Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.COC1C=CC=CC=1[Li].[Cl:23][C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1>CCOCC.O1CCCC1>[Cl:23][C:24]1[N:25]=[C:26]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[O:7][CH3:8])[CH:27]=[C:28]([CH3:30])[N:29]=1
Reactant: COc1ccccc1
Reactant: Cc1ccnc(Cl)n1
Agent: [Li]CCCC
Agent: [Li]c1ccccc1OC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(C)nc(Cl)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Part A: Anisole (2.16 g), n-butyllithium (2.5 M in hexanes, 4.0 mL), and dry ether (4.0 mL) were stirred 18 h at room temperature. Ether (5 mL) and tetrahydrofuran (SmL) were added to make a 0.47 M solution of 2-methoxyphenyllithium (21.12 mL), of which 0.47 mL was added to 2-chloro-4-methylpyrimidine (0.71 g, prepared as described by Strekowski et al (J. Heterocylic Chem. 27, 1393 (1990)) dissolved in dry ether (37 mL) and stirred 30 minutes at -30° C. and 2 hours at 0° C. The reaction was quenched with acetic acid (515 μL), water (36 μL) and tetrahydrofuran (5 mL). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.31 g) dissolved in tetrahydrofuran (5 mL) was added to the reaction which was then stirred 20 minutes. 1N Sodium hydroxide (aq.) (10 mL) was added at 0° C. and the reaction was washed with iN sodium hydroxide (3×10 mL). The organic layer was filtered through silica gel and concentrated to dryness to give 2-chloro-6-methyl-4-(2-methoxyphenyl)pyrimidine (0.72 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[OH:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][O:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[N:4]=2)=[CH:9][CH:10]=1
Reactant: O=C(CO)c1ccccc1
Reactant: Fc1ccc(-c2nc(CCl)cs2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: O=C(COCc1csc(-c2ccc(F)cc2)n1)c1ccccc1
Yield: 74.1 %

Procedure:
11.2 g (0.05 mol) of 4-chloromethyl-2-(4-fluorophenyl) thiazole (see Example 4), 5.4 g (0.04 mol) of 2-hydroxyacetophenone, 7.5 g (0.055 mol) of potassium carbonate and 0.5 g of potassium iodide in 20 ml ethanol are refluxed for 24 hours. The mixture is filtered, the filtrate is concentrated, the residue is taken up in dichloromethane, the solution is extracted with dilute sodium hydroxide solution and then with water, and the organic phase is dried over MgSO4. Removal of the solvent by distillation under reduced pressure results in a solid residue which is washed with diisopropyl ether to give 9.7 g (59% yield) of 2-[2-(4-fluorophenyl)-4-thiazolylmethyloxy]acetophenone as yellowish crystals of melting point 104°-106° C.
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:13][C:12]([CH:14]=O)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:16]1C=CC=CC=1.Cl.NO>CCO>[N:1]1([C:7]([C:9]2[S:13][C:12]([C:14]#[N:16])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C(=O)N2CCCCC2)s1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: N#Cc1ccc(C(=O)N2CCCCC2)s1
Temperature: 145 °C
Yield: 64.9 %

