Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17]1([CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[CH:28]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=2/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:28]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)/C=C/c1cc(F)ccc1CBr
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Product: CCOC(=O)/C=C/c1cc(F)ccc1Cc1cc2cc(OCc3ccccc3)ccc2[nH]1

Procedure:
The benzylic bromide of Step 2 (3.16 g; 11.0 mmol) was coupled with 5-(phenylmethoxy)indole according to the same procedure described in step 1 of example 2 to yield 2.27 g of the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:22][O:23][C:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[O:28])([CH3:26])[CH3:25])[C:12]([NH:14][CH:15]2[CH:18]([C:19]#[N:20])[NH:17][C:16]2=[O:21])=[O:13])[N:10]=1)=[O:4].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:19]([C@H:18]1[NH:17][C:16](=[O:21])[C@H:15]1[NH:14][C:12](=[O:13])[C:11]([C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][Cl:1])[S:7][CH:8]=1)=[N:22][O:23][C:24]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])([CH3:26])[CH3:25])(=[O:40])[NH2:20]
Reactant: OO
Reactant: CC(C)(ON=C(C(=O)NC1C(=O)NC1C#N)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C(N)=O)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 2 ml of dimethyl sulfoxide is dissolved 0.38 g of (3S,4S)-b 3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamido]-4-cyano-2-azetidinone and, following addition of 0.1 ml of 30% aqueous hydrogen peroxide and 0.1 ml of 1N sodium hydroxide, the mixture is stirred at approx. 25° C. for 30 minutes. The reaction mixture is chromatographed on an XAD-II column (eluant: 30% ethanol) to give 0.12 g of (3S,4S)-4-carbamoyl-3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamido]-2-azetidinone.
Reaction SMILES: [Cl:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([CH3:25])([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+:27]>C(O)C.O>[Cl:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([CH3:25])([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:3]([O-:5])=[O:4].[Na+:27]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC(C)(C)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(COc1ccc(CC(Cl)C(=O)[O-])cc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
In 15 ml of ethanol is dissolved 3.6 g of ethyl 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)phenyl]propionate, and under cooling with ice and stirring, a solution of 0.35 sodium hydroxide in 3.5 ml water is added. The mixture is kept under the same condition for 30 minutes, after which the solution is concentrated to dryness. The residue is dissolved in 10 ml of water, the solution is washed three times with ether, and then the solution is concentrated to dryness. The procedure yields 2.6 g of sodium 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)-phenyl]propionate, as white amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[H-].[Na+].[CH2:15]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[S:3][C:4]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[O:27])=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc(Cc2ccccc2)cc1
Reactant: CCNC(=O)c1sc(N)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=O)c1sc(NC(=O)c2ccc(Cc3ccccc3)cc2)nc1C
Temperature: 25 °C

