracts were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (120 g SiO2, 0-20% EtOAc: Hexanes, 75 minutes, 85 ml/min) to give clean (S)-[(3aS,5S,6R,6aS)-6-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl]-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-methanol (0.84 g, 1.5 mmol, 30%) plus the C5 epimer (0.83 g) and some mixed fractions (0.51 g).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:18])[CH:15](Br)[CH3:16])[CH3:3].[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:18])[CH:15]([NH:27][CH2:26][CH:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:16])[CH3:3]
Reactant: CC(Br)C(=O)Nc1c(C(C)C)cccc1C(C)C
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(NCC(c1ccccc1)c1ccccc1)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A solution of (±)-N-[2,6-bis(1-Methylethyl)-phenyl]-2-bromopropanamide (2.0 g, 6.4 mmol), 2,2-diphenylethylamine (1.26 g, 6.41 mmol) and triethylamine (1.8 mL, 13 mmol) in acetonitrile (30 mL) was refluxed (96 hours), then cooled (25° C.). The resulting slurry was diluted with ethyl acetate (300 mL), washed with water (1×100 mL), with saturated aqueous sodium bicarbonate (1×100 mL), with brine (1×100 mL), then dried (MgSO4) and concentrated. Crystallization from ethyl acetate/hexane yielded 2.0 g (72.8%) of the title compound as a white solid, mp 206.5°-208.5° C.
Reaction SMILES: [Cl:1]C1C=CC(OC)=C([C@@]2(F)C3C(=CC(C(F)(F)F)=CC=3)N(C([NH:23][C@@H:24]([C@@H:32]([CH3:35])[CH2:33][CH3:34])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=O)C2=O)C=1.C(N(CC)CC)C>>[ClH:1].[C:28]([O:27][C:25](=[O:26])[C@H:24]([C@H:32]([CH2:33][CH3:34])[CH3:35])[NH2:23])([CH3:30])([CH3:31])[CH3:29]
Reactant: CC[C@H](C)[C@H](NC(=O)N1C(=O)[C@@](F)(c2cc(Cl)ccc2OC)c2ccc(C(F)(F)F)cc21)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Product: Cl
Yield: 45 %

Procedure:
(2S,3S)-tert-butyl 2-((S)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indoline-1-carboxamido)-3-methylpentanoate (XVIII6): Following general procedure (F), after forming the intermediate, L-isoleucine t-butyl ester hydrochloride (0.342 g, 1.53 mmol) and triethylamine (0.41 mL, 2.92 mmol) were added. After work-up and purification, 0.362 g of the title compound as a white foam solid was obtained (45% yield). mp: 56–60° C. MS: 573 (MH+). Anal. Calcd. for C27H29ClF4N2O5: C, 56.60; H, 5.10; N, 4.89. Found: C, 56.53; H, 5.02; N, 4.80. 1H NMR (CDCl3): 8 0.95–1.02 (m, 6H), 1.26 (m, 1H), 1.51 (s, 9H), 1.55 (m, 1H), 2.05 (m, 1H), 3.55 (s, 3H), 4.54 (dd, J=8.3 Hz, 4.5 Hz, 1H), 6.78 (dd, J=8.8 Hz, 1.3 Hz, 1H), 7.25 (m, 1H), 7.37 (dd, J=8.7 Hz, 2.6 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.81 (dd, J=2.6 Hz, 1.0 Hz, 1H), 8.60 (s, 1H), 8.73 (d, J=8.1 Hz, 1H). IR (KBr, cm−1): 3338, 2973, 1761, 1736, 1716, 1530, 1491, 1439, 1319, 1261, 1176, 1132, 1061.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=[O:2].[CH3:11][C:12](=[N:16]O)[C:13](=O)[CH3:14].[ClH:18].C(OCC)(=O)C>>[Cl:18][CH2:11][C:12]1[N:16]=[C:1]([C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])[O:2][C:13]=1[CH3:14]
Reactant: CC(=O)C(C)=NO
Reactant: Cl
Reactant: N#Cc1cccc(C=O)c1
Solvent: CCOC(C)=O
Product: Cc1oc(-c2cccc(C#N)c2)nc1CCl
Temperature: 25 °C
Reaction time: 15 h
Yield: 27 %

Procedure:
A mixture of 3-formylbenzonitrile (25.00 g), 2,3-butanedione-2-oxime (19.31 g) and 4N hydrogenchloride-ethyl acetate (300 mL) was stirred at room temperature for 15 hrs. The reaction mixture was concentrated and the obtained oily substance was decanted and washed with diethyl ether. A mixture of the obtained residue, tetrahydrofuran (500 mL) and thionyl chloride (34.14 g) was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to obtain 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzonitrile as colorless crystals (12.01 g, yield 27%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 100-101° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=2)=[N:8][CH:9]=1)([O-])=O.[H][H]>CO.ClCCl.[Pd]>[NH2:1][C:4]1[C:5]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=2)=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1cccc(Oc2cc(Nc3ccccc3)c([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccccc3)c(N)cn2)c1

