Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].[ClH:32]>ClCCl.C(OCC)C>[ClH:32].[ClH:32].[Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3cccc(Br)c3)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCNCC2)cc1NCc1cccc(Br)c1
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of t-butyl 4-(3-(3-bromobenzylamino)-4-nitrophenyl)piperazine-1-carboxylate (104 mg, 0.23 mmol) in dry dichloromethane (1.0 mL) was added a saturated solution of HCl in diethyl ether (15 mL). The reaction mixture was stirred for 4 hours. The solvent was evaporated and the precipitate was recrystallized from methanol (0.3 mL), dichloromethane (0.5 mL) and diethyl ether (5 mL). The product was collected by filtration and dried in vacuo to afford the title compound (35.0 mg, 39% yield after recrystallization). 1H NMR (400 MHz, CD3OD): δ 8.07 (d, 1H), 7.42 (s, 1H), 7.33 (m, 2H), 7.28 (m, 1H), 6.40 (d, 1H), 6.03 (s, 1H), 4.61 (s, 1H), 3.56 (m, 4H), 3.27 (m, 4H); MS (ESI) m/z: Calculated for C17H20ClN4O2: 347.13; Observed: 347.5 (M++1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CC(C)=O>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CNCc1ccccc1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-methylbenzylamine (50 g, 0.41 moles), acetone (100 ml) and potassium carbonate 57 g (0.41 moles) were mixed at room temperature and to the slurry obtained, 1-bromopentane 105.7 g (0.7 moles) was added dropwise at the room temperature. Reaction mixture was then stirred at room temperature for 18 hrs. The reaction mixture was filtered, washed with acetone and concentrated under vacuum to an oily residue. The residue was dissolved in 100 ml of MDC and washed with water (3×50 ml). Organic layer was dried over sodium sulphate and concentrated under vacuum to get N-methyl N-pentyl benzylamine as an oil. (Yield=77 g, 98%).
Reaction SMILES: [CH3:1][CH2:2][C:3](=[N:6][CH2:7][CH3:8])[CH2:4][CH3:5].[Cl:9][CH:10]([Cl:14])[C:11](Cl)=[O:12].C(OCC)C>C(N(CC)CC)C>[CH2:7]([N:6]([C:3](=[CH:4][CH3:5])[CH2:2][CH3:1])[C:11](=[O:12])[CH:10]([Cl:14])[Cl:9])[CH3:8]
Reactant: CCN=C(CC)CC
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC=C(CC)N(CC)C(=O)C(Cl)Cl

Procedure:
In a similar procedure as Example I, 5.9 g. (0.052 mole) N-3-pentylidene ethylamine was reacted with 4.8 ml. (0.05 mole) dichloroacetyl chloride in 100 ml. diethyl ether and 7.2 ml. triethylamine. There was obtained 7.7 g. of the title compound, an oil, nD30 = 1.4826.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C@H:8]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O)([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[Cl:52][CH2:53][CH2:54][NH:55][CH2:56][CH2:57][Cl:58].C(N(CC)CC)C>C(#N)C>[Cl:52][CH2:53][CH2:54][N:55]([CH2:56][CH2:57][Cl:58])[C:12]([C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[CH2:9][C@@H:8]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:27])=[O:14]
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1C(=O)O)NC(=O)OC(C)(C)C
Reactant: ClCCNCCCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1C(=O)N(CCCl)CCCl)NC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
Adapting a literature known protocol (Levi and Weed, U.S. Pat. No. 3,235,594), to a reaction mixture of 2-[(2R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxo-butyl]benzoic acid (23b) (759 mg, 2.0 mmol), N-hydroxysuccinimide (NHS, HOSu) (235 mg, 2.2 mmol) in anhydrous acetonitrile (MeCN) (10 mL) is added solid dicyclohexylcarbodiimide (DCC) (433 mg, 2.1 mmol) in small portions at about room temperature. The reaction mixture is stirred for about 12 hours and the precipitated dicyclohexylurea side product is filtered off using a Büchner funnel. The filtrate is treated with commercial di-(2-chloroethyl)amine hydrochloride (2-chloro-N-(2-chloroethyl)ethanamine hydrochloride; HN(CH2—CH2—Cl)2.HCl) (393 mg, 2.2 mmol) followed by neat triethylamine (Et3N, TEA) (321 μL, 233 mg, 2.3 mmol). The reaction mixture is stirred for about 12 hours at room temperature. The reaction is followed by TLC and/or LC/MS to completion. Acidic aqueous work-up and purification by silica gel column chromatography furnish the title compound tert-butyl(3R)-4-[2-[bis(2-chloroethyl)carbamoyl]phenyl]-3-(tert-butoxycarbonylamino)butanoate (23c).
Reaction SMILES: CO.[F:3][C:4]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([C:13]2[C:14]([CH:23]=[O:24])=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[C:6]([O:25][CH3:26])[CH:5]=1.S(=O)(=O)([OH:29])N.[O-]Cl=O.[Na+]>C1COCC1.O>[F:3][C:4]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([C:13]2[C:14]([C:23]([OH:29])=[O:24])=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[C:6]([O:25][CH3:26])[CH:5]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C(=O)O
Reaction time: 1.5 h

