Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].O.Cl>C(OCC)C>[Br:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[CH:8]([OH:9])[CH2:1][CH3:2]
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(F)cc1Br
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCC(O)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Add ethylmagnesium bromide (1 M in ether, 8.37 mL, 8.37 mmol) at 0° C. under nitrogen to a solution of 2-bromo-4-fluorobenzaldehyde (1 g, 4.93 mmol) in diethyl ether (15 mL). Stir the mixture for 1 h at RT. Add water slowly followed by adjusting the mixture to acidic conditions with 2 M HCl. Extract the product with chloroform/IPA (3/1). Dry over sodium sulfate. Concentrate the solution in vacuo to a yellow oil. Purify by column chromatography (30% ethyl acetate in hexane) to give the title compound as a colorless oil (1.1 g, 96%). 1H NMR (400 MHz, CD3Cl) δ 0.99 (t, J=7.2 Hz, 3H), 1.75 (m, 2H), 4.99 (m, 1H), 7.03 (m, 1H), 7.25 (m, 1H), 7.53 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][C:4]1[NH:15][C:7]2=[N:8][CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:6]2[CH:5]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CO>[CH3:16][N:2]([CH2:3][C:4]1[NH:15][C:7]2=[N:8][CH:9]=[C:10]([NH2:12])[CH:11]=[C:6]2[CH:5]=1)[CH3:1]
Reactant: CN(C)Cc1cc2cc([N+](=O)[O-])cnc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)Cc1cc2cc(N)cnc2[nH]1
Temperature: 75 °C
Yield: 54.6 %

Procedure:
SnCl2 dihydrate (0.11 g, 0.463 mmol) was added to a solution of N,N-dimethyl-1-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)methanamine (0.017 g, 0.077 mmol) in ethyl acetate (0.8 mL) and methanol (0.2 mL). The mixture was heated at 75° C. for 2 hours, after which saturated aqueous sodium bicarbonate was added. The salts were filtered off, and then the layers were separated. The organic layers were dried over sodium sulfate, filtered, and evaporated to afford 2-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (0.008 g, 50%).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:22])[C:10]2[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=2[NH:12][C:13](=[O:17])[C:14]=1[O:15]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH2:1]([C:8]1[C:9](=[O:22])[C:10]2[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=2[NH:12][C:13](=[O:17])[C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Cc2ccccc2)c(=O)c2ccccc2[nH]c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2c(=O)c(Cc2ccccc2)c1O
Temperature: 0 °C
Yield: 78.4 %

Procedure:
To a solution of 4-benzyl-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.45 g) in dichloromethane was added boron tribromide (4.6 mL). Upon completion of the reaction, the mixture was added to ice water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated. The resulting solid was recrystallized from toluene to give the title compound (0.336 g); mp 199°-200° C.; NMR: 3.97 (s,2); MS(EI): m/z=279(M). Analysis for C17H13NO3.0.1 H2O: Calculated: C, 72.64; H, 4.73; N, 4.98; Found: C, 72.65; H, 4.59; N, 4.94.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:17].ClC(Cl)C>C(O)(C)(C)C>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:17][C:16]1[CH:18]=[CH:19][C:20]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([CH3:13])[CH:15]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Cc1cc(N)ccc1Oc1ccccc1
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Cc1cc(Nc2ncnc3ccc(I)cc23)ccc1Oc1ccccc1
Temperature: 90 °C

