Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[O:13][C:12](=[CH2:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)O[O:17]1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][C:12]2([CH2:14][O:17]2)[O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1CC(COCc2ccccc2)O1
Reactant: CC1(C)OO1
Solvent: ClCCl
Product: c1ccc(COCC2CC3(CO3)O2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 4-benzyloxymethyl-2-methyleneoxetane (0.025 g, 0.13 mmol) in CH2Cl2 under N2 was cooled to −78° C. Then, dimethyldioxirane (0.5 M, 0.52 mL, 0.26 mmol) was added dropwise, and the reaction was stirred at −78° C. for 1 h. The solvent was then evaporated to give 2-benzyloxymethyl-1,5-dioxaspiro[3.2]hexane, which was dissolved in dry THF (2 mL). The solution was stirred under N2 and cooled to 0° C. A solution of 1H-tetrazole (0.01 g, 0.14 mmol) in dry THF (2.0 mL) was added. The reaction mixture was stirred at 0° C. for 3 h and was then warmed to room temperature, followed by removal of the solvent in vacuo. The resultant oil was purified by preparatory TLC on silica gel (CH2Cl2/MeOH 96:4). 4-Benzyloxymethyl-2-hydroxymethyl-2-(tetrazol-2-yl)oxetane was isolated as a clear oil was (32 mg, 88% over 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.34 (m, 5H), 5.23 (m, 1H), 4.69 (d, J=11.9 Hz, 1H), 4.63 (d, J=11.9 Hz, 1H), 4.40 (app d, J=12.6 Hz, 1H), 4.17 (dd, J=12.2, 8.7 Hz, 1H), 3.83 (dd, J=11.7, 2.2 Hz, 1H), 3.68 (dd, J=11.7, 2.8 Hz, 1H), 3.60 (dd, J=12.3, 7.2 Hz, 1H), 3.40 (dd, J=12.3, 7.6 Hz, 1H), 3.24 (app d, J=5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 153.4, 137.6, 129.1, 128.6, 128.4, 97.8, 76.8, 74.2, 71.0, 65.4, 30.2; MS (EI) m/z 149, 107, 91 (100), 77, 65.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2n(Cc2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (80) and benzyl bromide according to General Procedure B. Yield 152 mg (21%), MP 130° C.; 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.15 (m, 4H), 3.90 (m, 4H), 4.32 (q, J=7.2 Hz, 2H), 5.55 (s, 2H), 7.14-7.30 (m, 6H), 7.45 (d, J=3.6 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 8.16 (dd, J=2.8, 8.8 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H); EIMS: 521 (M+1). Anal. (C27H25FN4O4S) C, H. N.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]1[CH2:11][C@@H:10]([CH2:12][N:13](C(OC(C)(C)C)=O)C(N)=NC(OC(C)(C)C)=O)[CH2:9][N:8]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.N(C[C@H]1CN[C@H](C(O)=O)C1)C(N)=N.Cl>O1CCOCC1>[C:1]([O:5][C:6](=[O:38])[C@@H:7]1[CH2:11][C@@H:10]([C:12]#[N:13])[CH2:9][N:8]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N=C(N)N(C[C@@H]1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N=C(N)NC[C@H]1CN[C@H](C(=O)O)C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](C#N)CN1C(=O)OC(C)(C)C

