Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[C:5]1([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[C:2]([NH:3][C:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:18][CH:17]=1)=[S:21])#[N:1]
Reactant: S=C=Nc1ccc(OCc2ccccc2)cc1
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
The suspension of monosodium cyanamide (1.33 g, 20.7 mmol) in absolute ethanol (50 mL) was slowly treated with 4-phenylmethoxyphenylisothiocyanate (5.0 g, 20.7 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (4.0 g), m.p. >270° C.
Reaction SMILES: O1C2C=CC(C([C:13]([CH:15](Br)[C:16]3[CH:25]=[CH:24][C:19]4[O:20][CH2:21][CH2:22][O:23][C:18]=4[CH:17]=3)=O)Br)=CC=2OCC1.[NH2:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:40]([O:42]C)=O)[CH:36]=2)[CH2:31]1)=[S:29].Cl.[NH2:45][OH:46].[OH-].[K+]>O1CCOCC1.CO>[O:20]1[C:19]2[CH:24]=[CH:25][C:16]([C:15]3[N:27]=[C:28]([N:30]4[CH2:39][CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]([NH:45][OH:46])=[O:42])[CH:36]=5)[CH2:31]4)[S:29][CH:13]=3)=[CH:17][C:18]=2[O:23][CH2:22][CH2:21]1
Reactant: O=C(C(Br)c1ccc2c(c1)OCCO2)C(Br)c1ccc2c(c1)OCCO2
Reactant: COC(=O)c1ccc2c(c1)CCN(C(N)=S)C2
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NO)c1ccc2c(c1)CCN(c1nc(-c3ccc4c(c3)OCCO4)cs1)C2
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A solution of 1,4-benzodioxan-6-ylbromomethyketone (0.051 g, 0.2 mmol), methyl 2-(aminocarbonothioyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (0.05 g, 0.2 mmol) in 1,4-dioxane (1 mL) heated at 40° C. for 2 h. Upon cooling to room temperature, the solvent was removed under reduced pressure to afford a solid residue. To the solid residue was added hydroxylamine hydrochloride (0.056 g, 0.8 mmol), potassium hydroxide (0.09 g, 1.6 mmol), and methanol (2 mL). The mixture was heated at 80° C. for 2 h. Upon cooling to room temperature, the solvent was then removed under reduced pressure, the residue dissolved in DMSO (1 mL) and purified on Gilson prep-HPLC [236 nm, rt=7.54 min (12 min), 30-70% gradient MeCN—H2O] to give 28.6 mg (35%) of the title compound as a white solid. LCMS: (FA) ES+ 410; 1H NMR (MeOD, 400 MHz) δ 8.51 (s, 1H), 7.60 (m, 2H), 7.33 (m, 3H), 6.82 (s, 2H), 4.74 (m, 2H), 4.25 (m, 4H), 3.84 (m, 2H), 3.08 (m, 2H).
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:25][N:26]=[N:27][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:25][N:26]=[N:27][C:13]4=[CH:12][N:11]23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=NCN12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=NCN12
Temperature: 70 °C
Yield: 87.5 %

Procedure:
To a solution of methyl 10-cyclohexyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxylate (66 mg, 0.16 mmol) in THF (6 mL) and MeOH (3 mL), was added aq NaOH (1.0N, 1.5 mL, 1.5 mmol), and the mixture was heated at 70° C. for 2 h. The solvents were removed, and the white solid residue was washed with water and EtOAc, isolated by centrifuge and dried under vacuum to yield crude 10-cyclohexyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxylic acid (54 mg, 0.14 mmol, 85%) as a white solid, which was used without further purification. 1H NMR (500 MHz, d6-DMSO) δ 1.07-1.19 (m, 1H), 1.34-1.46 (m, 3H), 1.65-1.75 (m, 2H), 1.86-2.12 (m, 4H), 2.73-2.84 (m, 1H), 5.04 (d, J=15.9 Hz, 1H), 5.93 (d, J=15.9 Hz, 1H), 7.63-7.74 (m, 5H), 7.79-7.85 (m, 1H), 8.18 (s, 1H), 9.08 (s, 1H). LCMS: m/e 399 (M+H)+, ret time 2.02 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[N:4][N:3]=1.Cl[C:15]1[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[N:16]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.O>[CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:15]3[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=4)[N:16]=3)[CH2:11][CH2:12]2)=[N:4][N:3]=1
Reactant: Cc1nnc(N2CCC(N)CC2)o1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc(N2CCC(Nc3nc(-c4ccc(C(F)(F)F)cc4)cc(C(C)(C)O)n3)CC2)o1