Procedure:
The 4-chloro-6-iodo-quinazoline (5.0 g, 17.2 mmol) and the 3-methyl-4-phenoxyaniline (17.2 mmol) were mixed together in 1:1 dichloroethane and t-butanol (50 ml). The reaction mixture was heated at 90° C. for 4 hours whereupon a yellow precipitate was observed. The reaction was cooled down and the precipitate was collected and afforded (6-iodoquinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine. (8.0 g, 94%). M/z, 454. 1H NMR (CD3OD): δ: 9.12(s, 1H), 8.83(s, 1H), 8.39(d, 1H, J=8.8 Hz), 7.63(d, 1H, J=8.8 Hz), 7.55 (d, 1H, J=2.1 Hz), 7.35(dd,1H, J1=J2=8.5 Hz), 7.28(t, 2H, J=8.1 Hz,), 7.05 (t, J=8.5 Hz), 6.87(d, 1H, J=8.1 Hz), 3.81(s, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19]>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:19][CH2:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCCOCCOCCN1CCOCC1
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOCCOCCOCCN1CCOCC1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
To a solution of 989 mg of 2-[2-(2-morpholin-4-yl-ethoxy)-ethoxy]-ethanol in 2.8 mL of anhydrous THF was added 1.04 mg of sodium. After heating at 40° C. for 2 hours 15 minutes, 793 μL of tert-butyl acrylate were added. After heating for a further two hours at 40° C., the reaction mixture was left for 20 hours at room temperature and then concentrated under reduced pressure and purified by flash chromatography on silica (Merck SuperVarioPrep 70 g column, Si60 15-40 μm), using a gradient of 0 to 6% MeOH in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 1 g of tert-butyl 3-{2-[2-(2-morpholin-4-yl-ethoxy)-ethoxy]-ethoxy}-propanoate were obtained. LC/MS (E): tr (ELSD)=0.59 min; [M+H]+: m/z 348
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[OH-].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]>CC(C)=O>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[CH2:16][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc2c1cnn2Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a solution of 4-nitro-1H-indazole (0.200 g, 1.226 mmol) in acetone (3 mL) cooled to 0° C., was added KOH (0.103 g, 1.839 mmol). After 15 minutes at 0° C., 1-(bromomethyl)-2,4-difluorobenzene (0.173 mL, 1.349 mmol) was added. The mixture was allowed to stir at ambient temperature overnight, concentrated and the residue purified on silica gel (5-25% EtOAc in hexanes) to provide 1-(2,4-difluorobenzyl)-4-nitro-1H-indazole (0.142 g, 40% yield) as a pale yellow solid.
Reaction SMILES: ClCCl.[C:4]1([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(N(CC)CC)C>[C:4]1([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][N:11]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(C2NCCc3ccccc32)cc1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2ccccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 130 ml dichloromethane solution containing 6.28 g of 1-phenyl-1,2,3,4-tetrahydroisoquinoline and 3.34 g of triethylamine, 3.1 ml of ethyl chloroformate was added dropwise under ice-cooling, followed by stirring at room temperature overnight. The reaction solution was washed successively with water, 1N hydrochloric acid, water and brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, thereby 10.58 g of ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate was obtained as pale yellow oil.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4]1.[O-]CC.[Na+].C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C>CCO>[NH2:21][C:20]1[N:7]([CH:3]2[CH2:6][CH2:5][CH2:4]2)[N:8]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: CCOC=C(C#N)C#N
Reactant: NNC1CCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnn(C2CCC2)c1N
Temperature: 25 °C

Procedure:
A suspension of cyclobutylhydrazine dihydrochloride (11.63 g, 73.12 mmol) in EtOH (110 mL) was cooled in an ice bath and treated portion-wise with solid sodium ethoxide (9.95 g, 146 mmol) over 45 mins, while keeping the internal temp of the reaction mixture at approximately 0° C. The mixture was stirred in the ice bath for an additional hour, and then a solution of (ethoxymethylene)malononitrile (8.93 g, 73.1 mmol) in EtOH (70 mL) was added drop-wise over about 1.5 h, at a rate which maintained the internal temperature of the reaction mixture between 0° C. and 5° C. The reaction was then allowed to warm to room temp over about 18 h, after which it was heated at reflux for 1.5 h. After cooling to room temp, solvents were removed in vacuo, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted twice with additional EtOAc, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to provide crude C14, which was used in the next step without purification. Yield: 14.1 g, >100% mass recovery. 1H NMR (300 MHz, CDCl3) δ 1.9 (m, 2H), 2.4 (m, 2H), 2.65 (m, 2H), 4.25 (br s, 2H), 4.45 (m, 1H), 7.5 (s, 1H).
Reaction SMILES: [CH2:1]([S:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)(=[O:8])=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH2:1]([S:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:8])=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCS(=O)(=O)CCCCCCl
Reactant: C1CCNCC1
Product: CC(C)CCS(=O)(=O)CCCCCN1CCCCC1

