Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=2)[N:15]=1.[C:28](=[O:30])=[O:29]>C1COCC1>[Cl:13][C:14]1[C:23]([C:28]([OH:30])=[O:29])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]([F:26])([F:25])[F:27])[CH:20]=2)[N:15]=1
Reactant: O=C=O
Reactant: FC(F)(F)c1ccc2nc(Cl)ccc2c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(C(F)(F)F)ccc2nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 1.54 ml (11.0 mmol) diisopropylamine in THF (38 ml) was cooled to 0° C. 6.9 ml (1.6 M in hexane, 11.0 mmol) n-BuLi were added dropwise at this temperature and then the mixture was stirred for 30 min at −78° C. Then a solution of 2.31 g (10.0 mmol) 2-chloro-6-(trifluoromethyl)quinoline in THF (12 ml) was added dropwise at −78° C. and the mixture was stirred for a further 30 min at −78° C. Then the reaction solution was poured onto finely dispersed dry ice. After heating to RT the mixture was concentrated to small volume under vacuum and the residue was taken up with water. It was made alkaline with a 1N aqueous NaOH solution and then washed with ether. Then it was acidified with a 10% aqueous hydrochloric acid and extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 198 mg (0.7 mmol, 72%) 2-chloro-6-(trifluoromethyl)quinoline-3-carboxylic acid were obtained as residue.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]3)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Oc1ccc2cc(Br)ccc2c1
Product: COc1ccc(-c2ccc3cc(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 6-bromo-2-naphthol (3.2 g, 18.8 mmol) with 3-fluoro-4-methoxyphenylboronic acid (3.5 g, 15.7 mmol) according to method A to yield 3.3 g (78%) of white solid: mp 174–176° C.; 1H NMR (DMDO-d6): δ 3.89 (3H, s), 7.11 (1H, dd, J=8.79 Hz, J=1.95 Hz), 7.13 (1H, s), 7.26 (1H, J=8.79 Hz), 7.57 (1H, d, J=8.79 Hz), 7.66 (1H, dd, J=13.18 Hz, J=1.95 Hz), 7.71 (1H, dd, J=8.79 Hz, J=1.46 Hz), 7.75 (1H d, J=8.79 Hz), 7.82 (1H, d, J=8.79 Hz), 8.07 (1H s), 9.81 (1H, s); MS (ESI) m/z 267 (M−H)−.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>O1CCCC1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
Isatoic anhydride (10.0 g) was suspended in tetrahydrofuran (150 ml) and treated dropwise with 4-methoxybenzylamine (9.61 ml). The reaction mixture was stirred at room temperature for 20 hours and then the solvent was distilled off under reduced pressure to give a crude crystal (17.8 g, about 100%) of the title compound. Recrystallization from ethyl acetate-isopropyl ether yielded a colorless crystal, melting point 104 to 105° C.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH:15]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=4)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=3)[CH3:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]([BH3-])#N.[Na+].C=O>C(#N)C>[CH3:35][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH:15]([C:17]2[CH:18]=[C:19]([C:27]3[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=2)[CH3:16])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: [BH3-]C#N
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(-c2ccc(C#N)cc2)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a suspension of (±)-3′-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (15 mg, 0.032 mmol) and sodium cyanoborohydride (10.2 mg, 0.16 mmol) in acetonitrile (1 mL) at 0° C. was added formalin (0.1 mL, 3.6 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and loaded onto an SCX cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 13 mg (84%) as a colorless film. 1H NMR (500 MHz, CDCl3) δ ppm 7.74 (m, 2H), 7.64 (s, 1H), 7.56 (m, 2H), 7.37 (s, 2H), 7.22-7.35 (m, 5H), 7.16 (m, 1H), 4.29 (q, J=6.4 Hz, 1H), 3.32 (d, J=8.9 Hz, 1H), 3.25 (d, J=8.9 Hz, 1H), 2.61 (m, 2H), 2.11-2.35 (m, 7H), 1.95-2.10 (m, 2H), 1.34 (m, 3H). Mass spec.: 479.30 (MH)+. Accurate mass spec.: m/z 479.2300 [MH]+, Δ=2.1 ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[N:24]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])[N:24]=2)=[CH:21][CH:22]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1nccc(-c2ccc(Cl)cc2)n1