Procedure:
A solution of 5-(Piperidine-1-carbonyl)-thiophene-2-carbaldehyde (Preparative Example 17, 2.23 g, 10 mmol) in EtOH (50 mL) was treated with pyridine (971 μL, 12 mmol, 1.2 eq) followed by hydroxylamine hydrochloride (833 mg, 12 mmol, 1.2 eq) and heated at reflux for 2 hr then evaporated in vacuo. The crude intermediate oxime was then dissolved in acetic anhydride and heated at 145° C. for 16 hr then evaporated in vacuo to a small volume which was partitioned between EtOAc (50 mL) and water (200 mL). The organic layer was further washed with a brine solution (50 mL), dried over MgSO4, filtered, evaporated in vacuo and the residue chromatographed on silica gel with EtOAc/hexanes (30 then 50%) as eluant to afford product as a yellow-tinted oil (1.43 g, 65%). 1H NMR (CDCl3) 1.65-1.76 (m, 6 H), 3.64 (br s, 4 H), 7.23 (d, J=4.0, 1 H), 7.56 (d, J=4.0, 1 H). 13C NMR 24.5, 26.2, 44.3 (br), 48.5 (br), 111.9, 113.7, 128.0, 137.0, 144.7, 161.3. LC/MS 5.09 min, [M+1]+ 221.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[C:19]2[CH2:24]Br)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=O.[NH3:26]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]3[C:22]([CH3:23])=[N:21][N:20]=[C:19]3[CH2:24][N:26]=[C:7]([C:9]3[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=3[F:16])[C:6]=2[CH:17]=1
Reactant: Cc1nnc(CBr)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Reactant: N
Solvent: CO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 10, 5-chloro-2',6'-difluoro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is reacted with a saturated solution of ammonia in methanol to give 8-chloro-1-methyl-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 126°-127° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:69])([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH:48]=1)\[C:13]([NH:15][CH:16]1[C:42](=[O:43])[N:18]2[C:19]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:20]([CH2:24]Cl)[CH2:21][S:22](=[O:23])[C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:70].[Na+].C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[C:1]([O:5][C:6]([C:8]([CH3:69])([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH:48]=1)\[C:13]([NH:15][CH:16]1[C:42](=[O:43])[N:18]2[C:19]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:20]([CH2:24][I:70])[CH2:21][S:22](=[O:23])[C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
The compound obtained in (A) was dissolved in 200 ml of acetone, and 3.38 g (22.5 mmol) of sodium iodide was added. The mixture was stirred at room temperature for 30 minutes. To the reaction solution, 600 ml of ethyl acetate and 200 ml of a 10% sodium thiosulfate aqueous solution were added for extraction. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by slica gel flush column chromatography (ethyl acetate/n-hexane=1/2), and concentrated under reduced pressure. Then, diisopropyl ether was added thereto, and 7.0 g (yield: 63.0%) of a powder of the above-identified compound was collected by filtration.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH3:22])[NH:14][CH:13]=[CH:12]2)C1C=CC=CC=1.[H][H].C(O)C>[Pd].C(Cl)Cl>[CH2:19]([O:18][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][C:9]=1[OH:8])[CH2:20][CH2:21][CH3:22]
Reactant: [H][H]
Reactant: CCCCOc1cc2[nH]ccc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CCCCOc1cc2[nH]ccc2cc1O
Yield: 54.5 %

Procedure:
5-Benzyloxy 6-butoxy indole (0.5 g, 0.0017 mole) is hydrogenated under 50 atmospheres of hydrogen in a reactor with 5 ml of absolute ethanol and 70 mg of 10% palladium on carbon for 2 hours. After filtration and evaporation of the solvent, the residue is purified by chromatography on silica 60 (eluent: CH2Cl2, to obtain 6-butoxy 5-hydroxy indole (0.19 g, beige powder, yield 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7].[CH:14]1([CH:20]=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C>C(O)C>[CH:14]1([CH:20]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=2[CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc(C(=O)NN)c1C
Reactant: O=CC1CCCCC1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cccc(C(=O)NN=CC2CCCCC2)c1C
Reaction time: 18 h

Procedure:
10.0 g (55.5 mmol) of 3-methoxy-2-methyl-benzoic acid hydrazide was dissolved in 200 mL of absolute ethyl alcohol. Cyclohexanecarbaldehyde (6.85 g, 61.0 mmol) and glacial acetic acid (3 mL) were added, and the reaction mixture was stirred for 18 h while monitoring by TLC. The precipitate was collected by filtration and washed with hexane. Product 3-methoxy-2-methyl-benzoic acid cyclohexylmethylene-hydrazide was obtained as a white solid (9.36 g, yield 61%): Rf=0.20 (3:1 EtOAc:n-Hexane); 1H NMR (400 MHz, CDCl3) δ 11.17 (s, 1H), 7.91 (s, 1H), 7.50 (d, J=4.8 Hz, 1H), 7.25 (t, J=6.4 Hz, 1H), 6.99 (t, J=5.6 Hz, 1H), 3.89 (s, 3H), 2.28 (s, 3H), 1.92-1.62 (m, 5H), 1.38-1.14 (m, 6H); HRMS (ESI) m/z calcd for C16H23N2O2 [M+H]+ 275.1760. found 275.1752, calcd for C16H22N2NaO2 [M+Na]+ 297.1579. found 297.1568.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1)=[O:14]>CCCCCC.C1COCC1>[OH:14][CH:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=1
Reactant: Brc1ccccn1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(O)c2ccccn2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 17.1 %