Procedure:
An 8.2 g quantity of a mixture of 4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl)methanol 16b and 4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde 56 [obtained, as a mixture, from a Suzuki coupling by methods described in WO2007/005572] was dissolved along with sulfamic acid (3.3 g) in a mixture of THF (50 mL) and water (50 mL). The solution was cooled in an ice bath. A solution of 80% NaClO2 (2.6 g) in water (50 mL) was added dropwise from an addition funnel. When addition was complete, the mixture was stirred at <8° C. for 1.5 hr. The mixture was quenched by addition of water and extracted with EtOAc. The organic phase was concentrated under reduced pressure to a volume of 50 mL and extracted with 2N KOH (20 mL×2). The organic phase was reserved. The aqueous solution was acidified to pH 2, and the solid filtered, to yield 300-400 mg of product 57 as a first crop. The reserved organic solution was concentrated under reduced pressure and the resulting crude product purified by chromatography on silica gel to give a total of 1.4-1.5 g of 57.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:53]1[CH:58]=[CH:57][C:56]([CH2:59]O)=[CH:55][CH:54]=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N:53]1[CH:58]=[CH:57][C:56]([CH2:59][O:23][C:22]([C:21]2[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]3[C:19]([C:20]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=3)=[O:24])=[CH:55][CH:54]=1
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: OCc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)OCc2ccncc2)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
To a mixture of 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg), triphenylphosphine (120 mg), 4-pyridinemethanol (51 mg) and THF (3.0 ml) was added diethyl azodicarboxylate toluene solution (40%, 210 μl) at 0° C. with stirring and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by medium pressure preparative LC (hexane/ethyl acetate=1/1-1/3) to give 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid pyridin-4-ylmethyl ester.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]([O:13][CH:14]([CH3:16])[CH3:15])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:2]3[C:3]([CH3:17])=[C:4]([O:13][CH:14]([CH3:16])[CH3:15])[C:5]4[O:9][CH:8]([CH3:10])[CH2:7][C:6]=4[C:11]=3[CH3:12])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Br)c(C)c(OC(C)C)c2c1CC(C)O2
Product: COc1ccc(N2CCN(c3c(C)c4c(c(OC(C)C)c3C)OC(C)C4)CC2)cc1
Yield: 33.6 %

