Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.C(N(CCC)CCC)CC.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(COc2ccccc2)nc2ccccc12
Agent: CCCN(CCC)CCC
Product: Clc1nc(COc2ccccc2)nc2ccccc12
Temperature: 110 °C

Procedure:
To a solution of 4-hydroxy-2-phenoxymethylquinazoline (2 g, 7.93 mmol) in phosphorus oxychloride (10 mL) is added tripropylamine (3.02 mL, 15.8 mmol) and the reaction mixture is heated for 30 minutes at 110° C. The excess phosphorus oxychloride is evaporated in vacuo, the residue is poured on ice cold aqueous NaHCO3 and extracted with ethyl acetate. The organic layer is washed with brine, dried, filtered and evaporated. The resulting residue is purified on flash chromatography (SiO2, hexane/AcOEt gradient) to give 4-chloro-2-phenoxymethylquinazoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH-:19].[Na+].OO>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]([NH2:9])=[O:19])=[N:6][CH:7]=1
Reactant: Cc1cc(C)nc(Nc2cc(Br)cnc2C#N)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)nc(Nc2cc(Br)cnc2C(N)=O)c1
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile (PrepEx 1.4) (2.6 g, 8.6 mmol) in DMSO (60 mL) was added sodium hydroxide (6.0 M in water, 1.4 mL, 8.6 mmol). The reaction mixture was cooled in an ice bath, and hydrogen peroxide (30% w/w solution in water, 2.0 mL, 20 mmol) was added. After 2 hours, the reaction mixture was diluted with water (100 mL) and stirred. After 10 min, the reaction mixture was filtered, and the collected solids were washed with water (2×50 mL) and dried under reduced pressure to afford 5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide. 1H NMR (600 MHz, CD3OD) δ 9.63 (d, J=2.4 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H), 6.63 (s, 1H), 6.48 (s, 1H), 2.40 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:7][C:8]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][S:10][N:9]=1)[CH2:4][CH2:5][CH3:6]>CC(C)=O>[I-:2].[CH2:3]([O:7][C:8]1[C:12]([C:13]2[CH:14]=[N+:15]([CH3:1])[CH:16]=[CH:17][CH:18]=2)=[N:11][S:10][N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CCCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.3 ml, 5 mmol) and 3-(3-butoxy-1,2,5-thiadiazol-4-yl)pyridine (580 mg, 2.5 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.60 g (64%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][O:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:17]=2)=[CH:3]1.[NH:35]1[CH2:39][CH2:38][NH:37][C:36]1=[S:40]>C(O)C>[CH3:32][S:29]([OH:31])(=[O:30])=[O:28].[NH:37]1[CH2:38][CH2:39][N:35]=[C:36]1[S:40][CH2:27][CH2:26][CH2:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:15]2[C:14](=[O:33])[NH:13][C:12](=[O:34])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:17]1
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: S=C1NCCN1
Solvent: CCO
Product: CS(=O)(=O)O
Product: Cn1cc(C2=C(c3cn(CCCSC4=NCCN4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Yield: 27.5 %

Procedure:
150 mg of the product of Example 58 and 50 mg of 2-imidazolidinethione were heated together at reflux for 24 hours in 5 ml of ethanol. The solvent was evaporated and the residue was chromatographed on silica gel with 10 % to 25% methanol in dichloromethane to give 50 mg of 3-[1-[3-(2-imidazolin-2-ylthio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione methanesulphonate, m.p. 134°-136° C.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>CC#N>[Br-:22].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: BrCCCOc1ccc2ccccc2c1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3ccc4ccccc4c3)(CC1)C2
Product: [Br-]
Yield: 77.2 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (31.5 mg, 0.113 mmol) and 2-[(3-bromopropyl)oxy]naphthalene (45.5 mg, 0.172 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (47.5 mg, 77%). EI-MS m/z 464 (M+) Rt (2.0 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20](Br)[CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[C:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:32]3[CH:33]=[CH:34][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][CH:31]=3)[CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cncc(Br)c1)N2
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cncc(-c3ccc(C(C)(C)C)cc3)c1)N2
Yield: 99.4 %