Procedure:
(4R)-4-(Guanidinomethyl)-L-Proline Dihydrochloride (4R)-1-(tert-Butyloxycarbonyl)-4-[N,N'-bis(tert-butyloxy-carbonyl)guanidino-methyl]-L-proline tert-butyl ester (98 mg, 0.181 mmol) was treated with 4N HCl in dioxane (1.5 mL) for 48 hours at room temperature. The reaction mixture was evaporated under diminished pressure, coevaporated several times with diethyl ether and several times with methanol. The product was dried under high vacuum; yield 44 mg (94%). Mass spectrum: m/z 187 (M+1); 400 MHz 1H NMR (CD3OD): δ2.19 (m, 1H); 2.43 (m, 1H); 2.68 (m, 1H); 3.11 (dd, 1H); 3.63 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:19][C:18]3[CH:20]=[CH:21][C:15]([Br:14])=[CH:16][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3ccc(Br)cc3)c2cn1
Temperature: 200 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (261 mg, 1.36 mmole) and 4-bromoaniline (1.00 g, 5.81 mmole) is stirred under N2 at 200° C. for 15 min. The resulting product is chromatographed on silica gel (10-15% EtOH/EtOAc) to give 7-amino-4-(4-bromoanilino)pyrido[4,3-d]pyrimidine (200 mg, 46%) as a pale yellow solid. 1H NMR (DMSO) δ 9.88 (1H, brs), 9.34 (1H, s), 8.40 (1H, s), 7.83 (2H, d, J=8.8 Hz, 7.55 (2H, d, J=8.8 Hz), 6.64 (2H, brs), 6.44 (1H, s).
Reaction SMILES: [OH-].[Na+].C([NH:6][C:7]1[C:16]([F:17])=[C:15]([N:18]2[CH2:24][C@@H:23]([NH:25]C(OC(C)(C)C)=O)[C:20]3([CH2:22][CH2:21]3)[CH2:19]2)[C:14]([CH3:33])=[C:13]2[C:8]=1[C:9](=[O:40])[C:10]([C:37]([OH:39])=[O:38])=[CH:11][N:12]2[CH:34]1[CH2:36][CH2:35]1)(=O)C.Cl>>[NH2:6][C:7]1[C:16]([F:17])=[C:15]([N:18]2[CH2:24][C@@H:23]([NH2:25])[C:20]3([CH2:21][CH2:22]3)[CH2:19]2)[C:14]([CH3:33])=[C:13]2[C:8]=1[C:9](=[O:40])[C:10]([C:37]([OH:39])=[O:38])=[CH:11][N:12]2[CH:34]1[CH2:36][CH2:35]1
Reactant: CC(=O)Nc1c(F)c(N2C[C@@H](NC(=O)OC(C)(C)C)C3(CC3)C2)c(C)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(N2C[C@@H](N)C3(CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C

Procedure:
A 20% sodium hydroxide aqueous solution (4.8 ml) was added to 76.7% purity 5-acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (400.1 mg) under stirring at room temperature, and the mixture was stirred at 80° C. for 5 hours. While stirring at room temperature, the reaction solution was mixed with concentrated hydrochloric acid and stirred for 1 hour. When quantitative analysis was carried out by a high performance liquid chromatography after neutralization of the reaction solution by adding 20% sodium hydroxide aqueous solution, formed amount of the compound of interest 5-amino-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid corresponded to 207.2 mg. The formation ratio was 92%.
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]3[NH:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[O:30][CH3:31])=[CH:24][CH:23]=4)=[CH:20][N:21]=3)[CH2:13]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[CH3:33][C:34]([O:37][C:38]([NH:40][C:41](=[N:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[NH:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=1)=[O:39])([CH3:36])[CH3:35]>>[CH3:59][C:56]([O:55][C:53]([NH:52][C:41](=[N:40][C:38]([O:37][C:34]([CH3:36])([CH3:35])[CH3:33])=[O:39])[NH:42][C:43]1[CH:51]=[CH:50][C:46]([C:47]([N:15]2[CH2:16][C@H:12]([CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH2:13][C@@H:14]2[C:17]2[NH:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:32])[O:30][CH3:31])=[CH:26][CH:27]=3)=[CH:20][N:21]=2)=[O:48])=[CH:45][CH:44]=1)=[O:54])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)O)cc1
Reactant: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)[nH]2)cc1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2cnc([C@H]3C[C@@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)c3ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3)[nH]2)cc1

Procedure:
The compound prepared in Example 66 was treated with the compound prepared in Example 10 following the procedure described in Example 8 to give the title compound as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:16])[CH:12]([CH3:15])[CH2:13][CH3:14].[Br:17]Br>C(O)(=O)C>[Br:17][C:12]([CH3:15])([CH2:13][CH3:14])[C:11]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([Cl:8])[C:2]=1[Cl:1])=[O:16]
Reactant: BrBr
Reactant: CCC(C)C(=O)c1ccc(OC)c(Cl)c1Cl
Solvent: CC(=O)O
Product: CCC(C)(Br)C(=O)c1ccc(OC)c(Cl)c1Cl