Procedure:
By using 5-bromo-2,4,6-trimethyl-7-(1-methylethoxy)-2,3-dihydro-1-benzofuran (598 mg, 2.0 mmol) synthesized in Reference example 85 and 1-(4-methoxyphenyl)piperazine (768 mg, 4.0 mmol), the was carried out in the same manner as Example 21 to synthesize the title compound 276 mg (yield 34%). Melting point was 110 to 112° C. (ethanol-water).
Reaction SMILES: [F-].[Cs+].Cl[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][N:12]=2)[N:9]=1.[NH2:24][CH2:25][C:26]1([OH:33])[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>CS(C)=O>[CH3:32][N:29]1[CH2:30][CH2:31][C:26]([CH2:25][NH:24][C:4]2[CH:5]=[CH:6][C:7]3[N:8]([C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=4)=[CH:11][N:12]=3)[N:9]=2)([OH:33])[CH2:27][CH2:28]1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: CN1CCC(O)(CN)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: CN1CCC(O)(CNc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Temperature: 120 °C
Yield: 10.9 %

Procedure:
CsF (50 mg, 0.33 mmol) was added to the mixture of 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (150 mg, 0.48 mmol) and 4-(aminomethyl)-1-methylpiperidin-4-ol (150 mg, 1.04 mmol) in DMSO (1.5 mL). The mixture was heated to 120° C. over night and partitioned with EtOAc (10 mL) and water (10 mL). The organic layer was washed with brine (8 mL×3), dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by pre-HPLC to give the product 1-methyl-4-(((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)methyl)piperidin-4-ol (22 mg, 10%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]=[C:12]=S)[CH:6]=[CH:7][C:8]=1OC.[NH2:14][C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][C:31]=1[NH:32][CH2:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])[C:18]([N:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:19].N.[ClH:46].[O:47]1CCC[CH2:48]1>C(OCC)C>[ClH:46].[CH2:38]([N:36]([CH3:37])[CH2:35][CH2:34][CH2:33][N:32]1[C:31]2[CH:30]=[CH:29][C:17]([C:18]([N:20]([CH2:21][CH:22]([CH3:23])[CH3:24])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:19])=[CH:16][C:15]=2[N:14]=[C:12]1[NH:11][C:5]1[CH:6]=[C:7]([O:47][CH3:48])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccc(N=C=S)cc1OC
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)Cc2ccccc2)c(N)c1
Reactant: C1CCOC1
Agent: Cl
Agent: N
Solvent: CCOCC
Product: COc1cc(Nc2nc3cc(C(=O)N(CC(C)C)CC(C)C)ccc3n2CCCN(C)Cc2ccccc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,4 dimethoxyphenylisothiocyanate (35 mg, 1.2 eq) and N-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; charge 1.69 mmol/g, 355 mg, 4 eq) are added successively to a solution of 3-amino-4-({3-[benzyl(methyl)amino]propyl}amino)-N,N-diisobutylbenzamide (65 mg, 1 eq) in tetrahydrofuran (2 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and aminomethyl polystyrene resin (acquired from Novabiochem, 2 eq) is added. After stirring for 4 hours at ambient temperature, the mixture is filtered on frit and the filtrate is concentrated under reduced pressure at 40° C. The residue obtained is dissolved in ethyl ether and a 1N solution of HCl in ethyl ether is added dropwise in order to produce the expected compound in the form of the hydrochloride salt (81 mg, 92% yield).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)C#N)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(C)=[O:26]>>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[O:26])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(c1cccs1)C1CCN(Cc2ccccc2)CC1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: O=C(c1cccs1)C1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 35 %

Procedure:
To a stirred mixture of 29.6 parts of 1-(phenylmethyl)-α-(2-thienyl)-4-piperidineacetonitrile in 100 parts of dimethyl sulfoxide are added portionwise 4 parts of sodium hydride dispersion 60%. Upon completion, stirring is continued overnight. The reaction mixture is poured onto water. The precipitated product is sucked off and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 10 parts (35%) of [1-(phenylmethyl)-4-piperidinyl](2-thienyl)methanone; mp. 100.5° C.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16].C([O-])([O-])=O.[K+].[K+]>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.O.CN(C=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[N:14][C:9]=1[C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH:15]=[O:16]
Reactant: Clc1ncccn1
Reactant: O=Cc1cccc(B(O)O)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(-c2ncccn2)c1
Yield: 39.3 %

