Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]([CH:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[NH:23][CH:24]=[CH:25][CH:26]=3)=[O:21])=[CH:15][C:14]=2[F:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH3:36][C:37]([O-])(C)C.[Na+].C(Br)C>C1COCC1>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[N:23]([CH2:36][CH3:37])[CH:24]=[CH:25][CH:26]=3)=[O:21])=[CH:15][C:14]=2[F:27])[CH2:11][CH2:12]1)=[O:5])[CH3:35]
Reactant: CC(C)(C)[O-]
Reactant: CCN(CC)C(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)c3ccc[nH]3)cc2F)CC1
Agent: [Na+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCN(CC)C(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)c3cccn3CC)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To the solution of 1H-pyrrole-2-carboxylic acid {4-[4-(diethylcarbamoyl-phenyl-methyl)-piperidin-1-yl]-3-fluoro-phenyl}-amide (40 mg, 0.084 mmol) in THF (5 mL), NaOtBu (48 mg, 0.50 mmol) and ethyl bromide (54 mg, 0.50 mmol) was added. The mixture was stirred at 25° C. for 1 h and purified by PTLC to provide the title compound (27 mg, 42%). MS: 505.4. 1H NMR (CDCl3): 7.65 (s, 1H), 7.46 (dd, J=4.0, 2.4, 1H), 7.28-7.21 (m, 5H), 7.10-7.16 (m, 1H), 6.90-6.82 (m, 2H), 6.69-6.67 (m, 1H), 6.12 (dd, J=3.9, 2.6, 1H), 4.49 (dd, J=14.3, 6.8, 2H), 3.50-3.12 (m, 7H), 2.71-2.63 (m, 1H), 2.53-2.46 (m, 1H), 2.31-2.21 (m, 1H), 2.08-2.00 (m, 1H), 1.50-1.21 (m, 6H), 1.15-1.04 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH:9][C:10]2[N:11]([CH3:21])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[N:3]=1.[C:22]([Zn])#[N:23]>CN(C=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>[CH3:21][N:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=[C:10]1[CH:9]=[CH:8][C:4]1[N:3]=[C:2]([C:22]#[N:23])[CH:7]=[CH:6][CH:5]=1
Reactant: N#C[Zn]
Reactant: Cn1cc(-c2ccccc2)nc1C=Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccccc2)nc1C=Cc1cccc(C#N)n1
Temperature: 130 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a solution of 2-bromo-6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)vinyl)pyridine (120 mg, 0.354 mmol) in dry DMF (3 mL) was added cyanozinc (97 mg, 1.062 mmol) and tetrakis(triphenylphosphine)palladium(0) (41 mg, 0.035 mmol). The mixture was stirred at 130° C. for 3 h in a microwave. The residue was then filtered. The filtrate was concentrated and purified by reverse phase column chromatography to yield 6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)vinyl)-picolinonitrile (100 mg) as a yellow solid. MS (ESI): m/z 287 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]1[C:14]1[CH:15]=[C:16]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:22]1[CH:21]=[CH:20][C:19]([N:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:18][C:17]2=1.[C:46]([CH2:48][C:49]([OH:51])=[O:50])#[N:47]>C(O)(=O)C.C([O-])(=O)C.[NH4+]>[C:46](/[C:48](=[CH:12]\[C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[C:3]([C:14]3[CH:15]=[C:16]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:22]3[CH:21]=[CH:20][C:19]([N:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[CH:18][C:17]4=3)=[CH:4][CH:5]=2)=[CH:8][CH:9]=1)/[C:49]([OH:51])=[O:50])#[N:47]
Reactant: N#CCC(=O)O
Reactant: CCCCCCn1c2ccc(-c3ccc(-c4ccc(C=O)s4)n3C)cc2c2cc(N(c3ccccc3)c3ccccc3)ccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCCCCn1c2ccc(-c3ccc(-c4ccc(/C=C(\C#N)C(=O)O)s4)n3C)cc2c2cc(N(c3ccccc3)c3ccccc3)ccc21