Procedure:
To a mixture of 2-(5-bromo-pyridin-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (778 mg, 2 mmol), 4-tert-butylphenylboronic acid (358 mg, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) in dioxane (10 mL) was added 2 M sodium carbonate solution in water (2 mL). The resulting mixture was subjected to microwave irradiation for 1 h at 110° C. The mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (880 mg, 99%) as a yellow solid: LC/MS m/e calcd for C29H34N2O2 (M+H)+: 443.61, observed: 443.2.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[Cl:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[CH:25][C:26]([NH:30][CH3:31])=[C:27]([CH:29]=1)[NH2:28].C(Cl)CCl>CC#N>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:30]([CH3:31])[C:26]2[CH:25]=[C:24]([N:32]3[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]3)[C:23]([Cl:22])=[CH:29][C:27]=2[N:28]=1
Reactant: CNc1cc(N2CCN(C)CC2)c(Cl)cc1N
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Solvent: ClCCCl
Solvent: CC#N
Product: CN1CCN(c2cc3c(cc2Cl)nc(Nc2cc(CNC(=O)C4(C(F)(F)F)CC4)ccc2Cl)n3C)CC1

Procedure:
The title compound was prepared from N-(4-chloro-3-isothiocyanato-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide (176 mg, 0.5 mmol), 5-chloro-2-methylamino-4-(4-methyl-piperazin-1-yl)-aniline (134 mg, 0.5 mmol) and EDC (93 μL, 0.5 mmol) in MeCN (5 mL) in analogy to example 1 step (g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([OH:13])(=[O:12])/[CH:9]=[CH:10]/[CH3:11]>C1(C)C=CC=CC=1>[C:2]1([NH:1][CH:10]([CH3:11])[CH2:9][C:8]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C/C=C/C(=O)O
Solvent: Cc1ccccc1
Product: CC(CC(=O)O)Nc1ccccc1
Yield: 60.7 %

Procedure:
A mixture of aniline (3.0 g, 32 mmol) and crotonic acid (2.0 g, 23 mmol) in toluene (20 mL ) was heated at reflux for 18 h. Removal of solvent and chromatography (silica gel, EtOAc/hexane, 9/1) of the crude material afforded 2.5 g (61%) of 3-phenylaminobutanoic acid. The acid was treated with PPA (20 mL) at 110° C. for 6 h and the reaction mixture was poured into ice water (50 mL) and then was neutralized with Na2CO3 to pH 7. Extraction with EtOAc (3×60 mL) followed by chromatography (silica gel, EtOAc/hexane, 4/6) afforded 1.0 g (44%) of 1,2,3,4-tetrahydro-2-methyl-4-quinolinone (structure 59A of Scheme XLVIII, where R1═R3=H, R2=methyl) as a yellow solid. The quinolinone was treated with di-tert-butyl dicarbonate (2.2 g, 10 mmol) and DMAP (0.84 g, 6.8 mmol) in THF (15 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) to afford 1.1 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinone as a yellow oil. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2-methyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.99 (d, J=7.5, 1H), 7.78 (d, J=7.5, 1H), 7.50 (t, J=7.5, 1H), 7.12 (t, J=7.5, 1H), 5.10 (m, 1H), 3.04 (dd, J=17.3, 5.8, 1H), 2.57 (dd, J=17.3, 1.7, 1H), 1.56 (s, 9H), 1.22 (d, J=6.9, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)([CH3:5])[CH3:4].[CH3:16][C@@H:17]1[CH2:19][O:18]1.O>O1CCCC1.CCOCC>[CH:3]([C:6]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:16][C@H:17]([OH:18])[CH3:19])([CH3:5])[CH3:4]
Reactant: C[C@@H]1CO1
Reactant: CC(C)c1c(F)ccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)c1c(F)ccc2c1ccn2C[C@@H](C)O
Yield: 81 %

Procedure:
A suspension of 0.16 g of sodium hydride dispersion in 22 ml of tetrahydrofuran was treated with 0.38 g of 4-isopropyl-5-fluoroindole at 0° and stirred at this temperature for I hour. After the addition of 0.6 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 120 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene-ethyl acetate (19:1). 0.41 g (81%) of (R)-1-(4-isopropyl-5-fluoro-indol-1-yl)-propan-2-ol was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]([OH:21])([CH2:19][CH3:20])[CH2:17][OH:18])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](=O)[CH2:23][CH3:24]>S(=O)(=O)(O)O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([CH2:19][CH3:20])[CH2:17][O:18][CH:22]([CH2:23][CH3:24])[O:21]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)(CO)c1cc(F)cc(OCc2ccccc2)c1
Reactant: CCC=O
Agent: O=S(=O)(O)O
Product: CCC1OCC(CC)(c2cc(F)cc(OCc3ccccc3)c2)O1