Procedure:
Heat 5-chloropentyl isopentyl sulfone (770 mg, 3.2 mmoL) and piperidine (2 mL) at 125° C. for 1 hour. Partition between 5N sodium hydroxide and ethyl ether. Separate the organic phase and extract the aqueous phase with ethyl ether (2×25 mL). Combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo to yield 590 mg orange oil. Purify by silica gel chromatography (CHCl3 :MeOH:NH4OH/100:10:1) to yield 740 mg (80%) yellow oil which crystallizes. Purify further by silica gel chromatography (ethyl acetate) to yield 540 mg dark yellow oil. Purify further by silica gel chromatography (50% methanol/methylene chloride) to yield 80 mg of the title compound as a yellow oil.
Reaction SMILES: [S:1]1C2C=CC(C(C3C4C(=C(CSC)C=CC=4)NC=3)CCC#N)=CC=2[CH:3]=[CH:2]1.F[C:28]1[C:36]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])=[C:35]2[C:31]([C:32]([CH:42]([C:47]3[CH:52]=[CH:51][C:50](C(F)(F)F)=[CH:49][CH:48]=3)[CH2:43][CH2:44][C:45]#[N:46])=[CH:33][NH:34]2)=[CH:30][CH:29]=1>>[S:1]1[C:50]2[CH:51]=[CH:52][C:47]([CH:42]([C:32]3[C:31]4[C:35](=[C:36]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:28]=[CH:29][CH:30]=4)[NH:34][CH:33]=3)[CH2:43][CH2:44][C:45]#[N:46])=[CH:48][C:49]=2[CH:3]=[CH:2]1
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc4sccc4c3)c[nH]c12
Reactant: CS(=O)(=O)Cc1c(F)ccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12
Product: CS(=O)(=O)Cc1cccc2c(C(CCC#N)c3ccc4sccc4c3)c[nH]c12

Procedure:
The title compound was prepared starting from 284 mg (0.75 mmol) of the compound from Example 52 in analogy to the synthesis of the compound from Example 72. 409 mg (54% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>CS(C)=O>[CH3:1][C:2]1[C:7]2[C:8](=[O:10])[N:14]3[CH2:21][CH2:20][CH2:19][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cc1cccc2[nH]c(=O)oc(=O)c12
Solvent: CS(C)=O
Product: Cc1cccc2c1C(=O)N1CCC[C@H]1C(=O)N2

Procedure:
A solution of 13.6 g (0.0768 mol) of 6-methylisatoic acid anhydride and 8.8 g (0.0768 mol) of L-proline is heated at 110° C. for 1 hour in 75 ml of dimethyl sulphoxide. Subsequently, the mixture is evaporated to dryness in a high vacuum and the residue is recrystallised from ethyl acetate with the addition of active carbon. There is obtained (S)-1,2,3,11a-tetrahydro-6-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 212°-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH:13]C(=O)C3C=CC=CC=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cnn(-c2cccc(Cl)c2)c1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cnn(-c2cccc(Cl)c2)c1
Reaction time: 3 h
Yield: 94.1 %

Procedure:
N-(1-(3-chlorophenyl)-1H-pyrazol-4-yl)benzamide (1.34 g, 4.5 mmol) was heated with 68% sulfuric acid (24 mL) at 100° C. for 2 hours and then at 110° C. for 3 hours. The reaction was diluted with water (100 mL) and basified with sodium hydroxide solution. The aqueous mixture was extracted with ethyl acetate. The combined extracts were dried (sodium sulfate), filtered and evaporated. The solid were dried under high vacuum to provide the title compound (0.82 g; 94%) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:20])=[O:19]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:10][C:9](=[O:8])[CH:16]=[CH:15][C:14]2[CH:11]=[CH:12][CH:20]=[C:18]([O:19][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=2)[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Solvent: CCO
Product: O=C(C=Cc1cccc(OCc2ccccc2)c1)C=Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
The title compound was prepared as described in General Method 2 using 5.03 g (23.7 mmol) of 3-benzyloxy-benzaldehyde, 150 mL of EtOH, 0.65 mL (11.2 mmol) of acetone, and 0.31 g of Ba(OH)2.(H2O)8. The mixture was heated at room temperature overnight and filtered to give the title compound. 1H NMR (CDCl3) δ 5.08 (s, 4 H), 7.03-7.07 (m, 4 H), 7.22-7.47 (m, 16 H), 7.69 (d, 2 H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[S:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:25][N:26]=1>>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:21][C:22]2[S:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[CH:25][N:26]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: CN1CCN(c2cnc(N)s2)CC1
Product: CN1CCN(c2cnc(NC(=O)C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)s2)CC1