Procedure:
A solution of 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidin-4-ylamine (36.5 mg, 0.2 mmol), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol (69.1 mg, 0.22 mmol)) and N,N-diisopropylethylamine (52 L, 0.3 mmol) in dioxane (2 mL) was heated at 160° C. in a microwave oven for 5.5 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc/EtOH 9:1 (v/v) as eluent. The title compound was obtained as a white solid (29 mg, 31%).
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[CH:21]=[C:20]1[CH3:29].[C:31]1([S:37]([C:40]2[N:44]([CH3:45])[CH:43]=[N:42][C:41]=2[CH:46]=O)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl.ClCCCl>[CH3:15][O:16][C:17](=[O:30])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=2)[C:21]([CH2:46][C:41]2[N:42]=[CH:43][N:44]([CH3:45])[C:40]=2[S:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)(=[O:38])=[O:39])=[C:20]1[CH3:29]
Reactant: Cn1cnc(C=O)c1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)Cn1c(C)c(Cc2ncn(C)c2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A mixture of triethylsilane (0.17 g), trifluoroacetic acid (0.10 g) and 1,2-dichloroethane (5.0 mL) at −5° C. was treated dropwise with a mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.022 g), 5-benzenesulfonyl-1-methyl-1H-imidazole-4-carbaldehyde (0.030 g) and 1,2-dichloroethane (3.0 mL), and the resulting mixture was stirred at room temperature overnight and then at 45° C. for 2 hours. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and dried using a phase separation cartridge. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0:1 to 2:5 by volume) to afford the title compound as a yellow oil (0.027 g).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[C:28]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:26])=[C:20]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C1COCC1.CN(C=O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[C:27]2[CH:32]=[CH:31][CH:30]=[N:29][C:28]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:20]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:19]=1
Reactant: O=C(Nc1ccc(NC(=O)c2cccnc2OCc2ccccc2)c(OCc2ccccc2)c1)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Nc1ccc(NC(=O)c2cccnc2OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
{3-Benzyloxy-4-[(2-benzyloxy-pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (424) (0.430 g, 0.664 mmol) was dissolved in a mixture of THF (6 mL) and DMF (3 mL). Piperidine (12.88 mmol) was added. The mixture was shaken at room temperature for 1 h. LC-MS indicated complete de-protection at this point. The mixture was concentrated under reduced pressure to give a dark brown/purple oil. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (15–100% EtOAc/hexane 25 minutes) gave the desired product (425) as an orange oil upon concentration (0.229 g, 0.538 mmol, 81% yield). LC-MS (ESI): (exact mass: 425.17) m/e=426.2 [M+1]+ (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:3]=1[NH2:15].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1>>[Cl:16][C:17]1[N:22]=[C:21]([NH:15][C:3]2[C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: Nc1c(F)cc(F)cc1N1CCOCC1
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: Fc1cc(F)c(Nc2nc(Cl)ncc2Cl)c(N2CCOCC2)c1

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(2,4-difluoro-6-morpholin-4-yl-phenyl)-amine was prepared from 2,4-Difluoro-6-morpholin-4-yl-phenylamine and 2,4,5-Trichloropyrimidine in an analogous manner to Example 1230a. Title compound was isolated as an off-white foam (337 mg, 57%) HPLC 97% purity, LCMS 363.10 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.23 (s, 1H), 6.90 (s, 1H), 6.72 (dd, 1H), 6.64 (d, J=9.6 Hz, 1H), 3.79-3.77 (m, 4H), 2.90-2.87 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]2[N:14]=[C:15](N)[N:16]=[C:4]2[N:3]=1.N([O-])=O.[Na+].C(OCC)(=O)C.C(Cl)[Cl:29]>Cl.O.C(Cl)Cl.C(OCC)(=O)C>[Cl:29][C:15]1[N:16]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]2[N:14]=1
Reactant: ClCCl
Reactant: Cc1cc(-c2ccccc2)n2nc(N)nc2n1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2)n2nc(Cl)nc2n1
Reaction time: 0.17 h