Procedure:
By following the procedure described in Example 5, Step B, using as the reactants 2',3'-dichloro-4'-methoxy-2-methylbutyrophenone (26 g., 0.10 mole), acetic acid (75 ml.) and bromine (16 g., 0.10 mole), there is obtained 2-bromo-2-methyl-2',3'-dichloro-4'-methoxybutyrophenone.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(=O)(O)[O-].[Na+:26].O>C1C=CC=CC=1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([O-:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[Na+:26]
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C(=O)[O-])c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
0.278 g. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)-propionic acid is added to a solution of 0.084 g. of sodium bicarbonate in 2 ml. of water. About 20 ml. of benzene is added and the mixture evaporated to dryness. This process is repeated several times, and the residue is recrystallized from methanol/ether to afford sodium 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate (m.p. 145°-148° C). By employing 0.327 g. of potassium bicarbonate in place of the sodium bicarbonate above, there is obtained potassium 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2yl)propionate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1cc([N+](=O)[O-])cc2cc[nH]c12
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cc2cc[nH]c12
Yield: 55 %

Procedure:
A solution of 7-methyl-5-nitroindole (0.35 g, 2.0 mmol) and 10% Pd/C (50 mg) in 20 mL of MeOH was stirred under H2. The reaction mixture was filtered and concentrated in vacuo, yielding an oil (0.16 g, 1.1 mmol, 41%), which was characterized by NMR and subjected to the following reaction without further purification.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([CH:30]([CH3:32])[CH3:31])=[C:27]([SH:29])[CH:28]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:29][C:27]1[CH:28]=[C:23]([CH3:22])[CH:24]=[CH:25][C:26]=1[CH:30]([CH3:32])[CH3:31]
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: Cc1ccc(C(C)C)c(S)c1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(C(C)C)c(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.1 mmol of 5-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 183°-184° C.). 1H NMR (DMSO-d6) δ1.15 (d, 6H), 1.85 (s, 3H), 3.22 (m, 1H), 3.80 (bs, 2H), 5.88 (bs, 1H), 6.77 (d, 1H), 7.03 (d, 1H), 7.32-7.47 (m, 10H).
Reaction SMILES: [Cl:1][CH2:2][S:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)=[O:4].ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[Cl:1][CH2:2][S:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:16])=[CH:11][CH:12]=2)[N:7]([CH3:17])[CH:6]=1)(=[O:23])=[O:4]
Reactant: Cn1cc(S(=O)CCl)c(=O)c2ccc(F)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc(S(=O)(=O)CCl)c(=O)c2ccc(F)cc21
Yield: 77.6 %

Procedure:
6.33 g (0.0232 mole) of monochloroflosequinan (4) and 225 ml of methylene dichloride were placed in a 500 ml round bottom flask and stirred. Into this mixture a 5.98 g of 77% pure m-chloroperoxybenzoic acid (8) was added in four equal portions in 15 minute intervals and the mixture was stirred for an additional 30 minutes to complete oxidation. The reaction mixture was then concentrated to a final volume of 100 ml and the crystals which formed were filtered off and washed with two 10 ml portions of methylene dichloride. After high vacuum drying 5.2 g (77.6% yield) of white crystalline 3-chloromethylsulfonyl-7-fluoro-1-methyl-4-quinolone (9) were collected. The product was 99+% pure (by 1H NMR). 1H NMR, CDCl3, δ=8.52 dd, 1H, J=6.3 & 9.0 Hz, H at C5; 8.41 s, 1H, H at C2; 7.20 dd, 1H, J=2.1 & 9.6 Hz, H at C8; 7.32-7.26 m, 1H, H at C6; 5.03 s, 2H, CH2; 3.94 s, 3H, N—CH3.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]#[N:18])[CH:12]=1)[Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[OH:1][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]#[N:18])[CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccnc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cc(CCO)ccn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.9 %