Procedure:
As shown in scheme 3, 3,6-dibromo-9-hexyl-9H-carbazole (31) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain N-methyl-2-(3-bromo-9-hexyl-9H-carbazol-6-yl)pyrrole (32). Then, in the presence of sodium tert-butoxide, Pd(dba)2, and tri-tert-butyl phosphine, N-methyl-2-(3-bromo-9-hexyl-9H-carbazol-6-yl)pyrrole (32) is reacted with diphenylamine to obtain N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrole (33). n-butyl lithium is reacted with N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrole (33), and then tributylstannylchloride is added thereto to obtain N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)-5-tributyl-stannylpyrrole (34). N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)-5-tributylstannylpyrrole (34) is reacted with 5-bromo-2-thiophene-carboxaldehyde by Stille coupling reaction to obtain 5-[N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (35). Finally, 5-[N-methyl-2-(3-diphenylamino-9-hexyl-9y-carbazol-6-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (35) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[5-(N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrol-5-yl)thiophen-2-yl]acrylic acid (36) is obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=3[N:7]=[CH:6]2)[CH2:3][CH2:2]1.Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23]>>[CH:1]1([CH2:4][N:5]2[C:13]3[C:12](=[O:14])[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=3[N:7]=[CH:6]2)[CH2:2][CH2:3]1
Reactant: CC(C)(O)CCCCCl
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CC1CC1
Product: Cn1c(=O)n(CCCCC(C)(C)O)c(=O)c2c1ncn2CC1CC1

Procedure:
The title compound was prepared by using 7-cyclopropylmethyl-3-methylxanthine and 1-chloro-5-hydroxy-5-methylhexane as starting materials.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:19]=1[CH:20]=[O:21].[Cl-].[NH4+]>O1CCCC1>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([CH:20]([OH:21])[C:19]2[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:18]=2[S:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[F:10])[CH2:3][CH2:4]1
Reactant: CN1CCC(Cl)CC1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Sc1ccccc1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C(O)c2cc(C(F)(F)F)ccc2Sc2ccccc2F)CC1
Yield: 100.2 %

Procedure:
A solution of the Grignard reagent is prepared by a reaction of 12.0 g 4-chloro-1-methylpiperidine with 2.3 g of magnesium in 70 ml of tetrahydrofuran and is treated for 10 minutes with a solution of 17.4 g 2-(2-fluorophenylthio)-5-trifluoromethylbenzaldehyde in 40 ml of tetrahydrofuran added dropwise. The mixture is refluxed for 4 hours and after cooling, decomposed with a 20% ammonium chloride solution and extracted with benzene. The extract is dried with potassium carbonate and evaporated. There are obtained 23.2 g (100%) crude oily α-(1-methyl-4-piperidyl)-2-(2-fluorophenylthio)-5-trifluoromethylbenzyl alcohol which is used in this state for the final reaction.
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[CH2:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][CH3:28])[CH2:22]1)[CH3:20]>C1C=CC=CC=1>[CH3:28][N:27]([CH:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[O:12][C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([CH2:19][CH3:20])[CH2:22]1
Reactant: CCN1CCCC(NC)C1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: c1ccccc1
Product: CCN1CCCC(N(C)C2c3ccccc3Oc3ccccc32)C1
Temperature: 25 °C