Procedure:
To a solution of 2-amino-N-ethyl-4-methylthiazole-5-carboxamide (0.17 g, 0.93 mmol) in dichloromethane (2 mL) at −78° C. was added sodium hydride (excess) followed by the addition of 4-benzylbenzoyl chloride (1 equiv of 0.5 M in N,N-dimethylformamide). The reaction was allowed to warm to ambient temperature over 18 h then concentrated in vacuo. The crude product was purified by preparative HPLC (acetone/water gradient) to afford the title compound (0.005 g); 1H NMR (CD3OD, 400 MHz) δ 7.90 (d, J=8.6 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.27-7.13 (m, 5H), 4.03 (s, 2H), 3.32 (q, J=7.6 Hz, 2H), 2.50 (s, 3H), 1.17 (t, J=7.6 Hz, 3H); MS (ES+) m/z 380 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].[C:19](/[CH:24]=[C:25]1\[CH2:26][C:27]([CH3:33])([CH3:32])[CH2:28][C:29](O\1)=[O:30])([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[C:19]([CH:24]=[C:25]1[N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:1]([O:3][CH3:4])=[O:2])=[CH:18][CH:17]=2)[C:29](=[O:30])[CH2:28][C:27]([CH3:32])([CH3:33])[CH2:26]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)/C=C1\CC(C)(C)CC(=O)O1
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CC(C)(C)CC(=O)N1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
Compound (i) of Example 9 (1.2 g, 0.005 mole) and compound (b) of Example 2 (1.1 g, 0.005 mole) are combined in toluene (50 mL) and refluxed for 5 hours. The toluene is removed in vacuo and the residue is chromatographed on silica gel using hexane/ethyl acetate as the mobile phase. The title compound is isolated as a colorless oil (1.2 g, 52%). Mass Spec. (DCI) m/z 436 (M+H). Analysis-calc'd for C26H29NO5 : C, 70.96; H, 6.76; N, 3.18; found: C, 70.76; H, 7.11; N, 2.77.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+].Cl>CO.O>[Br:1][C:2]1[O:6][C:5](/[CH:7]=[CH:12]/[N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Br)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])/C=C/c1ccc(Br)o1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-furaldehyde (5.26 g, 0.0300 mol) and nitromethane (2.2 ml, 2.43 g, 0.0300 mol) in methanol (40 ml) were added to NaOH (1.20 g, 0.0300 mol) in water (40 ml) at 0° C. The resulting mixture was stirred at 0° C. for 2 h and then diluted with ice-cold water (25 ml). The resulting solution was added slowly to 10% HCl (10 ml) at <0° C. The separated precipitate was filtered off, washed with water and heptane and dried to afford the title compound. 1H NMR (400 MHz, DMSO-d6): 6.90 (1H, d), 7.30 (1H, d), 7.77 (1H, d), 7.96 (1H, d)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([N:17]4[CH2:21][CH2:20][CH2:19][C:18]4=[O:22])[CH:14]=[CH:15][CH:16]=3)[C:5]2=[N:6][CH:7]=1.[C:23]([O:26][CH2:27][CH3:28])(=O)[CH3:24]>>[O:26]1[CH:27]=[CH:28][C:24]([C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([C:11]4[CH:12]=[C:13]([N:17]5[CH2:21][CH2:20][CH2:19][C:18]5=[O:22])[CH:14]=[CH:15][CH:16]=4)[C:5]3=[N:6][CH:7]=2)=[CH:23]1
Reactant: CCOC(C)=O
Reactant: O=C1CCCN1c1cccc(-n2cnc3cc(Br)cnc32)c1
Product: O=C1CCCN1c1cccc(-n2cnc3cc(-c4ccoc4)cnc32)c1

Procedure:
The title compound was prepared from 1-[3-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]pyrrolidin-2-one as described in Example 1. Free base, yellow crystals, m.p. 208-210° C. (from ethyl acetate); δH (360 MHz, d6-DMSO) 2.11 (2H, quin, J 7), 2.54 (2H, t, J 8), 3.93 (2H, t, J 7), 7.16 (1H, s), 7.60 (1H, t, J 8), 7.68-7.71 (1H, m), 7.78-7.81 (2H, m), 8.28 (1H, t, J 2), 8.35 (1H, s), 8.48 (1H, s), 8.76 (1H, s), 8.90 (1H, s); m/z (ES+) 345 (M++H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14](/[CH:16]=[CH:17]/[CH:18]([OH:20])[CH3:19])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:21][C:22]1([CH3:31])[CH2:27][CH:26]([NH2:28])[CH2:25][C:24]([CH3:30])([CH3:29])[NH:23]1.CCN(C(C)C)C(C)C>CO>[CH3:21][C:22]1([CH3:31])[CH2:27][CH:26]([NH:28][C:5]2[N:10]=[C:9]([C:11]3[S:15][C:14](/[CH:16]=[CH:17]/[CH:18]([OH:20])[CH3:19])=[CH:13][CH:12]=3)[CH:8]=[CH:7][N:6]=2)[CH2:25][C:24]([CH3:30])([CH3:29])[NH:23]1
Reactant: CC(O)/C=C/c1ccc(-c2ccnc(S(C)(=O)=O)n2)s1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)/C=C/c1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Temperature: 120 °C