Procedure:
Using the procedures described in the last two paragraphs of the portion of Example 1 which is concerned with the preparation of starting materials, 2-(3-benzyloxy-5-fluorophenyl)butane-1,2-diol (1.02 g) was reacted with propionaldehyde (6 ml) in the presence of concentrated sulphuric acid (1 drop) to give 4-(3-benzyloxy-5-fluorophenyl)-2,4-diethyl-1,3-dioxolane, as an oil and as a mixture of diastereoisomers, and this product was hydrogenolysed to give the required starting material (0.5 g, 60%), as an oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[NH:33][C@@H:32]([CH3:34])[CH2:31][N:30]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[C@H:32]([CH3:34])[CH2:31][N:30]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:29][C@@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1
Product: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline.
Reaction SMILES: [C:1](I)([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].I[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.CS(C)=O.CCOCC>[Cu].N1C=CC=CC=1C1C=CC=CN=1.O>[F:2][C:1]([F:3])([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([F:12])([F:11])[C:13]([F:15])([F:14])[C:16]([F:18])([F:17])[C:19]([F:21])([F:20])[C:22]([F:25])([F:24])[F:23]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.2 %

Procedure:
A solution of C8F17I (12 g, 22 mmol) was added dropwise over 10 min to a stirred mixture of 4-iodobenzotrifluoride (3 g, 11 mmol), copper powder (5.6 g, 0.088 mmol), 2,2′-bipyridine (120 mg, 0.8 mmol), and DMSO (30 mL) at 70° C. The reaction mixture was subsequently stirred for a further 72 h at this temperature. After cooling to room temperature, it was poured into a beaker containing ether (100 mL) and water (100 mL). After filtering, the organic layer was separated, washed with water (3×50 mL) and dried over MgSO4. Sublimation gave the product 210 as a white solid (5.6 g, 90%): 1H NMR (300 MHz, CDCl3): 7.77 (4H, dd, J=8.1 and 8.4 Hz); 19F NMR (282 MHz, CDCl3):−64.0, −81.4, −111.6, −121.4, −122.0, −122.1, −122, 9, −126, 3.
Reaction SMILES: C1(S(N[CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([C:29]5[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=5)=C[CH:26]=[CH:27][CH:28]=4)=[O:22])[CH:17]=3)[CH2:12]2)(=O)=O)C=CC=CC=1.FC(F)(F)C1C=CC(C2[N:55]=CC=CC=2C([Cl:51])=O)=CC=1.NC1C=C2C(=CC=1)CCC2>>[ClH:51].[CH2:12]1[C:13]2[C:18](=[CH:17][C:16]([NH:20][C:21](=[O:22])[C:23]3[CH:28]=[CH:27][CH:26]=[N:55][C:24]=3[C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)=[CH:15][CH:14]=2)[CH2:19][CH2:11]1
Reactant: O=C(Cl)c1cccnc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: Nc1ccc2c(c1)CCC2
Product: Cl
Product: O=C(Nc1ccc2c(c1)CCC2)c1cccnc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound is prepared in a manner similar to that described for the title E compound of Example 1 using 2-(4-trifluoromethyl-phenyl)-nicotinoyl chloride (2.228 mmol) and 5-aminoindan (0.296 g, 2.228 mmol) to give the product as the free base. The hydrochloride salt is prepared by bubbling HCl(g) through an ethyl acetate solution of the free base and trituation of the salt with diethyl ether; mp 190-205° C. MS (ES+) m/z 383 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccc2c(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CCC(N)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
tert-Butyl-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate (55.7 g, 128 mmol) was dissolved in dichloromethane (200 mL) and trifluoroacetic acid (215 ml) was slowly added (careful: immediate gas evolution!). The resulting solution was stirred overnight at room temperature under a nitrogen atmosphere and evaporated to dryness. To the residue were added equal amounts of water and dichloromethane (300 mL). The obtained emulsion was basified to pH 9 with 33% aq. NaOH. The emulsion was cleared by the addition of methanol, and the layers were separated. The aqueous layer was extracted with dichloromethane (200 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to dryness to yield crude 2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol. The crude material was purified by column chromatography (SiO2, 2% methanol in dichloromethane) to yield 2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (44 g, 97%) as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 8.52 (dd, J=2.1, 8.1 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.37 (dt, J=1.5, 7.2 Hz, 1H), 7.22 (dd, J=1.5, 9.0 Hz, 1H), 7.04 (dd, J=1.2, 6.9 Hz, 1H), 6.92 (dt, J=1.2, 7.2 Hz, 1H), 4.49-4.39 (m, 2H), 3.34 (dt, J=2.4, 12.2 Hz, 2H), 3.12-3.02 (m, 1H), 2.54 (s, 3H), 2.09-2.00 (m, 2H), 1.68-1.55 (m, 2H), 1.40-1.25 (m, 2H) ppm.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:17]I>C1COCC1>[CH3:17][O:3][CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To the sodium hydride (48 mg, 2 mmol) in THF (5 ml) at −78° C., (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate was slowly added. After 15 min, methyl iodide (0.124 ml, 2 mmol) was added and the reaction mixture was slowly allowed to come to rt overnight. Then the reaction mixture was quenched with MeOH and diluted with water (15 ml). Aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over sodium sulfate and then filtered. The solvent was removed under vacuum, and the crude product was purified by silica gel chromatography (eluting with 15% EtOAc/hexanes) to afford (R)-tert-butyl 2-(methoxymethyl)pyrrolidine-1-carboxylate in 80% yield. (R)-2-(methoxymethyl)pyrrolidine was generated by removal of the Boc protecting group by treatment with trifluoroacetic acid.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:13][CH:14]=[CH:15][C:16]=2[CH2:17]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>>[C:5]1([C:11]2[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:13][CH:14]=[CH:15][C:16]=2[CH2:17][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1CCNCC1
Reactant: OCc1ccnc(-c2ccccc2)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: c1ccc(-c2nccc(CN3CCCCC3)c2-c2ccccc2)cc1
Yield: 71 %