Procedure:
Butyllithium, 1.6M in hexane (146 ml) was added dropwise at −78° C. under N2 flow to a solution of 2-bromopyridine (0.1348 mol) in THF (300 ml). The mixture was stirred at −78° C. for 20 minutes. A solution of N-(4-formylphenyl)acetamide (0.1226 mol) in THF (300 ml) was added at −60° C./−70° C. The mixture was stirred at −60° C./−70° C. for 1 hour, then poured out into ice water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (27 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether and 2-propanone. The precipitate was filtered off and dried, yielding 5.09 g (17%) (±)—N-[4-[hydroxy(2-pyridinyl)methyl]phenyl]acetamide (compound 688).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:28])[N:10]2[CH2:29][CH2:30][CH2:31][C@H:9]2[CH:8]1[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)=[O:6])[CH:2]=[CH2:3].[OH-].[Na+]>CO.O>[CH2:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:28])[N:10]2[CH2:29][CH2:30][CH2:31][C@H:9]2[CH:8]1[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1c2cc(OCCCC(=O)OC)c(OC)cc2C(=O)N2CCC[C@H]2C1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOC(=O)N1c2cc(OCCCC(=O)O)c(OC)cc2C(=O)N2CCC[C@H]2C1OC1CCCCO1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
The methyl ester 18 (2.2 g, 4.26 mmol) was dissolved in MeOH (30 mL). Sodium hydroxide (340 mg, 8.5 mmol) was dissolved in water (7 mL) and added to the ester solution. The reaction mixture was stirred at 70° C. for 15 min. The methanol was then removed under vacuum and water (20 mL) was added. The aqueous solution was allowed to return to room temperature and a 5% aqueous citric acid solution was added to adjust the pH to <4. The precipitate was extracted with EtOAc (100 mL). The organic layer was washed with brine (30 mL) and dried over MgSO4. The solvent was removed under vacuum, then diethylether (50 mL) was added to the residue and removed under vacuum, then dried under vacuum to yield the pure 19 as white foam 2.10 g (98%). 1H NMR (d6-DMSO) as a mixture of 4/5 of diastereoisomers δ 7.10 (2H, s×2), 6.90-6.84 (2H, s×2), 5.84-5.68 (4H, m), 5.45-4.91 (6H, m), 4.72-4.30 (4H, m), 4.09-3.93 (4H, m), 3.91-3.75 (8H, m), 3.60-3.44 (4H, m), 3.44-3.22 (8H, m), 2.46-2.33 (4H, m), 2.20-1.76 (14H, m), 1.76-1.31 (12H, m). 13C NMR (d6-DMSO) δ 173.9, 173.9, 171.9, 166.1, 166.0, 149.6, 148.4, 148.3, 132.6, 116.5, 114.4, 110.5, 110.3, 99.2, 67.5, 67.4, 65.6, 65.5, 62.8, 59.4, 55.7, 45.9, 30.5, 30.2, 29.8, 29.7, 28.4, 28.3, 24.9, 24.8, 23.9, 23.8, 22.9, 22.7; MS (ES+) m/z (relative intensity) 519.2 ([M+H]+, 100). This compound was proved optically pure at C11a by reesterification (EDCI, HOBt, then MeOH), THP removal (AcOH/THF/H2O) and chiral HPLC, as in Tercel et al., J. Med. Chem., 2003, 46, 2132-2151).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1)[CH2:24][CH3:25])[CH3:22].Cl>C(O)CC>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:24][CH3:25])[CH3:22]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CCN(CC)CC1CCCCN1
Agent: Cl
Solvent: CCCO
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
The title compound is prepared analogously to Example 2 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (+)-2-[(diethylamino)methyl]piperidine to give colorless crystals, mp. 210°-211.5° C. (n-propanol/activated charcoal): [α]D20 =-12° (dilute aqueous hydrochloride acid).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][C@H:7]1[CH2:17][OH:18])=[O:4].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][N:25]=[C:24]2N.C(N(CC)CC)C>C(O)C>[C:13]([NH:12][C@@H:9]1[CH2:10][CH2:11][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:24]2[C:23]3[C:28](=[CH:29][CH:30]=[C:21]([C:20]([F:32])([F:33])[F:19])[CH:22]=3)[N:27]=[CH:26][N:25]=2)[C@H:7]([CH2:17][OH:18])[CH2:8]1)([CH3:14])([CH3:15])[CH3:16]
Reactant: Nc1ncnc2ccc(C(F)(F)F)cc12
Reactant: CC(C)(C)N[C@@H]1CC[C@H](NC(=O)CN)[C@H](CO)C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)N[C@@H]1CC[C@H](NC(=O)CNc2ncnc3ccc(C(F)(F)F)cc23)[C@H](CO)C1
Yield: 22.1 %