Procedure:
(E)-4-[5-(2-Methanesulfonyl-pyrimidin-4-yl)-thiophen-2-yl]-but-3-en-2-ol (100 mg, 0.32 mmol) was mixed with 2,2,6,6-tetramethyl-piperidin-4-ylamine (0.2 ml, 1.15 mmol) and DIEA (0.2 ml, 1.17 mmol) and heated to 120° C. in a closed flask for 2 hours. The residue was then diluted with MeOH and purified by preparative HPLC to give the title compound. Yield: 25 mg (20%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[NH:28][CH:27]=1>O1CCOCC1>[N:26]1([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=3[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: c1ccc2[nH]cnc2c1
Solvent: C1COCCO1
Product: CC(C)Cc1cc(-c2cccc(Cn3cnc4ccccc43)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 93 %

Procedure:
To a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (71.8 mg, 0.162 mmol; see Example 1(e)) in dioxane (2.0 mL) was added benzimidazole (57.3 mg, 0.485 mmol) and the reaction mixture was stirred for 5.5 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (3:97) as eluent to give the sub-title compound in 93% yield as a colourless syrup (72.3 mg, 0.151 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:16]([CH3:18])[CH3:17].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Br)cc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
A mixture of 4-bromophenol (16-2, 7.02 g, 39.4 mmol) and potassium carbonate (12.6 g, 90.9 mmol) in DMSO (20.0 mL) was added with 2-iodopropane (16-1, 5.2 mL, 49.0 mmol). The mixture was heated at 60° C. overnight. The solution was cooled to room temperature and added with water (200 mL). The reaction was extracted with EtOAc, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc:hexanes=1:100 as eluant) to give 1-bromo-4-isopropoxybenzene (6.66 g) as colorless oil in 79% yield: 1H NMR (CDCl3) δ 7.34 (m, 2 H), 6.77 (dd, J=8.9, 3.1 Hz, 2 H), 4.49 (m, 1 H), 1.33 (s, 3 H), 1.31 (m, 3 H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:24](=[O:28])[CH2:25][CH2:26][CH3:27])=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:24]([C:5]1[C:4](=[O:3])[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([CH2:14][O:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:10]=2)[NH:7][CH:6]=1)(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(=O)C(=CNc1ccc(COC(=O)c2ccccc2)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2ccc(COC(=O)c3ccccc3)cc2c1=O
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Ethyl-2-butyryl-3-(4-benzoyloxymethylphenylamino)acrylate (50 g) was added portion wise to boiling diphenyl ether (500 ml) and heating continued under relfux for 30 minutes. On cooling, crystals started to appear and the mixture was diluted with petroleum ether to give 3-butyryl-6-(benzoyloxymethyl)4(1H)quinolone (39.7 g, 96%) as light brown crystals, m.p. 220° C.-3° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:16])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1.[Br:17]N1C(=O)CCC1=O>CN(C=O)C>[Br:17][C:5]1[S:1][C:2]([C:6]2([OH:16])[CH2:7][CH2:8][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: OC1(c2ncc(Br)s2)CCC2(CC1)OCCO2
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
The product of Step 1 (60.5 g, 251 mmol) was diluted with DMF (365 mL). N-bromosuccinimide (49.1 g, 276 mmol) was added, and the solution was heated to 50° C. and stirred for 2 h. The reaction was removed from heat and cooled to 45° C. and H2O (600 mL) containing 15.8 g Na2SO3 was added dropwise affording a solid. The mixture was stirred at room temperature for 1 h, then filtered and washed 2× with H2O (300 mL). The cake was dried overnight under a nitrogen bag to afford 8-(5-bromo-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (68.2 g; 85%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH2:10])[CH3:3].[NH:11]1[CH2:15][CH2:14][N:13]=[C:12]1S(O)(=O)=O>C(O)C(C)C>[CH2:2]([C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH:10][C:12]1[NH:13][CH2:14][CH2:15][N:11]=1)[CH3:3]
Reactant: CC[C@@H]1CCCC[C@H]1N
Reactant: O=S(=O)(O)C1=NCCN1
Agent: Cl
Solvent: CC(C)CO
Product: CC[C@@H]1CCCC[C@H]1NC1=NCCN1
Temperature: 125 °C
Yield: 65 %

