Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].N#N>CN(C=O)C.C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:23][C:22]3[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
To a solution of 5.0 g (1.0 eq, 28.6 mmol) 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine in 30 mL DMF under N2 at rt was added 1.37 g (1.2 eq, 34.3 mmol) of a 60% oil dispersion of NaH. After stirring for 5 minutes, 8.64 g (1.4 eq, 40.0 mmol) of p-nitrobenzyl bromide was added. The dark brown mixture was stirred for 2 hours under a blanket of N2 at rt. The mixture was diluted with 1 L CH2Cl2 and washed with 500 mL H2O and 500 mL saturated aqueous NaCl. The organic phase was dried over MgSO4 and concentrated to a yellow oil. The oil was flash chromatographed with 50% ethyl acetate/hexane. The product containing fractions were combined and concentrated to a yellow oil which crystallized on standing, yielding 6.81 g (76.8%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24])[C:20]([CH2:27][O:28][CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH:26][C:38](=[O:40])[CH3:39])([CH3:24])[CH3:25])[C:20]([CH2:27][O:28][CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
2-(7-Benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethylamine (1.88 g, 4.65 mmol), triethylamine (1.3 mL, 9.3 mmol), and dichloromethane (50 mL) were combined and cooled to 0° C. Acetyl chloride (0.36 mL, 5.11 mmol) was added and the reaction was stirred for 30 minutes. The cooling bath was removed and the reaction was stirred for an additional 3.5 hours. Water was added and the layers were separated. The organic fraction was sequentially washed with brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure to provide a tan solid. The solid was purified by flash column chromatography on silica gel (eluting with a gradient of 6-7.5% methanol in dichloromethane) to yield 1.71 g of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide as a cream colored solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][NH:14][C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[O:23][C:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[CH:25][N:26]=3)[CH:17]=2)=O)=[CH:6][CH:5]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:38].O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[S:38][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[O:23][C:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)=[CH:25][N:26]=4)[CH:17]=3)=[N:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)c1ccc(CC(=O)NNC(=O)c2cccc(-c3ncc(-c4ccc(OC)cc4)o3)c2)cc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(Cc2nnc(-c3cccc(-c4ncc(-c5ccc(OC)cc5)o4)c3)s2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a suspension of 0.25 g (0.51 mmol) 4-[2-(N′-{3-[5-(4-Methoxy-phenyl)-oxazol-2-yl]-benzoyl}-hydrazino)-2-oxo-ethyl]-benzoic acid methyl ester from Preparation 8 in 10 mL dry dioxane was added P2S5 in one portion. The resulting mixture was warmed to 50° C. for 1 hour before cooling to room temperature and adding about 20 mL water. Stirred 2 hours and then filtered off solid product. Triturated in hot MeOH and filtered. Dissolved in THF and filtered through a plug of flash silica gel with THF eluent. Concentration gave 0.18 g (73%) desired product. Used directly in the procedure of Example B3 without characterization.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].[CH:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:25])[C:22](N)=[O:23])=[CH:17][CH:16]=1.CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].Cl>>[CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH:9][C:22]([C@H:21]([NH2:25])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:20][CH:19]=3)=[O:23])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13]
Reactant: NC(=O)C(N)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1

Procedure:
The reaction is carried out at 25° C. and pH 7.5 in a fixed bed reactor. 10 ml of an aqueous solution of a mixture 0.2 M 7-ADCA and 0.2 M D-phenylglycinamide are passed through a column with 0.5 ml of the immobilized penicillin amidase. During the reaction, the pH is kept constant by adding HCl in an attached stirred reservoir container. Samples are taken and analyzed by HPLC as shown in example 5 at particular time intervals.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.Cl>CN(C)C=O>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:24]
Reactant: Clc1ccccc1CBr
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccccc2Cl)c1=O
Reaction time: 8 h
