Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[F:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>CC(=O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[F:26]
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(O)c2C)c1F
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)-3-methyl-phenyl]methyl amino]-2-methyl-phenol (269 mg, 0.8 mmol, 1 eq), in 2-butanone (10 mL) was added Cs2CO3 (368 mg, 0.9 mmol, 1.5 eq) and isopropyl 2-bromoacetate (163.5 mg, 0.9 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 2 h, then filtered to remove the solids. The filtrate was evaporated in vacuo and the crude residue obtained purified by column chromatography (petroleum ether:EtOAc, 100:1 to 15:1) to give the title compound as a yellow oil (300 mg, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:22].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH:10]([CH3:22])[C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1C(=O)c2ccccc2N(C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone (0.10 g, 0.36 mmol) and iodomethane (0.50 mL, 8.0 mmol) in DMF (4 mL ) was added NaH (60% in mineral oil, 20 mg, 0.50 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction was quenched with water (5 mL) and was extracted with EtOAc (2×15 mL). Removal of solvent and chromatography of the crude residue on a silica gel column using a 10% mixture of EtOAc and hexane as solvents afforded 90 mg (86%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2,3-trimethyl-4-quinolinone as a colorless oil. The oil (90 mg, 0.32 mmol) was treated with NaBH4 (50 mg, 1.3 mmol) in methanol (5 mL ) for 1 h and the reaction mixture was concentrated. Filtration from the inorganic material through a silica gel pad provided a colorless oil, which was then subjected to hydrogenation over 10% Pd/C (10 mg) in EtOAc (5 mL ) under a hydrogen balloon for 15 h. Filtration from the catalyst through a Celite™ pad followed by removal of solvent gave 70 mg (82%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2,3-trimethylquinoline as a colorless oil. The crude oil (70 mg, 0.26 mmol) was treated with TFA (0.50 mL, 6.5 mmol) in CH2Cl2 for 30 min. and was quenched with 5% NaOH (6 mL). The mixture was extracted with EtOAc (2×15 mL) and was concentrated. Chromatography on silica gel using a 10% mixture of EtOAc and hexane afforded 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline as a colorless oil (40 mg, 89%). Data for 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.00-6.91 (m, 2H), 6.60 (t,J=7.3, 1H), 6.45 (d,J=7.3, 1H), 3.61 (br s, 1H), 2.74 (dd,J=16.6, 5.3, 1H), 2.47 (dd,J=16.6, 10.3, 1 H), 1.82 (m, 1H), 1.20 (s, 3H), 1.05 (s, 3H), 0.97 (d,J=7.2, 3H).
Reaction SMILES: C[O:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C.O>[N:18]1([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:9])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCNCC1
Reactant: COC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)CCCCN1CCCCC1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
5-Bromopentanoic acid methyl ester (1.22 g) was dissolved in acetonitrile (24.4 ml) and added with potassium carbonate (1.30 g), potassium iodide (0.104 g), and piperidine (0.928 ml) and the whole was stirred at 70° C. for 2.5 hours. The reaction solution was added with water and the whole was subjected to separation/extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was again dissolved in 18% hydrochloric acid (20 ml) and the whole was refluxed under heating for 3 hours. The reaction solution was concentrated under reduced pressure. Recrystallization was performed with acetone/acetic acid, thereby obtaining a hydrochloride (1.15 g) of the subject compound as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:13])=[O:12])=[CH:6][CH:5]=1)=[O:3].[Br:14]Br>O1CCOCC1.C(OCC)C>[Br:14][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[CH3:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Reactant: BrBr
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.5 %

Procedure:
To a suspension of 4-acetamidoacetophenone (Lancaster, 5.32 g, 0.03 mol) in 1,4-dioxane/diethyl ether (100 mL, 1:2, v/v) was added bromine (1.53 mL, 0.03 mol) via a syringe. The reaction mixture was stirred at room temperature for 4 hours until the color of the mixture was changed from brown to white. The solid was collected by filtration, washed with diethyl ether, and dried under high vacuum to give the title compound as a white solid (4.8 g).
Reaction SMILES: [N:1](=[CH:9][CH2:10]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]Cl.[C:12]([O:16][C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:10][CH2:9][N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:21][CH2:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: ClCC=NCCCCCCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCN2CCCCCC2)CC1