Product: Cc1cn(-c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 112b) from 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 4-(4-chloro-phenyl)-pyrimidin-2-ylamine. The title compound was obtained as a colorless solid (Yield=35%). MS ISP (m/e): 387.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.31 (s, 1H), 8.69 (d, 1H), 8.47 (s, 1H), 8.25-8.15 (m, 3H), 7.97 (s, 1H), 7.55-7.50 (m, 3H), 7.57 (d, 1H), 7.29 (s, 1H), 2.20 (s, 3H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH3:46])[CH2:31][CH2:32][CH2:33][N:34]([S:42]([CH3:45])(=[O:44])=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1>>[CH3:46][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][N:34]([C:35]1[CH:40]=[CH:39][C:38]([NH:41]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:37][CH:36]=1)[S:42]([CH3:45])(=[O:44])=[O:43]
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CN(C)CCCN(c1ccc(N)cc1)S(C)(=O)=O
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCCN(C)C)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and N-(3-dimethylamino-propyl)-N-methylsulphonyl-p-phenylenediamine Rf value: 0.6 (silica gel, methylene chloride/ethanol/ammonia=5:2:0.01) C30H34N4O5S
Reaction SMILES: C([Li])CCC.[N:6]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=2)[CH2:9][CH2:8][CH2:7]1.CN(C)[CH:19]=[O:20]>O1CCCC1>[N:6]1([C:10]2[N:11]=[C:12]([CH:19]=[O:20])[CH:13]=[CH:14][CH:15]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: Brc1cccc(N2CCC2)n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(N2CCC2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
A solution of n-butyllithium in hexanes (0.3 g, 4.69 mmol) was added dropwise to a solution of 2-(azetidin-1-yl)-6-bromopyridine (0.5 g, 2.34 mmol) in dry tetrahydrofuran (20 mL) at −78° C. After stirring for 30 min at −78° C., N,N-dimethylformamide (0.34 g, 4.69 mmol) was added. The reaction mixture was stirred for 3 h at −78° C., then the reaction mixture was quenched with an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (60-120 mesh silica; 4-5% ethyl acetate in petroleum ether, twice) to afford 6-(azetidin-1-yl)picolinaldehyde (0.2 g, 43%). MS (ES+) (M+H) 163.1380; LCMS retention time: 5.59 minutes (Method X).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: c1cc(CN2CCCCC2)cc(OCCCNc2ccc3ccccc3n2)c1
Yield: 25.6 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.0 g) and 2-chloroquinoline (1.31 g) were fused at 140° C. for two hours. The oily residue was taken up in methanol/water (5:50), neutralised with solid potassium carbonate and extracted into chloroform. The chloroform extract was dried, evaporated under reduced pressure and subjected to medium pressure liquid chromatography (chloroform) to afford the title product as an oil (0.77 g). This was treated with maleic acid to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]quinoline dimaleate (0.4 g), m.p. 148°-150° C. (recrystallised from ethanol).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[O:8]C([S:11][C:3]=2[CH:2]=1)=O.[OH-].[Na+].[CH:14](I)([CH3:16])[CH3:15].Cl>>[CH:14]([S:11][C:3]1[CH:2]=[CH:1][C:6]([OH:7])=[CH:5][C:4]=1[OH:8])([CH3:16])[CH3:15]
Reactant: CC(C)I
Reactant: O=c1oc2cc(O)ccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Sc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.4 g of tioxolone (1 eq) are added to an aqueous sodium hydroxide solution (3.5 eq) (6.7 g of sodium hydroxide in 84 ml of water) at room temperature. After complete dissolution (30 minutes), 5.5 ml of isopropyl iodide are added. After stirring for two hours at room temperature, the mixture is acidified with hydrochloric acid and then extracted with ethyl ether. The organic phases are washed, dried and evaporated. The residue is recrystallized from an alcohol/water mixture to obtain pale-yellow crystals having a melting point of: 67° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16]([O:18]CCCC)=O)[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24].[CH2:25]([CH2:27][NH2:28])[OH:26]>C(#N)C>[OH:26][CH2:25][CH2:27][NH:28][C:16]([C@@H:14]1[O:13][C:12](=[O:23])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:24])[S:4][C:5]=3[CH:10]=2)[CH2:15]1)=[O:18]
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Reactant: NCCO
Solvent: CC#N
Product: Cn1c(=O)sc2cc(N3C[C@H](C(=O)NCCO)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of butyl (5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 29, Step 2, 300 mg, 0.856 mmol) in acetonitrile (3.4 mL) is treated with ethanolamine (103 μL, 1.71 mmol) and stirred at ambient temperature for 18 h. Solvent is removed under reduced pressure, and the crude product is triturated and filtered from hot ethyl acetate to give the title compound, mp 217–219° C.; MS (ESI+) for C14H15N3O5S m/z 338 (M+H)+; [α]25D−43 (c 0.99, DMSO).