Procedure:
To 2.0 g (8.9 mmol) of 5-methyl-7-phenyl-1,2,4triazolo[1,5-a]pyrimidin-2-amine stirring in 25 ml of concentrated hydrochloric acid, 1.2 g (17.4 mmol) of sodium nitrite dissolved in 4.0 ml of water was added dropwise at ambient temperature. After the addition, the reaction suspension was warmed at about 60° for 15 minutes followed by stirring another 10 minutes without heat. Ethyl acetate (150 ml) and excess water were added. The ethyl acetate layer was separated whereby a certain amount of insoluble material present was ignored and the extract washed with water (2X), saturated sodium bicarbonate, brine, dried over magnesium sulfate, and evaporated in vacuo to give a solid residue. Silica gel column chromatography (methylene chloride followed by 10:1 methylene chloride/ethyl acetate) afforded the title compound, m.p. 179°-181° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[C:5]([C:7]1[S:20][C:10]2[C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[O:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:6].CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([NH:1][CH2:2][CH2:3][N:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[C:5]([C:7]1[S:20][C:10]2[C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[O:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:6])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: NCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Yield: 17.4 %

Procedure:
To a solution of N-(2-aminoethyl)-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 131 (0.300 g, 0.6 mmol) in methylene chloride (1.5 ml) was added DIEA (0.262 ml, 1.5 mmol). The reaction mixture was cooled with an ice water bath and acetyl chloride (0.0944 g, 1.2 mmol) was added drop-wise via syringe. The reaction mixture was stirred at cool temperature for 30 minutes and equilibrated to room temperature. The reaction mixture was washed with water, then saline and concentrated to a solid. The crude solid was taken into DMF and purified by RP-HPLC to give 46 mg of 258 (yield 18% of theoretical). MS: (ESI+) 441.1
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[ClH:19].[N:20]1([CH2:26][CH2:27][NH:28][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCCN1CCCCC1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCN3CCCCC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 60 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-(piperidin-1-yl)ethylamine as described in Steps 5 and 6, Example 24 to give the title compound as a white solid (60% yield). LC/MS: RT 2.07 min; m/e 410; 1H NMR (δ, ppm): 10.68 (1H, br), 8.39 (1H, s), 7.64 (1H, s), 7.35 (1H, s), 7.20 (1H, s), 3.25-3.50 (4H, m), 2.80-3.00 (2H, m), 2.10-2.60 (7H, m), 1.60-2.00 (4H, m), 1.20-1.40 (2H, m), 1.10 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.Cl.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH:21]1[C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:23]3[CH2:24][CH2:25][NH:20][CH:21]([C:26]([O:28][CH3:29])=[O:27])[CH2:22]3)=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Reactant: COC(=O)C1CNCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)C2=Cc3cc(OC)c(OC)cc3CCC2)CCN1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 81.6 %

Procedure:
A solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (2.14 g) in dichloromethane (20 ml) is added dropwise, taking 40 minutes while stirring at 0° C., to a mixture of methyl piperazine-2-carboxylate hydrochloride (1.75 g), triethylamine (3.2 g) and dichloromethane (40 ml). The reaction mixture is poured into ice-water and shaken. The organic layer is separated and subjected to distillation under reduced pressure. The residue is dissolved in 1N-HCl (20 ml) and washed with ethyl acetate. The aqueous layer is separated and then neutralized with sodium hydrogencarbonate, followed by extraction with dichloromethane. The organic layer is dried, and the solvent is distilled off. Crystals obtained from the residue are recrystallized from ethyl acetate - hexane to afford methyl 4-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)piperazine-2carboxylate as colorless needles (2.45 g), m.p. 103-104° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+:24]>C(O)C.O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O-:20])=[O:19])=[CH:21][CH:22]=1.[Na+:24]
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])c1ccc(NCCCCCCCCCCCO)cc1

Procedure:
A mixture of 3.62 g. of 4-(11-hydroxyundecylamino)benzoic acid and 25 ml. of ethanol-water (9:1) containing 400 mg. of sodium hydroxide is stirred for 4 hours. The mixture is filtered and the solid washed with ethanol-water and dried in vacuo to yield sodium 4-(11-hydroxyundecylamino)benzoate as a white, amorphous solid.
Reaction SMILES: C(O[C:4](=[O:18])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[CH3:19][NH:20][C:21]([NH2:23])=[O:22].C[O-].[Mg+2].C[O-].CO>>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4]([NH:23][C:21]([NH:20][CH3:19])=[O:22])=[O:18])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CNC(N)=O
Reactant: CCOC(=O)C(CC1CCCC1)c1ccccc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccccc1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
A mixture of 3-cyclopentyl-2-phenyl-propionic acid ethyl ester (1.70 g, 7.06 mmol) and methyl urea (1.04 mg, 14.13 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 130.3 mL, 21.18 mmol) was refluxed at 100° C. for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 1-(3-cyclopentyl-2-phenyl-propionyl)-3-methyl-urea (1.21 mg, 62.4%) as a white solid: mp 145-147° C.; EI-HRMS m/e calcd for C16H22N2O2 (M+) 274.1681, found 274.1682.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1.C[Si](C)(C)[C:14]([F:17])([F:16])[F:15].Cl.CCOC(C)=O>C1(C)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Br:10][C:6]1[CH:5]=[C:4]([C:3](=[O:11])[C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(c1cccc(Br)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 20 h
Yield: 63.7 %