Procedure:
3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-[5-(4-methyl-piperazin-1-yl)-thiazol-2-yl]-propionamide was prepared from 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid and 2-amino-5-(4-methyl-piperazin-1-yl)thiazole as described in Example 1. 1H-NMR (CD3OD): δ 7.92 (d, 2H), 7.68 (d, 2H), 6.80 (s, 1H), 3.95 (t, 1H), 3.57 (m, 4H), 3.29 (m, 2H), 3.16 (m, 2H), 3.11 (s, 3H), 2.95 (s, 3H), 2.22-2.15 (m, 1H), 1.88-1.43 (m, 8H), 1.21-1.11 (m, 2H); HPLC-MS: m/z=477 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:9]([Cl:10])=[C:8]([C:11]2[NH:28][C:14]3[C:15]([O:26][CH3:27])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])=[CH:18][C:13]=3[N:12]=2)[N:7]([CH3:29])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1.C[O-].[K+:37]>CO>[C:1]([C:5]1[C:9]([Cl:10])=[C:8]([C:11]2[N-:28][C:14]3[C:15]([O:26][CH3:27])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])=[CH:18][C:13]=3[N:12]=2)[N:7]([CH3:29])[N:6]=1)([CH3:4])([CH3:2])[CH3:3].[K+:37]
Reactant: COc1nc(-c2ccccc2Cl)cc2nc(-c3c(Cl)c(C(C)(C)C)nn3C)[nH]c12
Agent: C[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(-c2ccccc2Cl)cc2nc(-c3c(Cl)c(C(C)(C)C)nn3C)[n-]c12

Procedure:
A 50 mL, single neck round bottom flask was charged with 2-(3-tert-butyl-4-chloro-1-methyl-1H-pyrazol-5-yl)-6-(2-chlorophenyl)-4-methoxy-3H-imidazo[4,5-c]pyridine (1.99 g, 4.27 mmol, prepared as described in Example 35 above), tetrahydrofuran (4.00 mL), and methanol (4.00 mL) to yield a solution. The solution was treated with potassium methoxide (˜25% w/w in methanol, 1.20 mL, 4.28 mmol). The resulting solution was then concentrated to yield potassium 2-(3-tert-butyl-4-chloro-1-methyl-1H-pyrazol-5-yl)-6-(2-chlorophenyl)-4-methoxyimidazo[4,5-c]pyridin-3-ide as a yellow foam. 1H NMR (DMSO-d6) δ: 7.71 (dd, J=7.6, 1.7 Hz, 1H), 7.50 (dd, J=7.9, 1.3 Hz, 1H), 7.39 (td, J=7.5, 1.2 Hz, 1H), 7.35 (s, 1H), 7.27-7.34 (m, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 1.39 (s, 9H)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)=[O:32])[CH2:18][CH2:17]2)[C:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCOC(=O)c1csc2nc(N)nc(N3CCNCC3)c12
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1csc2nc(N)nc(N3CCN(C(=O)Nc4ccc(OC)cc4)CC3)c12
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a solution of Example 20 (70 mg, 0.23 mmol) in dichloromethane (2 mL) and acetonitrile (2 mL) was added 4-methoxyphenyl isocyanate (31 μL, 0.24 mmol). The reaction mixture was stirred overnight. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually increasing from 1% to 3% methanol in dichloromethane), yielding the title compound (61 mg) as a white powder. 13C NMR δ (75 MHz, CD3OD) 171.65, 162.60, 160.54, 159.64, 155.32, 154.73, 133.60, 127.71, 124.13, 121.41 (2C), 113.30 (2C), 106.19, 60.79, 54.73, 47.93 (2C), 43.38 (2C), 13.73. MS (m/z) 457 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:38][CH2:39][C:40](=O)[CH3:41])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([NH:17][C@@H:18]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:19][N:20]([CH3:30])[C:21](=[O:29])[O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[BH3-]C#[N:45].[Na+]>CO>[NH2:45][CH:40]([CH3:41])[CH2:39][O:38][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([NH:17][C@@H:18]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:19][N:20]([CH3:30])[C:21](=[O:29])[O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])=[O:16])[CH2:10]1
Reactant: CC(=O)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(N)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 494.6 %