Procedure:
Thionyl chloride (1 mL) (Wako Pure Chemical Industries, Ltd.) was added to Compound 9 described above (0.30 g, 1.15 mmol), and the mixture was refluxed for 30 minutes. Then, the solvent was distilled off under reduced pressure. The residue was dissolved in acetonitrile (20 mL), and piperidine (0.75 g, 8.80 mmol) (Wako Pure Chemical Industries, Ltd.) was added thereto, followed by reflux for 3 hours. The mixture was returned to room temperature, and then a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added thereto, followed by extraction with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.27 g, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:42]([O:46][C:47](=[O:56])[CH:48](N1C=CC(N)=N1)C)([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[C:42]([O:46][C:47](=[O:56])[CH2:48][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[N:17]1)([CH3:45])([CH3:44])[CH3:43]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 2.66 g, 8.04 mmol) in methylene chloride (20 mL), a 2.0 M solution of oxalylchloride in methylene chloride (4.42 mL, 8.84 mmol) was added and allowed to stir for 1 h at 0° C. then for 1 h at 25° C. 2,6-lutidine (1.12 g, 10.0 mmol) was then added dropwise at 0° C., turning the solution light brown and resulting in effervescence. To this solution was added (3-amino-pyrazol-1-yl)-propionic acid tert-butyl ester (1.87 g, 8.84 mmol) dissolved in methylene chloride (5 mL). The reaction was allowed to proceed at 0° C. for 1 h and then overnight at 25° C. The reaction was washed with 1.0 M aqueous hydrochloric acid solution (20 mL) and the organic layer was dried with anhydrous sodium sulfate. The solvent was then removed in vacuo and was purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 10% ethyl acetate/methylene chloride) to afford 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid tert-butyl ester (3.06 g, 73%) as a white solid: ESI-LRMS m/e calcd for C25H34ClN3O5S [M+] 523.2, found 524.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.20 (m, 2H, CH2), 1.40 (s, 9H, 3×CH3), 1.39-1.92 (m, 8H, 4×CH2), 2.10-2.31 (m, 1H, CH), 2.70 (t, J=6.6 Hz, 2H, COCH2), 3.25 (s, 3H, SO2CH3), 3.57 (t, J=7.6 Hz, 1H, CH), 4.21 (t, J=6.6 Hz, 2H, NCH2), 6.60 (d, J=2.3 Hz, 1H, Ar), 7.28 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.58 (d, Jm=1.7 Hz, 1H, Ar), 8.06 (d, Jo=8.2 Hz, 1H, Ar), 8.17 (s, 1H, NH).