Yield: 44.3 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles) and 2-chlorobenzyl bromide (300 mg, 1.5 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (193 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s, 1 H), 10.13 (br. s, 1 H), 7.45-7.50 (m, 1 H), 7.26-7.32 (m, 2 H), 7.05-7.09 (m, 1 H), 5.05 (s, 2 H), 4.65 (t, J=11.87 Hz, 1 H), 4.13 (d, J=5.56 Hz, 2 H), 2.20-2.30 (m, 2 H), 1.79 (d, J=13.14 Hz, 2 H), 1.59-1.69 (m, 3 H), 1.28 (q, J=12.97 Hz, 2 H), 1.06-1.16 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:16]=1)#[CH:10]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: O=C(Nc1cc(C#Cc2ccnc(Cl)n2)ccc1F)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloropyrimidine (5.1 g, 34 mmol), anhydrous degassed THF (250 mL), dichlorobis(triphenylphosphine)-palladium(II) (595 mg, 0.85 mmol), copper(I) iodide (97 mg, 0.5 mmol), and TEA (9.5 mL, 68 mmol), and the resulting suspension was heated to 60° C. A solution of N-(5-ethynyl-2-fluorophenyl)-2,2,2-trifluoroacetamide (3.9 g, 17 mmol) in THF (100 mL) was added dropwise, and the resulting mixture stirred overnight at 60° C. After 16 h, the crude reaction mixture was filtered through celite, adsorbed to silica gel, and purified by column chromatography to afford the desired product (4.6 g, 78%) as an off white solid. 1H NMR (400 MHz, CDCl3): δ 8.65 (d, J=5.1 Hz, 1H), 8.58 (d, J=7.3 Hz, 1H), 7.49 (m, 1H), 7.41 (d, J=5.0 Hz, 1H), 7.24 (m, 1H). ES-LC/MS m/z ˜344 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[Cl:16]N1C(=O)CCC1=O.CN(C)C=O>O>[NH2:1][C:2]1[C:3]([Cl:16])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(Cl)c(N)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A mixture of ethyl 7-amino-1H-indole-2-carboxylate (2.30 g), N-chlorosuccinimide (1.40 g) and N,N-dimethylformamide (10 ml) was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. The obtained crystals were subjected to silica gel column chromatography to give the title compound (1.59 g, yield 63%) as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 217-218° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:12])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=O)[CH:17]=[N:18][CH:19]=1.OOS([O-])=O.[K+]>CN(C=O)C.O.C([O-])([O-])=O.[K+].[K+]>[F:12][C:4]1[C:5]([C:6]#[N:7])=[CH:8][C:9]2[N:10]([CH3:11])[C:20]([C:16]3[CH:17]=[N:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: O=Cc1cncc(F)c1
Reactant: CNc1cc(C#N)c(F)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2cncc(F)c2)nc2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-amino-2-fluoro-5-methylamino-benzonitrile (0.15 g, 0.00090 mol) and 5-Fluoro-pyridine-3-carbaldehyde (0.11 g, 0.0090 mol) in DMF (5 mL) and H2O (2 mL) was added OXONE® monopersulphate (0.19 g, 0.0012 mol). The reaction mixture was stirred at room temperature for 5 h, and was diluted with 10% K2CO3 solution to PH˜8-10 and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford the crude compound, which was purified by column chromatography to obtain title compound 5-fluoro-2-(5-fluoropyridin-3-yl)-1-methyl-1H-benzimidazole-6-carbonitrile (398) as a brown solid. C14H8F2N4; 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.83 (d, J=2.4 Hz, 1H), 8.47 (d, 5.4 Hz, 1H), 8.29 (d, J=9.6 Hz, 1H), 7.88 (d, J=9.6 Hz, 1H), 3.98 (s, 3H); MS (M+1): 271.1. HPLC purity: 99.44%.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1F)OC
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(F)cc1F)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 55 %

Procedure:
3-[(2,4-Difluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 60-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (55% yield); mp 141–149° C., dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.1 (3H, s, NCH3), 3.77 (3H, s, OCH3), 4.14 (2H, s, NCH2), 4.92 (2H, s, NCH2), 6.8–6.9 (2H, m, aromatics), 7.35–7.41 (1H, m, aromatic).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[CH2:33]([N:36]=[C:37]=[O:38])[CH2:34][CH3:35]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:37]([NH:36][CH2:33][CH2:34][CH3:35])=[O:38])[CH2:28][CH2:27]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Reactant: CCCN=C=O
Solvent: ClCCl
Product: CCCNC(=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 44 h
Yield: 112.9 %

Procedure:
1-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-[(4-piperidinyl)acetyl]piperazine (Preparative Example 10) (490 mg, 0.8 mmoles) was dissolved in anhydrous dichloromethane (5 ml) and n-propyl isocyanate (322.1 mg, 3.2 mmoles) was added. The mixture was stirred under argon at 25° C. for 44 h. The solution was chromatographed on silica gel using 2% (10% concentrated NH4OH in methanol)dichloromethane as the eluant to give 544.8 mg of the title compound (Yield: 95%).