Procedure:
A solution of 3.7 g. (15.4 mmoles) of 9-acetoxyxanthene and 2.2 g. (15.5 mmoles) of 1-ethyl-3-methylaminopiperidine in 80 ml. of benzene was refluxed under nitrogen for 22.5 hours. It was then cooled to room temperature, washed with aqueous sodium bicarbonate solution, and dried over potassium carbonate. After removal of solvent in vacuo, the residue was dissolved in 25 ml. of petroleum ether and filtered from a small amount of crystals. The filtrate was then concentrated in vacuo and chromatographed on silica gel (ether solvent) to give N-methyl-N-(N-ethyl-3-piperidinyl)-9-xanthenylamine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11](C(F)(F)F)=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.[C:46](O)([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[CH:41]([C:38]1[N:37]=[CH:36][C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:44])[NH:24][C:9]4[CH:10]=[C:11]([C:48]([F:51])([F:50])[F:49])[C:12]([O:47][CH2:46][C:48]([F:51])([F:50])[F:49])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:40][CH:39]=1)([CH3:42])[CH3:43]
Reactant: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M160) (339 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (203 mg, 73%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][C:7](=[O:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O.Cl>CO>[OH:15][CH:7]([CH2:6][CH2:5][O:4][CH3:3])[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: COCCC(=O)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCC(O)C(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
At 0° C., 1.05 g (27.6 mmol) of sodium borohydride were added a little at a time to a solution of 5.20 g (27.6 mmol) of tert-butyl 4-methoxy-2-oxobutanoate in 68.5 ml of methanol. The reaction mixture was stirred for another 5 min, 5 ml of water were added and the pH was adjusted to 6 using aqueous hydrochloric acid (1N). Methanol was removed under reduced pressure at 30° C. and the aqueous phase that remained was extracted three times with 50 ml of diethyl ether. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure (25° C., 70 mbar). Yield: 4.48 g (77% of theory)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][NH2:14])=[O:12].C(N(CC)CC)C.[C:22](C1NC=CN=1)(C1NC=CN=1)=[O:23]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[O:12][C:22](=[O:23])[NH:14][N:13]=1
Reactant: NNC(=O)c1ccc2ccccc2c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2ccc3ccccc3c2)o1
Temperature: 0 °C
Reaction time: 17 h
Yield: 96.9 %

Procedure:
To a stirred mixture of naphthalene-2-carboxylic acid hydrazide (2.0 g, 10.7 mmol, prepared as described in example 1) and triethylamine (1.1 g, 10.7 mmol) in dry tetrahydrofuran (40 ml) was added carbonyl diimidazole (2.2 g, 13.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 17 h. The resulting reaction mixture was evaporated in vacuo and to the residue was added water (50 ml) and ethyl acetate (50 ml). The phases were separated and the organic phase was washed with saturated aqueous sodium chloride (2×25 ml), dried (MgSO4) and filtered and evaporated in vacuo affording 2.2 g of crude product which was recrystallised from a mixture of ethyl acetate and heptane 1:1 (60 ml) affording after drying in vacuo at 50° C. 1.2 g (52%) of the title compound as a solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:17][CH2:18][C:19]2[CH:33]=[CH:32][C:22]([O:23][C:24]([CH3:31])([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=2)=[N:14][CH:15]=1)(=O)[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C(O)(C)(C)C>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:42])([F:44])[F:43])=[CH:37][CH:36]=2)[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:23][C:24]([CH3:31])([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:32][CH:33]=2)=[N:14][CH:15]=1)([CH3:1])=[CH2:8]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(C(C)=O)cn2)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C=C(C)c1ccc(N(CCc2ccc(OC(C)(C)C(=O)OCC)cc2)Cc2ccc(C(F)(F)F)cc2)nc1
Reaction time: 0.17 h
Yield: 30 %