Procedure:
EX-603A) To a toluene (15 mL) solution of 2-chloropyrimidine (1.00 g, 8.7 mmol) was added 3-formylphenylboronic acid (1.42 g, 9.5 mmol) and DMF (8 mL). To the resulting solution was added K2CO3 (2.63 g, 19.0 mmol) and Pd(PPh3)4 (0.52 g, 0.45 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0.63 g (39%) of the desired 3-(2-pyrimidinyl)benzaldehyde product as a brown oil which solidified upon standing. MS: m/z=185.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[OH:12].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[O:12][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2ccncc2cc1Br
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccncc4cc3Br)c2cc1OC
Temperature: 140 °C
Reaction time: 7 h
Yield: 44.6 %

Procedure:
7-Bromo-6-hydroxyisoquinoline (11 mg), 4-chloro-6,7-dimethoxyquinoline (31 mg), and 4-dimethylaminopyridine (17 mg) were suspended in o-dichlorobenzene (2 ml), and the mixture was stirred at 140° C. for 7 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (9 mg, yield 48%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH3:8][C:9](O)([CH3:11])[CH3:10].[ClH:13]>>[ClH:13].[NH2:1][CH:2]([CH2:3][S:4][C:9]([CH3:11])([CH3:10])[CH3:8])[C:5]([OH:7])=[O:6]
Reactant: CC(C)(C)O
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Product: CC(C)(C)SCC(N)C(=O)O
Yield: 84 %

Procedure:
A solution of L-cysteine (30.3 g, 0.25 mol) and t-BuOH (62.2 mL, 0.65 mol) in 2N HCl (110 mL) was heated at 120° C. in a sealed flask for 48 h. After cooling, it was concentrated to dryness and triturated with acetone to give 14 as a white solid (45.0 g, 84%). 1H NMR (400 MHz, DMSO-d6) δ 8.58 (br s, 3H), 4.06 (t, 1H), 3.03 (m, 2H), 1.29 (s, 9H).
Reaction SMILES: N[CH:2]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:17])[C:11]=3[C:10]3=[N:18][O:19][C:20]([CH3:21])=[C:9]3[C:8]2=[O:22])[CH2:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:35][C:36]([OH:38])=O)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32].CC[N:41](CC)CC.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:12]1[C:11]2[C:10]3[C:9](=[C:20]([CH3:21])[O:19][N:18]=3)[C:8](=[O:22])[N:7]([C:4]3([C:29]4([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=[C:27]([CH2:35][C:36]([NH2:41])=[O:38])[CH2:28]4)[CH2:3][CH2:2][CH2:6][CH2:5]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCN(CC)CC
Reactant: Cc1onc2c1c(=O)n(C1CCC(N)C1)c1cccc(Cl)c21
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC1=C(OC)C(OC)(C2(n3c(=O)c4c(C)onc4c4c(Cl)cccc43)CCCC2)CC(CC(N)=O)=C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a stirred solution of racemic 5-(3-aminocyclopentyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (81 mg, 0.26 mmol) in CH2Cl2 (3 mL) was added 3,4,5-trimethoxy phenyl acetic acid (114 mg, 0.52 mmol), Et3N (0.1 mL, 0.50 mmol), HOBt (41 mg, 0.3 mmol),DMAP (catalytic amount) and EDCI (72 mg, 0.38 mmol). The reaction mixture was stirred at r.t. for 18 hours. The mixture was diluted with CH2Cl2, washed (brine), dried (Na2SO4), filtered and concentrated. Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave the racemic title compound (89 mg, 66%). Mass Spectrum (FIA) (m/z) 454.0 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:14])[C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[C:32]([Si:29]([CH3:31])([CH3:30])[O:14][C@@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11])([CH3:35])([CH3:34])[CH3:33]
Reactant: C[C@@H](C(=O)O)[C@@H](O)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C[C@@H](C(=O)O)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (2R,3R)-3-(4-chloro-phenyl)-3-hydroxy-2-methyl-propionic acid (0.76 g, 3.5 mmol) in DCM (20 mL) was cooled to 0° C. and treated with 2,6-lutidine (1.24 mL, 10.6 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (1.9 mL, 8.27 mmol). The reaction solution was stirred at 0° C. for 30 min then allowed to warm to rt and stir 1 h. The reaction was quenched with 1 M HCl and the mixture was extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to give the crude bis-silylated ester. The silyl ester was stirred in MeOH (10 mL) at rt and treated with 5% aq. K2CO3 (5 mL). The mixture was stirred 3 h, then was concentrated, diluted with 1 N HCl, and extracted with DCM (4×). The combined organic layers were dried (Na2SO4) and concentrated to give the crude acid, which was used without further purification (1.06 g, 91%). 1H NMR (400 MHz, CDCl3): 7.32-7.27 (m, 2H), 7.27-7.22 (m, 2H), 5.01 (d, J=5.3, 1H), 2.70 (dq, J=7.2, 5.6, 1H), 1.11 (d, J=6.8, 3H), 0.88 (s, 9H), 0.03 (s, 3H), −0.18 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12](=[O:45])[CH:13]([N:20]3[CH2:26][CH2:25][CH2:24][C:23]4[CH:27]=[C:28]([O:32][CH3:33])[C:29]([OH:31])=[CH:30][C:22]=4[CH:21]3[CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[CH2:47][CH:48]([F:50])[F:49]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12](=[O:45])[CH:13]([N:20]3[CH2:26][CH2:25][CH2:24][C:23]4[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:31][CH2:47][CH:48]([F:50])[F:49])=[CH:30][C:22]=4[CH:21]3[CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(C(C(=O)NCc1ccc3c(c1)OCO3)c1ccccc1)CCC2
Reactant: FC(F)CBr
Product: COc1ccc(CC2c3cc(OCC(F)F)c(OC)cc3CCCN2C(C(=O)NCc2ccc3c(c2)OCO3)c2ccccc2)cc1OC