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH3:10])=[O:9])[C:3](OCC)=O.[H-].[Na+].[CH2:13]1C[O:19][S:16](=[O:18])(=[O:17])[CH2:15][CH2:14]1.[OH-].[Na+].Cl>CN(C=O)C.O>[CH3:1][CH:2]([C:8](=[O:9])[CH3:10])[CH2:3][CH2:13][CH2:14][CH2:15][S:16]([OH:19])(=[O:18])=[O:17]
Reactant: O=S1(=O)CCCCO1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C(C)CCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
Ethyl 2-methylacetoacetate (50 g) in DMF (25 ml) was added to a suspension of sodium hydride (12.0 g of 60% NaH in mineral oil) in DMF (100 ml), dropwise with ice-bath cooling over 1 hour, (internal temperature 0-4° C.). This mixture was allowed to warm to ambient temperature for 45 mins with stirring before re-cooling. A solution of 1,4-butanesultone (45 g) in DMF (25 ml) was then added dropwise over 15 minutes. The final mixture was heated at 60° C. for 18 hours. The solvent was removed by rotary evaporation and the residue partitioned between water and diethyl ether. The aqueous layer was collected, washed with fresh diethyl ether and rotary evaporated to yield a sticky foam. This intermediate was dissolved in water (100 ml) and sodium hydroxide (17.8 g) added over 15 minutes with stirring. The mixture was heated at 90° C. for 18 hours. The cooled reaction mixture was adjusted to ˜pH2 by the addition of concentrated hydrochloric acid (˜40 ml). The solution was rotary evaporated and dried under vacuum. The yellow solid was washed with ethanol containing 2% hydrochloric acid (3×150 ml). The ethanolic solution was filtered, rotary evaporated and dried under vacuum to yield a yellow solid. Yield 70 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[H-].[Na+].Cl[CH2:20][C:21](=O)[CH3:22]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:10][C:11](=[O:16])[C:12]2[C:21]([CH3:22])=[CH:20][O:15][C:13]=2[CH2:14]1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2c(Cl)cccc2Cl)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1c(Cl)cccc1Cl)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2,6-dichlorophenyl)cyclohexane-1,3-dione (mp203-204° C.; 1.29 g) in DMF (20 ml) was added 60% sodium hydride (0.22 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 150° C. overnight (15 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2,6-dichlorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.42 g).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9].[C:12](O)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Zr+4].C(=O)([O-])[O-].O>[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)CCCCCCCO
Agent: [Zr+4]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CCCCCCCOC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
Isodecyl alcohol (791.4 grams; 5.-0 mol), benzoic acid (622.8 grams; 5.1 mol), zirconium carbonate (3.3 grams) and toluene (75 ml) were placed into a three-necked, round bottom flask equipped with stirrer, thermometer, 10" Vigeraux column, water trap and condenser. The reaction temperature was 184° C., washed first with water (25 mls) at 90°-95° C. for 30 minutes, then with sodium carbonate (15%) at 90°-95° C. for 30 minutes and twice with water (300 ml) at 90° C. for five minutes. After being washed, the product was dried at 125° C. and filtered to yield the desired product (1254.6 grams; 95.6% yield). It assayed 99.5% with the following properties:
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]([C:41]([NH:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[O:42])=[N:39][CH:40]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([NH:5][CH2:4][C:3]3[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:2]=3[C:35]3[CH:36]=[CH:37][C:38]([C:41]([NH:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[O:42])=[N:39][CH:40]=3)=[CH:7][CH:8]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)c1ccc(CNc2ccc(-c3ccc(Cl)cc3)cc2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