Procedure:
A solution of methyltriphenylphosphonium bromide (101 mg; 0.28 mmol) in 0.76 ml of THF was treated under nitrogen with potassium tert-butoxide (0.28 ml of a 1M solution in tert-butanol). After 10 minutes, ethyl 2-[4-(2-{(5-acetylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (100 mg; 0.19 mmol) was added. After 2 hours the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate and concentrated. Purification by flash chromatography using 10% ethyl acetate-hexane mixtures afforded ethyl 2-[4-(2-{(5-isopropenylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (30 mg; 30% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[N:16]1([CH2:21][C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:28][CH:27]=1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: Nc1ccc(CN2CCCC2)cc1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CN2CCCC2)cc1
Yield: 24.7 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (200 mg, 0.83 mmol) was reacted with 4-(pyrrolidin-1-ylmethyl)aniline (310 mg, 1.24 mmol) to afford the desired product (78 mg, 25%) as a brown-orange solid: 1H NMR (300 MHz, CDCl3) δ 11.06 (s, 1H), 9.03 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 3.85 (br s, 2H), 2.80 (br s, 4H), 2.60 (s, 3H), 1.92 (br s, 4H); ESI MS m/z 381 [M+H]+
Reaction SMILES: [CH:1]([Si:4]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[O:5][C@H:6]([CH3:11])[CH2:7][C:8](O)=[O:9])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>ClCCl>[CH:1]([Si:4]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[O:5][C@H:6]([CH3:11])[CH2:7][C:8]([Cl:21])=[O:9])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)[Si](O[C@H](C)CC(=O)O)(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](O[C@H](C)CC(=O)Cl)(C(C)C)C(C)C
Reaction time: 5 h

Procedure:
0.0475 mol (12.36 g ) of the product from stage 2 is dissolved in 200 ml of absolute dichloromethane and treated with stirring with 0.0523 mol (6.64 g) of oxalyl chloride. After 5 hours at room temperature, the mixture is concentrated under reduced pressure.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:8]=1[C:9]([NH:11][CH:12]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:13][CH2:14][OH:15])=O.C(N(CC)CC)C>O1CCCC1>[F:6][C:7]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:8]=1[C:9]1[O:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:11]=1
Reactant: O=C(NC(CCO)c1ccc(Cl)cc1)c1c(F)cccc1F
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1cccc(F)c1C1=NC(c2ccc(Cl)cc2)CCO1
Yield: 73 %

Procedure:
A mixture of 1.74 g (15.2 mmol) of methanesulfonyl chloride and 10 ml of tetrahydrofuran is added dropwise to a mixture of 4.5 g (13.8 mmol) of N-(2,6-difluorobenzoyl)-3-amino-3-(4-chlorophenyl)-1-propanol, 1.54 g (15.2 mmol) of triethylamine and 50 ml of tetrahydrofuran, while cooling with ice and stirring. The mixture is stirred at room temperature for 2 hours and filtered, and the filtrate is concentrated in vacuo. The residue is taken up in 50 ml of methanol, 2 g of potassium hydroxide are added and the mixture is stirred at 70° C. for 30 minutes. After customary working up, the crude product is purified by column chromatography on silica gel using the mobile phase n-hexane/ethyl acetate 8/2. 3.1 g (72.9%) of 2-(2,6-difluorophenyl)-4-(4-chlorophenyl)-5,6-dihydro-(4H)1,3-oxazine are obtained as a colorless oil.
Reaction SMILES: C(O)(=O)C.OO.[C:7]([C:10]1[C:11]([CH3:24])=[C:12]2[C:17](=[C:18]([Cl:20])[CH:19]=1)S[CH2:15][C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])(=[O:9])[CH3:8].[S:25]([O-:28])(O)=[O:26].[Na+]>O>[C:7]([C:10]1[C:11]([CH3:24])=[C:12]2[C:17](=[C:18]([Cl:20])[CH:19]=1)[S:25](=[O:28])(=[O:26])[CH2:22][C:14]([CH3:21])([CH3:15])[C:13]2=[O:23])(=[O:9])[CH3:8]
Reactant: O=S([O-])O
Reactant: CC(=O)c1cc(Cl)c2c(c1C)C(=O)C(C)(C)CS2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c2c(c1C)C(=O)C(C)(C)CS2(=O)=O
Reaction time: 2.5 h
Yield: 88 %