Procedure:
A mixture of trans-2-ethylcyclohexylamine hydrochloride (0.30 g, 2.36 mmol), imidazoline-2-sulfonic acid (0.704 g, 4.72 mmol) and isobutanol (3 ml) was heated to 125° C. and maintained at that temperature for 2 hours. The mixture was cooled to room temperature, concentrated in vacuo and chromatographed (silica gel, 3:1 CHCl3 /CH3OH saturated with NH3 (g)) to yield 0.253 g (a yield of 65%) of the title compound as a white solid, which was characterized spectroscopically.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl[C:31]([O:33][CH3:34])=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([C:31]([O:33][CH3:34])=[O:32])[CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: COC(=O)Cl
Product: CCOC(=O)c1c(CN(C)C(=O)OC)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-methylaminomethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 86.1.) was reacted with methyl chloroformate as described in Example 77.1. to give 5-fluoro-3-[(methoxycarbonyl-methyl-amino)-methyl]-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless foam. MS: 419.5 ([M−H]−).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][C:10]=1[F:22])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:22][C:10]1[CH:11]=[C:12]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[CH:14][C:9]=1[CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2ccccc2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(Oc2ccccc2)cc1F
Yield: 33.2 %

Procedure:
Dissolve (2-fluoro-4-phenoxy-benzyl)-carbamic acid tert-butyl ester (2.44 g, 7.72 mmol) in DCM (200 mL). Add trifluoroacetic acid (50 mL) then stir at ambient temperature for 16 h. Evaporate the solvent, dissolve the residue in DCM and wash with 1N aqueous NaOH. Dry over Na2SO4 and concentrate in vacuo. Purify by SCX chromatography to obtain the title compound (557 mg, 33%). MS (ES+) m/z: 201 M+H−NH3)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:7]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(C)(C)C)n[nH]1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cc(C(C)(C)C)nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.7 %

Procedure:
To a mixture of tert-butyl (3-tert-butyl-1H-pyrazol-5-yl)methylcarbamate (501 mg, 1.98 mmol, 1 equiv.), 4-fluorophenylboronic acid (554 mg, 3.96 mmol, 2 equiv.) and copper acetate (541 mg, 2.97 mmol, 1.5 equiv.) in dichloromethane (30 mL) was added pyridine (315 mg, 0.315 mL, 3.96 mmol, 2 equiv) and the mixture was stirred in the presence of air for 2 d at room temperature. The reaction mixture was filtered over silica gel, the filter cake was washed with dichloromethane (250 mL) and the solvent of the filtrate was evaporated to give tert-butyl (3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methylcarbamate (232 mg, 34%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:13][C:14]([Cl:16])=[CH2:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([CH:15]=[C:14]([Cl:16])[Cl:13])=[O:5]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: C=C(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)c1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
25 g of 2,4,5-trifluorobenzoyl chloride in 10 ml of methylene chloride and 37.5 g of 1,1-dichloroethylene are successively added dropwise to a suspension of 18.5 g of anhydrous aluminum chloride in 75 ml of dry methylene chloride, while cooling with ice and stirring, during which the temperature does not exceed 15° C. The mixture is stirred at about 15° C. for 2 hours, is allowed to come to room temperature overnight and is poured onto a mixture of 150 g of ice and 15 ml of concentrated hydrochloric acid, the organic phase is separated off and the aqueous phase is subsequently extracted with methylene chloride. The methylene chloride solution is washed with water and dried with sodium sulphate and the diluent is distilled off in vacuo. The residue (44 g) is heated at 130°-140° C. with 0.1 g of triphenylphosphine until the initially vigorous evolution of gas has ended (about 45 minutes). Distillation in vacuo gives 23.8 g (72.8%) of 2,2-dichlorovinyl 2,4,5-trifluorophenyl ketone of boiling point 132° -134° C./14 mbar.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:9]=2[C:8]1=[O:27].[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:32][C:31]([F:34])([F:33])[C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([C:2]([F:35])([F:36])[F:1])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][CH:42]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:43][CH2:44]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:9]=2[C:8]1=[O:27]
Reactant: O=C1c2c(-c3ccccc3Cl)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CCN(C2CCNCC2)C1
Product: O=C1c2c(-c3ccccc3Cl)cc(N3CCC(N4CCCC4)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 47.5 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-chlorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (70.2 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-chlorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (57.7 mg, 48%).
Reaction SMILES: C([O:3][C:4]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:10]=[CH:9][C:8]=2[CH2:7][CH2:6][CH:5]=1)C>C(O)(=O)C.O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[N:10]=[CH:9][C:8]3[CH2:7][CH2:6][CH2:5][C:4](=[O:3])[C:13]=3[N:12]=2)=[CH:15][CH:16]=1
Reactant: CCOC1=CCCc2cnc(-c3ccc(OC)cc3)nc21
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2ncc3c(n2)C(=O)CCC3)cc1