N-(2-bromo-4-(trifluoromethyl)benzyl)-4′-chloro-[1,1′-biphenyl]-4-amine (1.4 g, 3.1 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate, prepared as in step a, (1.6 g, 4.7 mmol), Pd(dppf)Cl2 (255 mg, 0.3 mmol), and K2CO3 (859 mg, 6.2 mmol) were dissolved in 1,4-dioxane (24 mL) and water (6 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)C.C([Li])CCC.[Cl:32][Si:33](Cl)([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CCCCCC>[Cl:32][Si:33]([CH:40]1[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1)([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:10]1[C:9]2[CH2:8][C:7]3[C:15](=[CH:16][CH:17]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)[C:14]=2[CH:13]=[CH:12][C:11]=1[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: Cl[Si](Cl)(C1CCCCC1)C1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1[Si](Cl)(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.8 %

Procedure:
A 300 ml two-necked flask equipped with a three-way cock, a dropping funnel and a magnetic stirrer, was thoroughly purged with nitrogen. Into the flask was introduced 2,7-di-tert-butylfluorene 3.01 g (10.81 mmol), and dissolved by addition of dehydrated diethyl ether 60 ml. With cooling in an ice bath, 1.56 mol/L n-hexane solution of n-butyllithium, 6.9 ml (11.0 mmol), was added to the solution, and the mixture was stirred in a nitrogen atmosphere at room temperature for 20 hours. Separately, a 500 ml three-necked flask equipped with a 100 ml dropping funnel, a three-way cock and a magnetic stirrer was thoroughly purged with nitrogen, and dehydrated n-hexane 120 ml and dichlorodicyclohexylsilane 2.6 ml (11.0 mmol) were introduced into the flask. With the flask cooled in a dry ice/methanol bath, the above-prepared solution was dropwise added over a period of 1 hour by means of the dropping funnel. While allowing the liquid temperature to rise gradually to room temperature, the contents were stirred for 3 days in a nitrogen atmosphere. The resulting slurry was filtered to remove solids, and the solvent of the filtrate was distilled away under reduced pressure to obtain 5.5 g of chlorodicyclohexyl(2,7-di-tert-butylfluorenyl)silane as a light yellow solid (11.0 mmol, 100% yield). The 1H NMR spectrum as measured with respect to the chlorodicyclohexyl(2,7-di-tert-butylfluorenyl)silane is given below:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH:24]([CH3:26])[CH3:25])[N:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[CH3:26][CH:24]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1)[CH3:25]
Reactant: CC(C)n1nc(-c2ccc(OCc3ccccc3)cn2)c2ncccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)n1nc(-c2ccc(O)cn2)c2ncccc21
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of 3-[5-(benzyloxy)pyridin-2-yl]-1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridine (219 mg) and 10% Pd—C (50% wet, 73.1 mg) in MeOH (3 mL) and AcOEt (3 mL) was hydrogenated under balloon pressure at room temperature overnight. The solid was filtrated and washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to give the title compound (140 mg).
Reaction SMILES: BrC1C(OC)=C(C(C[S:14]([C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)(=[O:16])=[O:15])=CC=1)C(OCC)=O.Br[CH2:27][C:28]1[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:32]([O:39][CH3:40])[C:31]([I:41])=[C:30]([O:42][CH3:43])[CH:29]=1>>[C:17]1([S:14]([CH2:27][C:28]2[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:32]([O:39][CH3:40])[C:31]([I:41])=[C:30]([O:42][CH3:43])[CH:29]=2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(CBr)cc(OC)c(I)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)cc(OC)c(I)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 85, starting from ethyl 6-bromomethyl-3-iodo-2,4-dimethoxybenzoate (Intermediate 202).