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.CI.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][C:27]([S:33][CH3:34])=[N:28][CH:29]=2)[NH:24][C:23]1=[O:35].Cl>C(OCC)(=O)C.CN(C)C=O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][C:27]([S:33][CH3:34])=[N:28][CH:29]=2)[N:24]([CH3:2])[C:23]1=[O:35]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CSc1ncc2c(=O)n(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CSc1ncc2c(=O)n(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
211 μL of 1,8-diazabicyclo[5,4,0]undec-7-ene and 105 μL of methyl iodide were added to an N,N-dimethylformamide (5 mL) solution of 500 mg of 3-(2,6-dichlorophenyl)-7-(methylthio)pyrimido[4,5-d]pyrimidin-2,4(1H,3H)-dione obtained in Production Example 52, and stirred at room temperature for 1 hour. The reaction solution was added to ethyl acetate and aqueous 0.5 N hydrochloric acid solution with stirring, and the organic layer was separated. This was washed with saturated saline water, dried with anhydrous sodium sulfate, and the solvent was evaporated away. The crude product was solidified with methanol to obtain 420 mg of the entitled compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:14]([CH3:20])[C:15](I)=[C:16]([I:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[C:26](=[O:28])=[O:27]>C1COCC1>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:14]([CH3:20])[C:15]([C:26]([OH:28])=[O:27])=[C:16]([I:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(I)n2C)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1cccc(-c2nc(I)c(C(=O)O)n2C)c1
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of 7.27 g (14.7 mmol) of 2-(3-hexyl-phenyl)-4,5-diiodo-1-methyl-1H-imidazole in 150 ml of THF was cooled down to −75° C.; then, 11.95 ml (19.1 mmol) of an n-butyl lithium solution (1.6 molar in n-hexane) was added drop by drop below −70° C. 30 min later, the reaction mixture was treated with an excess of solid carbon dioxide and subsequently warmed up to RT. It was then poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 2.97 g (49%) of the title compound as light red oil. MS: 411.2 ([M-H]−).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.CN(OC)[C:17](=[O:20])[CH2:18][CH3:19]>O1CCCC1>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1)(=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)N(C)OC
Reactant: Oc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(O)c(F)c1
Temperature: -78 °C
Reaction time: 0.2 h

Procedure:
A mixture of 4-bromo-2-fluorophenol (1.0 g, 5.24 mmol) in tetrahydrofuran (15 mL) was chilled to -78° C. and butyllithium (4.6 mL, 11.5 mmol, 2.5 M solution) was added rapidly, dropwise. The reaction was stirred 12 min and N-methyl-N-methoxypropionamide (the compound of Preparation 9 , 0.735 g, 6.28 mmol in 1 mL of tetrahydrofuran with a 1 mL rinse) was added. The reaction was allowed to stir 5 min at -78° C. and then it was warmed to ambient temperature. A few drops of water were added; then the solvent was removed at reduced pressure. The residue was taken up in methylene chloride and washed with aqueous ammonium chloride and brine. The organic layer was dried and concentrated. The residue was flash chromatographed on silica gel (1×2.5 inches packed in hexane) with elution proceeding as follows: 10% ethyl acetate/hexane (250 mL), discarded forerun; 20% ethyl acetate/hexane (250 mL), 0.186 g of a yellow crystalline solid which had NMR identical to that of preparation 7.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=O)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[NH:17]([CH:6]([C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CCCC(=O)c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCCC(Nc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
(1)-(b) To 19.0 g of methyl 4-(4-chlorobenzoyl)butyrate was added 14.5 g of aniline, 0.6 g of p-toluenesulfonic acid monohydrate and 200 ml of toluene, and the mixture was refluxed with dehydration for 22.5 hours. The solvent was evaporated off under reduced pressure, and the residue was dissolved in 200 ml of methanol. A solution of 40 ml of an aqueous 20% sodium hydroxide solution and 3.0 g of sodium borohydride were added at 0° C., and the mixture was stirred at -3° to +5° C. for 1 hour. The reaction temperature was raised to room temperature, and then heated at 60° C. for 1 hour. After removal of solvent, the residue was diluted with 60 ml of water, adjusted to pH 6 to 7 with concentrated hydrochloric acid, extracted with ethyl acetate. The ethyl acetate extract was washed with diluted hydrochloric acid and a saturated aqueous sodium chloride solution, dried, and treated with activated charcoal. After removal of charcoal and the solvent, the residue was recrystallized from isopropyl ether to give 18.5 g of 5-anilino-5-(4-chlorophenyl)pentanoic acid as colorless prisms.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:14]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc2ncnc(Cl)c2c1