Procedure:
It is synthesized analogously to ester 4 starting from 2-(hexamethyleneimino)ethyl chloride (13.8 g) and ester 3 (12.4 g).
Reaction SMILES: [F:1][C:2](I)([F:25])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].S(S([O-])=O)([O-])=O.[Na+].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+].[CH3:42][S:43]SC>CN(C)C=O.O>[F:1][C:2]([S:43][CH3:42])([F:25])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10]
Reactant: CSSC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: O=P([O-])([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 20 %

Procedure:
Perfluorooctyl iodide (5.5 g), sodium dithionite (3 g), sodium hydrogen phosphate (3 g) and methyl disulphide (1 g) are stirred in dimethylformamide (10 cc) and water (5 cc) for 6 hours. After the usual treatment, methyl perfluorooctyl sulphide is obtained in 20% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[NH4+].[OH-]>C(O)C>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution under N2 of 3-nitro-4-chloropyridine (4.63 g, 29.2 mmol), prepared as described by Wright, G. C., J. Heterocyclic Chem. 1976, 13, 601, and Kruger, S. and Mann, F. G., J. Chem. Soc. 2 1955, 758, in absolute ethanol (100 mL) was added 4-aminobenzonitrile (3.45 g, 29.2 mmol) and the resulting purple-brown solution was stirred for 17 hours at ambient temperature, during which time it became a green-brown suspension. The reaction mixture was poured into cold 10% aqueous NH4OH and filtered. The solid was suspended in ethanol (75 mL) and heated for 10 min on the steam bath. The suspension was cooled to ambient temperature and filtered to give 4-(N-3-nitropyrid-4-ylamino)benzonitrile as a bright-yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18].N12CCCN=C1CCCCC2>O1CCOCC1>[C:10]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH:8]=[O:9])[CH2:18][CH2:17][C:16]#[N:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: C=CC#N
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCCC(C=O)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of diphenylacetaldehyde (11.0 mL) and acrylonitrile (4.5 mL) in dioxane (125 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10.5 mL). The solution was heated under reflux overnight and then concentrated in vacuo. The residue was purified by a silica gel column eluting with (95:5) hexane/ethyl acetate. The desired product (8.115 g) was obtained a colorless crystals, mp 80-82° C.: MS showed (M+NH4)+ @ 267; 1H-NMR (CDCl3, δ): 2.05-2.15 (m, 2H), 2.65-2.75 (m, 2H). 7.11-7.45 (m, 10 H), 9.80 (s, 1H); Anal. Calcd for C17HI5NO: C, 81.90; H, 6.60; N, 5.61. Found: C, 81.83; H, 6.64; N, 5.65.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][O:14][CH2:15][CH2:16]O>>[C:1]([O:12][CH2:16][CH2:15][O:14][CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: COCCO
Product: CCCCCCC/C=C/C(=O)OCCOC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and methyl cellosolve as starting materials to give the aimed compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.O.[NH2:30][NH2:31]>C(O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:30][N:31]=[C:19]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCc1ccncc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1c2c(CCc3ccncc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(pyridin-4-yl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (50 mg, 0.13 mmol, prepared in Synthetic Example 1) in ethanol (1 ml) was added hydrazine monohydrate (80%, 20 μl, 0.50 mmol, 3.7 eq.) and the resultant mixture was heated under reflux overnight. The liquid reaction mixture was cooled to room temperature, and then filtered to give precipitates which were dried to obtain 5-phenyl-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (40 mg, 81%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C(=O)(O)[O-].[Na+].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(OC)(C)C.O>[CH3:6][N:5]([CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])[C:21](=[O:22])[CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNCC(OC)OC
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(CN(C)C(=O)Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a 20 L Morton flask was added MTBE (5.52 L, 7 volumes) and (N-methyl-amino)-acetaldehyde dimethyl acetal (614 g, 5 mol) to form a solution at room temperature. A solution of sodium bicarbonate prepared by the addition of sodium bicarbonate (546 g, 6.5 mol) and water (6.31 L, 8 volume) was added to the Morton reaction flask. The mixture was cooled to less than 10° C and a MTBE (789 mL) solution of phenylacetyl chloride (789 g, 5 mol) was added dropwise to the cooled reaction mixture over a 1 h period. After addition, the reaction mixture was stirred at room temperature for 1 h. At this stage an HPLC analysis indicated that the reaction was completed. Extractive workup with MTBE (4 volumes), anhydrous magnesium sulfate drying followed by concentration on the rotary evaporator provided 1.187 kg (98%) of N-methyl-N-(2,2-dimethoxyethyl)phenylacetamide as a liquid, (M+H)+=237.9.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.Cl>CS(C)=O.O>[N:26]1[CH:27]=[CH:28][C:23]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)=[CH:24][CH:25]=1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cccc2cc(Oc3ccncc3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-hydroxy-1-napthoic acid (2 g, 10.6 mmol) in DMSO (5 mL), Cs2CO3 (14 g, 42.4 mmol) was added and stirred at RT 10 min. 4-Chloropyridine hydrochloride (1.9 g, 12.7 mmol) was added in one portion and the reaction mixture heated to 140° C. for 12 h. The reaction mixture was cooled to RT, diluted with water and made pH 5 using 6 N HCl, at which point a brown precipitate crashed out. The solid was filtered and rinsed with water and hexanes to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>C(#N)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:15](=[O:16])[CH2:14][C:13](=[O:17])[CH3:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Solvent: CC#N
Product: CC(=O)CC(=O)Nc1ccc2[nH]nc(Cl)c2c1
Temperature: 50 °C
Yield: 82.8 %