Procedure:
A solution of 2-amino-N-((1S,2R,4R)-4-(tert-butylamino)-2-(hydroxymethyl)cyclohexyl)acetamide (54 mg, 0.21 mmol), 6-(trifluoromethyl)quinazolin-4-amine (52 mg, 0.25 mmol), and triethylamine (25 mg, 0.25 mmol) in 3 mL of ethanol was heated at 100° C. in the microwvae for 1 hr. The reaction mixture was concentrated and the residue chromatographed on silica gel (eluting with 2-8% NH4OH/MeOH/CH2Cl2) to give 21 mg of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:5]=[C:4]([Cl:32])[N:3]=1.[CH3:33][O-:34].[Na+]>C1COCC1.C(Cl)Cl>[Cl:32][C:4]1[N:3]=[C:2]([O:34][CH3:33])[C:7]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:5]=1
Reactant: C[O-]
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(Cl)c12
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
4,6-dichloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 37B, 100 mg, 0.217 mmol) in THF (1086 μl) was treated with sodium methoxide (4.6 N in MeOH) (51.9 μl, 0.239 mmol) and stirred @ 40° C. for 1 h. Reaction was diluted in with DCM and concentrated in vacuo on silica. Material was purified by normal phase column chromotography eluting with Hex/EtOAc (0-10%) affording 6-chloro-3,4-dimethoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (56B, 86 mg, 0.189 mmol, 87% yield) as a white foam. MS: [M+H]+ m/z 456.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[C:12]2/[CH:13]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:15]([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17]/2)[CH:6]=1.C[Si](C)(C)[Cl:32].O>CC(C)=O>[ClH:32].[CH3:2][O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[C:12]2\[CH:13]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:15]([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17]\2)[CH:6]=1
Reactant: COC(=O)c1cccc(/C=C2/C=C(c3cccc(O)c3)C(CN(C)C)CC2)c1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cccc(/C=C2\C=C(c3cccc(O)c3)C(CN(C)C)CC2)c1
Yield: 27.6 %