Procedure:
4-[2-(tert-Butyldimethylsiloxy)ethyl]pyridine-2-carbonitrile (6.5 g, 24.8 mmol) obtained in Step 3 was dissolved in THF (100 mL), then a TBAF-THF solution (1.00 mol/L, 49.6 mL, 49.6 mmol) was added thereto, followed by stirring at room temperature for 10 hours. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was concentrated under reduced pressure. The concentrate was diluted with ethyl acetate, water was added thereto, and the mixture was separated into organic layer and aqueous layer. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 4-(2-hydroxyethyl)pyridine-2-carbonitrile (2.53 g, yield 69%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>CCO>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([CH2:17][N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[CH:15][CH:16]=1
Reactant: CC(C)N1CCNCC1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)N1CCN(Cc2ccc(Cl)nc2)CC1
Temperature: 65 °C

Procedure:
Isopropylpiperazine (2.3 g, 17.94 mmol), 2-chloro-5-chloromethylpyridine (3.2 g, 19.73 mmol) and K2CO3 (26.91 g, 3.713 mmol) were mixed in EtOH (50 mL) a strongly exothermic reaction. The reaction was heated further for 12 hours at 65° C. The reaction mixture was filtered and evaporated. The crude product was used without any further purification.
Reaction SMILES: [NH:1]1[CH2:4][C:3](=[CH:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=2[Cl:16])[CH2:2]1.C(N(CC)CC)C.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH:33]=O)[CH:31]=2)[CH:26]=[CH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(Cl)Cl.C(Cl)Cl>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][N:1]3[CH2:4][C:3](=[CH:5][C:6]4[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=4[Cl:16])[CH2:2]3)[CH:31]=2)[CH:26]=[CH:25]1
Reactant: COC(=O)c1ccc(C=C2CNC2)c(Cl)c1
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(C=C2CN(Cc3ccc4cc[nH]c4c3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 112 %

Procedure:
A solution of the hydrochloride salt of methyl 4-(azetidin-3-ylidenemethyl)-3-chlorobenzoate (0.20 g, 0.73 mmol) in THF:DCM (2:1) (25 mL) was neutralized by addition of triethylamine (0.14 mL, 0.88 mmol). After stirring at room temperature for 20 mins, indole-6-carboxaldehyde (0.16 g, 1.00 mmol) and sodium triacetoxyborohydride (0.50 g, 2.37 mmol) were added and the reaction mixture was heated at 50° C. overnight. It was then diluted with DCM (50 mL) and washed with saturated sodium bicarbonate (3×25 mL) and brine (1×15 mL). The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to give the crude product which was purified by silica gel column chromatography using 10-40% EtOAc in hexanes as eluent. Fractions containing the pure product were pooled and evaporated to give 0.3 g of methyl 4-((1-((1H-indol-6-yl)methyl)azetidin-3-ylidene)methyl)-3-chlorobenzoate (0.30 g) as a colorless oil. ES+(M+H)+367
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[CH2:21]([N:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=1[C:34]([F:37])([F:36])[F:35])[CH2:24][CH3:25])[CH3:22]>C(Cl)Cl.CO>[CH2:21]([N:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:17](=[O:19])[CH2:16][C:13]2[CH:14]=[CH:15][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:11][C:12]=2[CH3:20])=[CH:29][C:28]=1[C:34]([F:35])([F:36])[F:37])[CH2:24][CH3:25])[CH3:22]
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Reactant: CCN(CC)Cc1ccc(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)Cc1ccc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2C)cc1C(F)(F)F

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid and 4-diethylaminomethyl-3-trifluoromethyl-phenylamine (disclosed in WO2005/051366). Title compound: ES-MS: 496.0 [M+H]+; tR=3.31 min (System 1); Rf=0.43 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[CH:9]([CH2:10][CH:11]=1)[CH:8]1[CH2:12][CH:5]2[CH2:6][CH2:7]1.[NH4+].[OH-].C(O[C:19](=[O:21])[CH3:20])(=O)C>[Zn+2].[Br-].[Br-]>[CH3:1][C:2]1[CH:11]([C:19](=[O:21])[CH3:20])[CH2:10][CH:9]2[CH:4]([CH:3]=1)[CH:5]1[CH2:12][CH:8]2[CH2:7][CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1=CCC2C3CCC(C3)C2C1
Agent: [Br-]
Agent: [NH4+]
Agent: [OH-]
Product: CC(=O)C1CC2C3CCC(C3)C2C=C1C