Procedure:
A mixture of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(3-chlorophenyl)(2-oxopropoxy)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate (0.0487 g, 0.078 mmol, 1.0 equiv), NaBH3CN (0.0296 g, 0.471 mmol, 6.0 equiv), NH4OAc (0.2550 g, 3.31 mmol, 42 equiv), and 4 A molecular sieves (0.0555 g) in MeOH (1 mL) was stirred at rt for 22 h. The reaction mixture was diluted with MeOH and filtered through filter agent, Celite® 545. The filtrate was evaporated under reduced pressure to afford 0.2405 g of crude 2-(trimethylsilyl)ethyl (2S)-2-((3R)-3-((1R)-(2-aminopropoxy)(3-chlorophenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate, which was used in the next step without further purification. MS ESI +ve m/z 625 (M+H).
Reaction SMILES: [CH3:1][Mg]Cl.[Br:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@H:8]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:9]=[CH:10]2>C(OCC)C>[Br:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@H:8]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[NH:9][C@H:10]2[CH3:1]
Reactant: C[Mg]Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2C=N1
Solvent: CCOCC
Product: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(Br)cccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 170.8 %

Procedure:
Add methylmagnesium chloride (0.66 L, 1.99 mol, 3M in THF) to a solution of (3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,4 dihydroisoquinoline (93.5 g, 0.24 mol) in diethyl ether (2.8 L) at −65° C. in an appropriate vessel. Then heat the reaction mixture to 20° C. over 2 hours and stir. After 16 hours, cool the mixture to 0° C. and quench the reaction with saturated aqueous ammonium chloride solution (2.5 L) and extract with ethyl acetate (2.5 L) and filter the mixture. Wash the combined organic extracts with brine (1 L), dry over anhydrous magnesium sulfate and concentrate under reduced pressure to give the crude title compound as an oil. Combine the oil with crude products from substantially same reactions run with 48 mmol and 229 mmol of [(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane and purify them by silica gel chromatography eluting with ethyl acetate in hexanes (gradient 5-65% ethyl acetate) to give the title compound (151 g, 0.41 mol). MS (m/z): 370.1 (M+1 (79Br)), 372.1 (M+1 (81Br)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.[C:18]([OH:28])(=[O:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]=[CH:23][C:22]4[CH:25]=[CH:26][C:19]([C:18]([OH:28])=[O:27])=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1
Reactant: Cc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(C=Cc2ccc(-c3cc4cc(Cl)ccc4o3)cc2)cc1

Procedure:
When 5-chloro-2-(p-tolyl)benzofuran was condensed with the anil derivative of terephthalaldehydic acid according to the procedure described in Example 1, there was obtained 5-chloro-2-[4-(4-carboxystyryl)phenyl]benzofuran which melted at 347°-348°C following recrystallization from trichlorobenzene. The wavelength of maximum excitation of this compound was 372 nm and the wavelength of maximum emission was 424 nm.
Reaction SMILES: [CH2:1]1[CH:5]2[C@@H:6]3C=C[C@H]([CH:4]2C=[CH:2]1)C3.[CH2:11]([O:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH2:12][CH2:13][CH3:14].C1(C=CC(O)=CC=1)O>>[CH2:11]([O:15][C:16]([CH:17]1[CH2:4][CH:5]2[CH2:6][CH:18]1[CH:2]=[CH:1]2)=[O:19])[CH2:12][CH2:13][CH3:14]
Reactant: C=CC(=O)OCCCC
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Agent: Oc1ccc(O)cc1
Product: CCCCOC(=O)C1CC2C=CC1C2
Temperature: 190 °C
Yield: 78 %

Procedure:
DCPD (dicyclopentadiene, Aldrich, 180 mL, 1.34 mol), butylacrylate (Junsei, 500 mL, 3.49 mol) and hydroquinone (2.7 g, 0.025 mol) were charged into a 2 L high-pressure autoclave, and the temperature was raised to 190° C. The resulting mixture was reacted for 5 hours with stirring at 300 rpm. After the reaction was completed, the reaction mixture was cooled and transferred to a distilling apparatus. The reaction mixture was distilled under a reduced pressure (1 torr) using a vacuum pump to yield the title compound at 80° C. (yield: 78%, exo/endo=55/45).