Procedure:
8-Ethoxy-2-(4-methoxy-phenyl)-5,6-dihydro-quinazoline (860 mg; 3.05 mmol) is dissolved in acetic acid/water (16 ml/1.6 ml) and refluxed for 15 minutes. Evaporation to dryness delivers the title compound as yellow crystals. 1H-NMR (400 MHz; DMSO-d6): 9.04 (s, 1H); 8.34 (d, 2H); 7.10 (d, 2H); 3.86 (s, 3H); 2.99 (t, 2H); 2.79 (t, 2H); 2.15 (m, 2H). MS (m/z) ES+: 255 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]=[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=2)[CH:12]=[CH:11][N:10]1CC1C=C2C(C=CN2C(OC(C)(C)C)=O)=CC=1.C([O-])(O)=O.[Na+].CC#N>ClCCl>[O:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:17]2[N:16]=[C:15]([C:13]3[CH:12]=[CH:11][NH:10][C:9](=[O:8])[CH:14]=3)[CH:20]=[CH:19][N:18]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(Cn3ccc(-c4ccnc(NC5CCOCC5)n4)cc3=O)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)cc[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
TFA (2 mL) was added to a solution of tert-butyl 6-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate (70 mg, 0.14 mmol) in dichloromethane (3 mL) at 20° C. The mixture was stirred at room temperature for 2 hours. LC-MS showed the tert-butyl 6-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate had disappeared. The reaction mixture was adjusted with a saturated NaHCO3 solution to a pH of around 8-9, then extracted with dichloromethane, and dried with Na2SO4. The organic phase was evaporated, and the residue was purified with prep-HPLC (A: H2O including 0.5% NH3HCO3, B: CH3CN) to afford 141H-indol-6-yl)methyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (11 mg, 20% yield). 1H NMR (500 MHz, (CD3)2SO) δ 11.10 (s, 1H), 8.41 (d, J=5.0 Hz, 1H), 7.92 (d, J=7.0 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.40-7.32 (m, 3H), 7.15-7.11 (m, 2H), 7.03 (d, J=8 Hz, 1H), 6.85 (d, J=7 Hz, 1H), 6.39 (s, 1H), 5.22 (s, 2H), 3.98 (m, 1H), 3.89-3.85 (m, 2H), 3.45-3.36 (m, 2H), 1.86-1.83 (m, 2H), 1.60-1.45 (m, 2H); LCMS (ESI) m/z: 402.2 [M+H+].
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](NC3C=CC(OC4C=NC=CC=4)=CC=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1OC.[CH3:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=O>>[N:31]1([CH:30]2[CH2:5][CH2:10][N:9]([C:8]3[C:7]([C:12]#[N:13])=[CH:6][C:5]4[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=4)[N:9]=3)[CH2:8][CH2:7]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1cc2c(Nc3ccc(Oc4cccnc4)cc3)c(C#N)cnc2cc1F
Reactant: CN1CCCC1=O
Product: N#Cc1cc2ccccc2nc1N1CCC(N2CCCC2)CC1

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.39 mmol) of 7-fluoro-6-methoxy-4-[4-(pyridin-3-yloxy)phenylamino]-quinoline-3-carbonitrile and 299 my (1.94 mmol) of 4-(1-pyrrolidinylpiperidine) are refluxed in 1-methyl 2-pyrrolidinone (1 mL) at 105° C. for 12 hours to yield the crude product. Purification by silica gel chromatography (95:5 methylene chloride/methanol) gives 120 my of 6-methoxy-4-[4-(pyridin-3-yloxy)phenylamino]-7-(4-pyrrolidin-1-yl-piperidin-1-ylquinoline-3-carbonitrile as a yellow solid, mp 194-196° C.