Procedure:
The product of Step 5 (37.7 g, 103.5 mmol) in MeOH (350 mL) and dichloromethane (350 mL) was hydrogenated for overnight with a balloon of hydrogen gas in the presence of 10% palladium on carbon (3.5 g). After filtration of the catalyst through a pad of Celite, the filtrate was concentrated in vacuo to afford the title compound as a crude foam (˜35 g, quantitative). 1H NMR (400 MHz, MeOD) δ ppm 7.56 (s, 1H), 7.39-7.40 (m, 1H), 7.19-7.34 (m, 5H), 7.07-7.11 (m, 1H), 6.73 (dt, 1H, 1.8 Hz, 7.1 Hz), 6.48 (s, 1H), 3.32-3.34 (m, 3H), 2.12 (s, 3H). MS (ES+) m/e 335 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH3:27])#[N:20].[CH2:28]1[O:30][CH2:29]1>C1COCC1>[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH2:27][CH2:28][CH2:29][OH:30])#[N:20]
Reactant: Cc1ccncc1C#N
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: N#Cc1cnccc1CCCO
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
Diisopropylamine (2.5 g, 25 mmol) is dissolved in THF (30 ml), and thereto is added a solution of n-butyl lithium in hexane (14.3 ml, 24 mmol) at −70° C. The mixture is stirred for 15 minutes, and thereto is added a solution of 3-cyano-4-methylpyridine (2.4 g, 20 mmol) obtained in Reference Example 33 in THF (20 ml). Ten minutes thereafter, ethylene oxide (1.1 g, 24 mmol) is added to the mixture, and the mixture is warmed to 20° C. over a period of time for one hour. The reaction is quenched with a saturated brine (50 ml), and the mixture is extracted with ethyl acetate (150 ml×2). The organic layer is washed with a saturated brine (100 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (1.2 g) as a pale brown oil.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[CH:10][CH:11]=1)[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(Cc2cccnc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 19.4 %

Procedure:
A mixture of 0.70 g of the phenol compound (prepared as described in Example 9), 0.30 g of sodium hydride (content 63%) and 14 ml of N, N-dimethylformamide was stirred at 100° C. for 20 minutes, and stirred with 0.64 g of ethyl bromoacetate at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and extracted with diethyl ether. The extract was washed with water, and a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 0.5% V/V solution of ethanol in chloroform as eluent to give 0.166 g of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1.[CH2:18]([I:21])[CH:19]=[CH2:20]>ClCCl>[I-:21].[CH2:18]([N+:2]1([CH3:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1)[CH:19]=[CH2:20]
Reactant: C=CCI
Reactant: CN1CCCN(c2nc3ccccc3o2)CC1
Solvent: ClCCl
Product: C=CC[N+]1(C)CCCN(c2nc3ccccc3o2)CC1
Product: [I-]
Reaction time: 1 h

Procedure:
A 540 mg portion of 2-(4-methyl-1-homopiperazinyl)-benzoxazole was dissolved in 5 ml of dichloromethane. Under cooling with ice, 0.32 ml of allyl iodide was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature and then for 1 hour at room temperature. The reaction solution was concentrated under a reduced pressure, and 5 ml of acetone was added to the resulting residue. The precipitate thus formed was collected by filtration, washed with acetone and then dried to obtain 821 mg of the title compound.
Reaction SMILES: [O:1]=[S:2]([Cl:4])Cl.[Cl:5][C:6]1[C:7]([F:16])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([CH:12]=1)N.N([O-])=[O:18].[Na+].Cl>O.Cl[Cu]>[Cl:5][C:6]1[C:7]([F:16])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([S:2]([Cl:4])(=[O:1])=[O:18])[CH:12]=1
Reactant: O=N[O-]
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: Cl[Cu]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1S(=O)(=O)Cl
Yield: 105.3 %

Procedure:
In a similar fashion using route 3a general procedure 10, SOCl2 (2.8 ml, 28.8 mmol) in water (15 ml), CuCl (26 mg, 0.26 mmol), 5-chloro-4-fluoro-2-nitroaniline (1 g, 5.2 mmol), NaNO2 (522 mg, 7.5 mmol) and conc. HCl (10 ml) gave the title compound (1.5 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][C:11]([CH2:17][NH2:18])=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH3:5].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][C:11]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCOc1ccc2c(c1)C=C(CN)CO2
Solvent: c1ccncc1
Product: CCCCCOc1ccc2c(c1)C=C(CNC(C)=O)CO2