Procedure:
ZnBr2 (3.0 g, 13.4 mmol) was added to a solution of acetic anhydride (30 mL) and 4-methyl-tricyclo[6.2.1.0(2,7)]undec-4-ene (10.0 g, 62 mmol) and then heated under reflux. After 2 hours at reflux the mixture was cooled then poured into dilute NH4OH (6%) and extracted with diethyl ether. The organic phase was washed with saturated NaHCO3, then brine, dried over Na2SO4, filtered and the solvents removed in vacuo. The crude ketone (9.3 g orange oil) was further purified by bulb to bulb distillation 0.1 mbar at 120° C. gave the desired ketone, 5.4 g as a mixture of isomers (7:6:16:21:16).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[N:5][C:6]([N:12]2[CH2:15][CH:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[CH2:13]2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].Cl.[NH2:30][C:31]1([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)[CH2:33][CH2:32]1>>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[N:5][C:6]([N:12]2[CH2:15][CH:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]=3)[CH2:13]2)=[C:7]([CH:11]=1)[C:8]([NH:30][C:31]1([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:9]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(C(F)(F)F)n2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4cccc(C(F)(F)F)n4)C3)CC2)cc1
Yield: 68.4 %

Procedure:
The title compound (D181) (75 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-(trifluoromethyl)-2-(3-((6-(trifluoromethyl)pyridin-2-yl)oxy)azetidin-1-yl)nicotinic acid (D130) (77 mg, 0.189 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (43.04 mg, 0.189 mmol).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CN(C=O)C.[Br:16][CH2:17][C:18](Br)=[O:19]>O1CCOCC1>[Br:16][CH2:17][C:18]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:19]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
A solution of anthranilic acid (50 g, 364.6 mmol) in anhyd DMF (125 mL) and dioxane (125 mL) in a 1 L Morton flask equipped with a mechanical stirrer and a constant addition funnel was cooled with an ice-bath to 0° C. Freshly distilled bromoacetyl bromide (73.6 g, 31.77 mL, 364.6 mmol) was added dropwise keeping the internal temperature between 0-1.5° C. over a 2.5 hour period. After addition of the bromoacetyl bromide was completed, the ice-bath was removed and stirring at rt was continued for 5 h. The reaction mixture was cooled in an ice-bath and slowly diluted with water (300 mL). A white precipitate formed, which was filtered, washed sequentially with 5% HBr solution (500 mL) and water (500 mL), and then dried in a vacuum desiccator. Further drying in a vacuum oven at 60° C. afforded 82.61 g (87.8%) of the title compound as a white powder, mp 164.6-167.6° C. [lit 165.5-172° C. (Hoffman LaRoche U.S. Pat. No. 3,244,698)]; 1H NMR (DMSO-d6) δ 13.7 (bs, 1H), 11.60 (s, 1H), 8.44 (d, J=8.0, 1H), 8.00 (dd, J=8.0, J=1.6, 1H), 7.62 (dt, J=8.0, J=1.6, 1H), 7.21 (t, J=8.0, 1H); 4.26 (s, 2H); 13C NMR (DMSO-d6) δ 169.20, 165.05, 139.95, 134.08, 131.13, 123.46, 120.02, 117.09, 30.67; MS (EI, m/z) 256.9 (M+), 258.9 (M+ 2+).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C:25]1([CH3:31])[O:29][C:28](=[O:30])[NH:27][CH2:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:27]4[CH2:26][C:25]([CH3:31])([CH3:24])[O:29][C:28]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Reactant: CC1(C)CNC(=O)O1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)nn3)CC2)c(C)c1
Yield: 43.7 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 230 and 5,5-dimethyloxazolidin-2-one (63 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (81 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:30])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([OH:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:29])[CH:17]=1>>[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:30])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([O:28][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:29])[CH:17]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: CCOC(=O)COc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from ethyl 2-bromoacetate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, CDCl3): δ 8.61 (s, 2H), 7.43 (d, 1H), 6.98 (d, 1H), 6.60 (s, 1H), 5.12 (s, 1H), 4.84 (s, 2H), 4.28 (q, 2H), 3.99 (s, 3H), 1.31 (t, 3H); MS (ESI): 438.9.