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: Cc1ccccc1
Product: O=Cc1ccc2ncnc(-c3ccccc3)c2c1

Procedure:
4-Chloro-quinazoline-6-carbaldehyde (50 mg, 0.26 mmol), Pd(PPh3)4 (13 mg, 0.01 mmol), phenylboronic acid (63 mg, 0.52 mmol) and sodium carbonate (sat. sol: 50 ul) were heated up in toluene at 100° C. for 12 h. After evaporation of the solvents, the residue was taken up in ethyl acetate and washed with brine twice. Organic phases were then concentrated and raw materiel was purified on silica gel using DCM/EtOH 95:5 as eluents to give 50 mgs (82%) of the desired cpd with a 85% purity.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C@@H:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:23])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C@@H:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[NH:23][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:37][CH:36]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(Cl)cc1)[C@@H]1CCC[C@H]1N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCCc1ccc(Cl)cc1)[C@@H]1CCC[C@H]1NC(=O)c1ccc(S(C)(=O)=O)cc1
Yield: 106.2 %

Procedure:
Using General Procedure C, (±)-trans-(2-aminocyclopentyl)-[3-(4-chloro-phenyl)propyl]carbamic acid tert-butyl ester (155 mg, 0.44 mmol) and 4-methanesulfonylbenzoic acid (105 mg, 0.53 mmol) were coupled in CH2Cl2 (3 mL) using HOBt (12 mg, 0.09 mmol) and DEC (106 mg, 0.66 mmol) at 0° C. for 2.5 hours to give 250 mg of (±)-trans-[3-(4-chlorophenyl)propyl]-[2-(4-methanesulfonylbenzoylamino)cyclopentyl]carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[CH3:19])[CH3:10].CC(N=NC(C#N)(C)C)(C#N)C.C(=O)(O)[O-].[Na+].[C:38]1([P:44]([C:51]2C=CC=CC=2)[C:45]2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br-:1].[CH2:9]([O:11][C:12]([C:13]1[C:14]([CH2:19][P+:44]([CH3:51])([CH3:45])[CH3:38])=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:20])[CH3:10]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccnc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccnc1C[P+](C)(C)C
Product: [Br-]
Temperature: 25 °C

Procedure:
A stirred mixture of N-bromosuccinimide (5.6 g, 31 mmol), 2-Methyl-nicotinic acid ethyl ester (4.1 g, 24 mmol), AIBN (0.05 g, 0.3 mmol) in 50 mL of carbon tetrachloride at 50° C. is irradiated with a 250 Watt heat lamp for 45 minutes. The reaction was cooled to room temperature and is poured into saturated sodium bicarbonate. The products are extracted into dichloromethane and the combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue which is immediately dissolved in 100 mL of toluene. To the solution is added triphenyl phosphine (8.1 g, 31 mmol) and the reaction is heated at reflux for 2 hours. The heat source is removed and filtration gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: C1CCNC1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N2CCCC2)cc1Cl

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to pyrolidine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyrrolidine-1-carbonyl)benzamide. MS (Q1) 441 (M)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=[O:17])C1.[OH-].[Na+]>O.FC(F)(F)C(O)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]2[CH:12]([O:17]2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1ccc(CN2CCC3OC3C2)cc1
Reaction time: 8 h
Yield: 3337.2 %

Procedure:
3.36 g of 1-benzyl-1,2,3,6-tetrahydropyridine (0.19 mmol) was dissolved in 35 mL of water containing 1.5 mL of trifluoroacetic acid (0.2 mmol). To that solution 5.87 g of NBS was added in small portions. After 4 hs reaction mixture was transferred to 50 mL of 20% NaOH solution and stirred overnight. On the morning reaction mixture was extracted with dichloromethane and combined organic fractions were dried over sodium sulfate and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate 3:1 as eluent. Evaporation of solvent produced 1.2 g of 3-benzyl-7-oxa-3-azabicyclo[4.1.0]heptane as colorless oil.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:29][C:30]1[CH:31]=[C:32]([C:36](=[N:38]O)[NH2:37])[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:36]2[N:38]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:37]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 34 mg (0.22 mmol, 1.1 eq.) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 71 mg (68% of theory)