Procedure:
0.34 g (1.38 mmol) of the amine obtained in Step F is acetylated with acetic anhydride in pyridine according to the usual procedure. The crude product of that reaction is purified on a silica column (eluant: ethyl acetate) to yield the title acetamide in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:69][O:70][C:71](=[O:75])[CH2:72][CH2:73][NH2:74].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:74][CH2:73][CH2:72][C:71]([O:70][CH3:69])=[O:75])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (Example 96) (200 mg, 0.43 mmol), HATU (179 mg, 0.47 mmol) and N,N-diisopropylethylamine (166 mg, 1.29 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (91 mg, 0.65 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propanoate as brown solid. Yield: 180 mg, 76%.
Reaction SMILES: [C:1]([C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[C:7]([O:36][CH2:37][CH3:38])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]([CH3:50])[C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[ClH:25].[C:1]([C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]2[N:15]([C:33]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([N:40]([CH3:50])[CH3:39])=[O:49])[CH2:48][CH2:47]3)=[O:34])[C@H:16]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[C:7]([O:36][CH2:37][CH3:38])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)c(OCC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)c(OCC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12f) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 708.4 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:17]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:17][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2
Reactant: BrBr
Reactant: CC(O)CNc1ccnc2cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(O)CNc1c(Br)cnc2cc(Cl)ccc12
Reaction time: 1.5 h
Yield: 50.6 %

Procedure:
A mixture of 12 g of 7-chloro-N-(2-hydroxypropyl)-4-quinolinamine in 112 ml of acetic acid was stirred at room temperature and to it 8 g of bromine was added dropwise over a thirty minute period. After 1.5 hours, a solid formed which was isolated by filtration, dissolved in water and basified with sodium hydroxide, whereupon a solid formed which was collected by filtration. Recrystallization from ethanol yielded 8 g of solid with a melting point of 161°-163° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](Cl)(=[O:14])[CH2:11][CH2:12][CH3:13].[C:16]([O:20][C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([OH:33])=[C:28]([CH:32]=1)[C:29]([OH:31])=[O:30])=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.Cl.CCOCC>ClCCl.C(OCC)C>[C:16]([O:20][C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([O:33][C:10](=[O:14])[CH2:11][CH2:12][CH3:13])=[C:28]([CH:32]=1)[C:29]([OH:31])=[O:30])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(C(=O)O)c1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)Oc1ccc(NC(=O)OC(C)(C)C)cc1C(=O)O
Temperature: 0 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
Diisopropylethylamine (3 eq) (complete dissolution) followed by butyryl chloride (2 eq) is added to a suspension of about 0.4 M of the compound (II) in dichloromethane, cooled to 0° C. and in inert atmosphere. It is stirred at ambient temperature for 16 hours. HCl 1N (cooled in an ice bath) up to acid pH is added. The organic phase is washed with water, anhydrified and evaporated. At this stage a mixture of the desired product (III) and deacylated product (probably the corresponding anhydride) is obtained as a whitish solid. The mixture is dissolved in ethyl ether (concentration of about 0.1 M), a 2N solution of HCl in ethyl ether (0.2 eq) is added and it is stirred at ambient temperature for 25 days, during which 2N hydrochloride ether is added other 2 times (0.4 eq HCl totally) up to obtaining complete conversion in the product (III). The solvent is evaporated, the resulting solid is triturated with hexane (2 times), it is filtered and it is dried, obtaining the product (III) as white solid. 88% yield, LC-MS 99% purity.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH2:19]>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:15]([Cl:14])[CH:16]=1
Reactant: Cc1cc(Cl)c2cccc(Cl)c2n1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(Cl)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4,8-dichloro-2-methylquinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[N+:12]([O-:14])=[O:13].C[CH2:17][C:18](Br)([CH3:22])[C:19]([O-:21])=[O:20].[C:24](=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[C:6]([NH:11][C:18]([C:19]([O:21][CH3:24])=[O:20])([CH3:22])[CH3:17])[C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1c(Br)ccc(N)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Reactant: CCC(C)(Br)C(=O)[O-]
Agent: [Cs+]
Agent: [I-]
Agent: [K+]
Product: COC(=O)c1c(Br)ccc(NC(C)(C)C(=O)OC)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 19.8 %

Procedure:
A solution of 3-amino-6-bromo-2-nitro-benzoic acid methyl ester (iv) (4.55 g, 16.54 mmol), methyl-bromoisobutyrate (21.0 mL, 162.29 mmol), cesium carbonate(21.94 g, 67.34 mmol), and potassium iodide (2.90 g, 17.44 mmol) was heated at 85° C. for 48 h and cooled to room temperature. The reaction mixture was partitioned between EtOAc (300 mL) and H2O (300 mL). The organic layer was washed with H2O (3×100 mL), brine and dried with Na2SO4. The solvents were removed under vacuum and the residue purified by flash column chromatography (silica gel, EtOAc/hexane) to yield the desired product v as an orange solid (1.23 g, 20%). 1H NMR (CDCl3): δ 8.22 (br s, 1H), 7.42 (d, J=9.0 Hz, 1H), 6.45 (d, J=9.0 Hz, 1H), 3.90 (s, 3H), 3.65 (s, 3H), 1.49 (s, 6H). Anal. Calcd for C13H15BrN2O6: C, 41.62; H, 4.03; N, 7.47. Found: C, 41.58; H, 3.93; N, 7.38.