Procedure:
The product of Step (b) (0.4 g, 2.4 mmol) was dissolved in acetonitrile (1 ml). In a separate flask, diketene (0.18 ml, 2.4 mmol, stabilized with copper sulfate) was dissolved in acetonitrile (1 ml). The diketene solution was added to the amine suspension in three portions, the reaction mixture was sealed and heated to 50° C. for 18 hours. The solvent was evaporated to dryness and purified by silica gel chromatography eluting with 5% MeOH In CH2Cl2 to afford the title compound, (0.5 g, 83%); MS (ES+) m/e 252 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:10][NH2:11])[C:6]([F:9])=[N:7][CH:8]=1)C.Cl.FC1C=CC(C)=CN=1>>[F:9][C:6]1[C:5]([CH2:10][NH2:11])=[CH:4][C:3]([CH3:1])=[CH:8][N:7]=1
Reactant: CCc1cnc(F)c(CN)c1
Agent: Cc1ccc(F)nc1
Agent: Cl
Product: Cc1cnc(F)c(CN)c1

Procedure:
(2-fluoro-5-methylpyridin-3-yl)methanamine (2-e) was prepared by the same synthetic route as that of (2-g) but utilizing the commercially available 2-fluoro-5-methylpyridine (2-c) as a starting material; 1H NMR (500 MHz, DMSO-d6) δ 8.65 (bs, 3 H), 8.07 (d, 1 H, J=1.0 Hz), 8.01 (dd, 1 H, J=15.5, 3.0 Hz), 4.02 (s, 2 H), 2.30 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].C[O:16][C:17]([C:19]1[O:20][C:21]([CH2:24]Cl)=[CH:22][CH:23]=1)=[O:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:24][C:21]1[O:20][C:19]([C:17]([OH:18])=[O:16])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Product: O=C(O)c1ccc(COc2ccc(-c3ccccc3)cc2Cl)o1

Procedure:
5-(3-Chloro-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid was prepared using general procedure A from 2-chloro-4-phenylphenol (available from TCI America, Portland, Oreg.) and 5-chloromethylfuran-2-carboxylic acid methyl ester (available from Aldrich, Milwaukee, Wis., or from Maybridge plc, Tintagel, UK). Yield: 66 mg. Mass spectrum (ES) MH+=329.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1cn(S(=O)(=O)c2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 4-chlorophenylsulfonyl chloride (0.507 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-(4-chlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.575 g, 89%).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].BrC[C:16]1[N:17]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2.O>O1CCCC1>[C:26]1([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:25]=[C:16]([CH2:3][CH2:2][C:1]([OH:9])=[O:8])[N:17]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1cc2ccccc2c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1cc2ccccc2c(-c2ccccc2)n1
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A solution of diethyl malonate (17.9 g) in anhydrous tetrahydrofuran (100 cc) is added dropwise under nitrogen to sodium hydride (3.36 g, 80% strength in oil) and anhydrous tetrahydrofuran (80 cc). After 1 hour's stirring, a solution of 3-bromomethyl-1-phenylisoquinoline (8.3 g) in tetrahydrofuran (100 cc) is added dropwise, and the mixture is left with stirring at room temperature (approximately 20° C.) for 1 hour. Water (200 cc) is added and the aqueous phase extracted with ethyl acetate (3×200 cc). The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel with a cyclohexane/ethyl acetate (4:1 by volume) mixture as eluant. An oil (9.6 g) is recovered, taken up in concentrated hydrochloric acid (95 cc) and brought to boiling for 20 hours. After the mixture is cooled, water (200 cc) is added, the aqueous phase is washed with ethyl acetate (2×50 cc), potassium hydroxide solution is added until the pH is 5 and the mixture is extracted with chloroform (3×50 cc). The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. 1-Phenyl-3-isoquinolinepropanoic acid (2.9 g), m.p. 146° C., is obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.CS(OS(C)(=O)=O)(=O)=O.CCN(C(C)C)C(C)C.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:39]1[CH2:40][CH2:41][N:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=2)[CH2:37][CH2:38]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: OCc1cc2ccccc2s1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(N2CCN(Cc3cc4ccccc4s3)CC2)nc1