Procedure:
4 Milliliters of acetic acid and 2.12 g (18.71 mmol) of a 30 wt % hydrogen peroxide aqueous solution were added to 2.20 g (7.79 mmol) of 6-acetyl-8-chloro-3,3,5-trimethylthiochroman-4-one in a 100-ml round-bottomed flask, and the mixture was reached at 80° C. for 2.5 hours. The reaction mixture was diluted with about 50 ml of water, and a sodium hydrogensulfite aqueous solution was added to decompose excess hydrogen peroxide. Then, the reaction mixture was extracted with ethyl acetate. An organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2.16 g (yield 88%) of 6-acetyl-8-chloro-3,3,5-trimethylthiochroman-4-one-1,1-dioxide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O-:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2]
Reactant: ClCCCN1CCOCC1
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc([O-])c(C#N)cc34)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCN5CCOCC5)c(C#N)cc34)cc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
The sodium 6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate (100 mg) synthesized in Example 87 was dissolved in dimethylformamide (2.5 ml), and then potassium carbonate (65 mg, 0.4690 mmol) and 1-chloro-3-(morpholin-4-yl)propane (38 mg, 0.2345 mmol, J. Am. Chem. Soc. 67, 736 (1945)) were added and the mixture was heated and stirred at 80° C. for 2 hours. After allowing the mixture to stand and adding saturated saline, it was extracted with ethyl acetate, the extract was washed with saturated saline and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system). The obtained crystals were suspended in ethyl acetate, the suspension was diluted with diethyl ether, and the crystals were filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (120 mg) as light yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH:40]4[CH2:41][CH2:42][CH2:43][O:39]4)[CH2:50][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1COC(CN2CCNCC2)C1
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC2CCCO2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(tetrahydro-furan-2-ylmethyl)-piperazine (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C40H51N4O3Cl2 [(M+H)+] 705.3333, observed 705.3332.
Reaction SMILES: [NH2:1][CH:2]([CH:8]([F:10])[F:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:11](Cl)(=[O:13])[CH3:12].Cl>[OH-].[Na+].O1CCOCC1>[F:9][CH:8]([F:10])[CH:2]([NH:1][C:11](=[O:13])[CH3:12])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: NC(CCC(=O)O)C(F)F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)NC(CCC(=O)O)C(F)F

Procedure:
To a solution of 2 mmole of 4-amino-4-difluoromethylbutyric acid in 5 ml of 1 N sodium hydroxide at 0° C. are added simultaneously from two syringes 160 mg of acetyl chloride diluted in 1 ml of dioxane and 2 ml of 1 N sodium hydroxide. After 30 minutes at 0° C. the solution is acidified by the addition of 6 N hydrochloric acid, then extracted well with dichloromethane. The organic phase is dried and concentrated to afford 4-difluoromethyl-4-(1-oxoethylamino)butyric acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1.[N:32]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)C>[C:19]([NH:18][C:16]1[S:17][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([O:8][C:6]3[CH:5]=[C:4]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[N:3]=[C:2]([N:35]4[CH2:34][CH2:33][N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36]4)[N:7]=3)[C:14]=2[N:15]=1)(=[O:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2s1
Solvent: CCO
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(N4CCN(C(=O)OC(C)(C)C)CC4)n3)cccc2s1
Temperature: 125 °C

Procedure:
A mixture of N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide (186 mg, 0.4 mmol, Example 7(d)) and tert-butyl 1-piperazine-carboxylate (149 mg, 0.8 mmol, Aldrich) in ethanol (1 mL) was heated in a microwave synthesizer at 125° C. for 40 min. The reaction mixture was evaporated under reduced pressure and the residue was treated with sat. aqueous solution of NaHCO3 (10 mL), and extracted with EtOAc (2×30 mL). The combined EtOAc extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (20% EtOAc/hexane) to give the title compound as a solid. MS (ESI, pos. ion) m/z: 615 (M+1). M.p.: 211° C.