Procedure:
8.1 g potassium tert-butylate and 35.4 g 3-(benzoic acid methyl ester)-methyltriphenylphosphonium chloride were suspended in 800 ml analytical grade toluene under a nitrogen atmosphere at room temperature and the suspension was then stirred at 70° C. for one hour. 7 g 3-(3-(tert-butyl-diphenyl-silanyloxy)-cyclohex-2-enone in 100 ml analytical grade toluene were added at this temperature and the mixture was stirred at 70° C. for 3 days. The mixture was quenched with 500 ml water. The phases were separated and the aqueous phase was washed 3 times with 200 ml ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and then freed from solvent in vacuo. The residue obtained in this way was taken up in a mixture of 150 ml ethyl acetate and 150 ml diiso-ether. The solid which had precipitated out was filtered off and washed with diiso-ether. The combined organic phases were freed from the solvent in vacuo. The residue (16.7 g) was dissolved in 70 ml tetrahydrofuran, and 16.7 ml tetrabutylammonium fluoride were added. After a reaction time of 10 minutes the reaction solution was quenched with 50 ml water and extracted three times with 50 ml ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and then freed from the solvent in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate/methanol=9/1. 2.5 g E-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester base were obtained as the first product fraction. To liberate the hydrochloride, the base was dissolved in 50 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 2 g (36.8% of theory) E-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester hydrochloride (37) were obtained in this way. 1.8 g (27.6% of theory) Z-3 [4-Dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester were obtained as the second product fraction. To liberate the hydrochloride, the base was dissolved in 50 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 1.5 g (27.6% of theory) Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester hydrochloride (38) were obtained in this way.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([NH2:15])=O)[N:9]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:7]=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]#[N:15])[N:9]=[C:8]([C:20]([F:22])([F:21])[F:23])[CH:7]=1
Reactant: NC(=O)c1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 102.2 %

Procedure:
2-[5-(2-Furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzamide (6.73 g, 21 mmol) and triethylamine (5.8 mL, 42 mmol) were combined in dry CH2Cl2 (55 mL) under argon and cooled to 0° C. Trichloroacetyl chloride (2.7 mL, 24 mmol) in CH2Cl2 (15 mL) was added dropwise over 30 min. The resulting solution was stirred at 0° C. for 20 min, then at room temperature for 65 min. The reaction was quenched with a small amount of water, then partitioned between 1M HCl and CH2Cl2. The organic layer was removed and extracted with sat. NaHCO3, then dried over Na2SO4, filtered, and evaporated to yield crude product (6.66 g). The crude product was chromatographed on silica gel (30-40% EtOAc/hexanes) to yield a yellow solid (6.51 g, >100%). 1H NMR (CDCl3) δ7.79 (m, 2H), 7.64 (m, 2H), 7.39 (d, 1H, J=1.8), 6.96 (s, 1H), 6.37 (m, 1H), 6.04 (d, 1H, J=3.7).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(N(CC)CC)C.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([Si:20]([CH3:23])([CH3:22])[O:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: OCC1CCCNC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CCCNC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
To a solution of piperidin-3-ylmethanol (2.10 g, 0.018 mol) in CH2Cl2 (20 mL) is added triethylamine (5.53 g, 0.0547 mol) followed by t-butyldimethylchlorosilane (4.127 g, 0.0275 mol) and the reaction mixture is stirred at room temperature. After 24 hours, the reaction mixture is washed with water, saturated solution of NaHCO3, and brine. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) over a gradient using 0-10% MeOH in dichloromethane to afford the title compound (2.50 g, 60%). Mass spectrum (m/z): 231.2 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[S:5][CH:6]=1.[CH3:17][S-:18].[Na+]>CN(C=O)C.[Cu](I)I>[CH3:17][S:18][C:2]1[N:3]=[C:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[S:5][CH:6]=1
Reactant: C[S-]
Reactant: O=c1[nH]c2ccccc2n1-c1nc(Br)cs1
Agent: I[Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1csc(-n2c(=O)[nH]c3ccccc32)n1
Temperature: 140 °C
Reaction time: 20 h

Procedure:
A mixture of 1-(4-bromo-1,3-thiazol-2-yl)-1,3-dihydro-2H-benzimidazol-2-one from Step A (1.0 g, 3.38 mmol), sodium methanethiolate (710 mg, 10.13 mmol), and copper iodide (643 mg, 3.38 mmol) in DMF (6 mL) were heated at 140° C. An additional amount of sodium methanethiolate (474 mg, 6.76 mmol) was added to the mixture after 3 h and 16 h and the reaction continued stirring at 140° C. After 20 h, the cooled mixture was partitioned between saturated aqueous NaHCO3 (30 mL) and CHCl3 (50 mL). The aqueous phase was extracted further with CHCl3 (50 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=264 (M+1).