Procedure:
The product from Example 8A (300 mg 1.8 mmol), methane sulfonic anhydride (313 mg, 1.8 mmol), and DIEA (200 μL 5.4 mmol) were combined. After stirring, 1-(2-pyridinyl)piperazine (328 mg, 2.9 mmol) in 4 ml DCM was also combined and the mixture was processed as described in Example 8B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.57 (m, 4H) 3.50 (m, 4H) 3.84 (s, 2H) 6.63 (m, 2H) 6.81 (d, J=8.48 Hz, 1H) 7.32 (m, 2H) 7.52 (m, 2H) 7.77 (m, 1H) 7.90 (m, 1H). (ESI) m/z 310 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](C=O)[CH:5]=[CH:4][CH:3]=1.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12].C1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: COC(OC)OC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: COC(OC)c1cccc(Br)n1

Procedure:
The procedure in Example 6: step b was followed using 6-bromo-pyridine-2-carbaldehyde (600 mg, 3.23 mmol), trimethyl orthoformate (8 mL), and toluenesulfonic acid (100 mg) in MeOH (50 mL). Analogous aqueous workup yielded the product (743 mg) which was used without further purification.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[N:15]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[CH:14]=[N:13][C:12]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:28]([NH2:30])[CH3:29]>>[NH2:30][CH2:28][CH2:29][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[N:15]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[CH:14]=[N:13][C:12]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2ccc(-c3c(-c4ccccc4)ncn3C3CCCCC3)cc2s1
Reactant: CCN
Product: NCCc1nc2ccc(-c3c(-c4ccccc4)ncn3C3CCCCC3)cc2s1

Procedure:
Beginning with 2-chloro-6-(1-(cyclohexyl)-4-(phenyl)-imidazol-5-yl)-benzothiazole and ethyl amine, prepare the title compound essentially as described in General Procedure B. MS(ES+): m/z=403.1 (M+H)+
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][NH:5][C@@H:4]([C:8]([NH:10][C:11]2([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>>[F:24][C:2]1([F:1])[CH2:7][CH2:6][N:5]([CH2:31][C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:34][CH:33]=2)[C@@H:4]([C:8]([NH:10][C:11]2([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:12][CH2:13]2)=[O:9])[CH2:3]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)(F)CCN3)CC2)cc1
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(F)(F)CCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (D136) (30 mg) was prepared according to the general procedure described in Description 135 starting from (R)-methyl 4-(1-(4,4-difluoropiperidine-2-carboxamido)cyclopropyl)benzoate (D98) (47 mg) and 4-(trifluoromethyl)-benzylbromide (0.027 ml).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][OH:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][S:14]([O:12][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Br)c(CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the (2-bromo-5-nitrophenyl)methanol from Step A (0.33 g, 1.42 mmol) in methylene chloride (20 ml) at 0° C., methanesulfonyl chloride (0.13 ml, 1.70 mmol) and triethylamine (0.3 ml, 2.1 mmol) were added. The solution was stirred at 0° C. for 1 h. The reaction was diluted with methylene chloride (30 ml). The solution was washed with water, brine, and dried over sodium sulfate. The title compound was obtained by flash column chromatography using 10:90 EtOAc/hexane as the eluant. 1H NMR (CDCl3, 500 MHz) δ 8.40 (d, J=2.5 Hz, 1H), 8.17 (dd, J=8.5, 3.0 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 5.40 (s, 2H), 3.20 (s, 3H).