Procedure:
prepared by reaction of N-benzo[1,3]dioxol-5-ylmethyl-2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-2-phenyl-acetamide with 2-bromo-1,1-difluoroethane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O/C=C/C(Cl)=O)C.OC1C=C[C:24]2[C:19](=[CH:20][CH:21]=CC=2)N=1.[Cl-].C(=O)/C=C/C>P(Cl)(Cl)(Cl)=O>[CH3:21][C:20]1[CH:19]=[CH:24][C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: Oc1ccc2ccccc2n1
Reactant: Nc1ccccc1
Agent: C/C=C/C=O
Agent: CCO/C=C/C(=O)Cl
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2ccccc2n1

Procedure:
Aniline 22 may be acylated with (E)-3-ethoxyacryloyl chloride and treatment of the resulting amide with sulfuric acid leads to hydroxyquinoline 29, which can be converted to the corresponding chloride 30 by heating in phosphorus oxychloride. Condensation of aniline 24 with crotonaldehyde in the presence of acid and an oxidant affords the 2-methylquinoline 31. The use of other aldehydes under similar conditions can lead to alternatively substituted quinolines. Oxidation of quinoline 31 with selenium dioxide can provide either aldehyde 32 or carboxylic acid 33, depending on the amount of oxidant used and the duration of the reaction. Reduction of aldehyde 32 with sodium borohydride provides the corresponding alcohol, and treatment of this with thionyl chloride may be used to give the chloride 34. Intermediates such as 30, 32, 33 and 34 may be converted to compounds of the present invention using a variety of known methodology. While the methodology shown in scheme 6 is exemplified using aniline 22, it is understood that it may be applied to a variety of aniline substrates, such as those described herein, in order to provide various quinoline intermediates.