Procedure:
In a dry round bottom flask, 3-bromo-benzoic acid methyl ester (2 g, 9.3 mmol, Aldrich Chemical Company) and trimethyl(trifluoromethyl)silane (1.72 mL, 11.6 mmol, Aldrich Chemical Company) were dissolved in dry toluene (50 mL). Upon cooling the solution to −78° C., TBAF (232 μL, 0.23 mmol) was added and the reaction was allowed to warm up slowly to rt overnight. After stirring for 20 hr, 2N HCl (50 mL) and EtOAc (100 mL) were added, the layers were separated, and the aqueous layer was extracted with another portion of EtOAc. The combined organic fractions were dried (MgSO4), concentrated in vacuo, and resulting crude oil was purified using SiO2 flash chromatography (elution: 5–20% EtOAc in hexanes) to give 1.5 g (65%) the title compound as a light yellow oil. 1H-NMR (CDCl3; 400 MHz) δ 8.18 (br s, 1H), 7.98–8.00 (m, 1H), 7.82–7.85 (m, 1H), 7.42–7.46 (m, 1H). 19F-NMR (CDCl3; 400 MHz) δ −72.06 (s).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[O:7][C:8](Br)=[CH:9][CH:10]=1>C(N)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:4][CH2:1][C:2]#[C:3][C:6]1[O:7][C:8]([C:3]#[C:2][CH2:1][OH:4])=[CH:9][CH:10]=1
Reactant: C#CCO
Reactant: Brc1ccc(Br)o1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCN
Product: OCC#Cc1ccc(C#CCO)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
Pd(Ph3P)4 (580 mg, 3%), CuI (140 mg, 2%) and propargyl alcohol (4.65 ml, 67.7 mmol) are added successively to a solution of 2,5-dibromofuran (5.1 g, 22.6 mmol) in n-propylamine (100 ml), and the mixture is stirred at RT for 1 h and then under reflux for 24 h. More propargyl alcohol (2.0 ml, 33 mmol) is then added and the mixture is stirred under reflux for another 8 h. After cooling, the reaction mixture is filtered off with suction through kieselguhr and washed with ethyl acetate (50 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [Tol/Ac (8:2)] over a silica gel column. This gives the title compound (3.8 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.40.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=2[F:42])[S:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:51](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[Si:1]([O:18][CH2:19][CH2:20][C:21]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][N:30]([CH3:51])[CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=2[F:42])[S:22]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)[Si](OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2)(c1ccccc1)c1ccccc1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0.157 g, 0.225 mmol) in 5 mL DCE was added formaldehyde (0.067 mL, 37 wt % in water, 0.901 mmol) followed by sodium triacetoxyborohydride (0.052 g, 0.248 mmol). The resulting suspension was stirred vigorously at room temperature overnight, then treated with saturated Na2CO3 solution (30 mL) and stirred for 10 minutes. The mixture was extracted with EtOAc (3×30 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (0-1% MeOH/DCM) to afford the desired product as a bright yellow foam, 0.119 g, 74%.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19](COCC[Si](C)(C)C)[C:20]3[N:24](COCC[Si](C)(C)C)[C:23]4[CH:33]=[CH:34][C:35]([CH:37]([OH:40])[CH2:38][CH3:39])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.O>CN(C)C=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]3[NH:24][C:23]4[CH:33]=[CH:34][C:35]([CH:37]([OH:40])[CH2:38][CH3:39])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)c1ccc2c(c1)nc(N(COCC[Si](C)(C)C)CC1CCN(Cc3cccc4ccccc34)CC1)n2COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(O)c1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Temperature: 100 °C
Reaction time: 13 h

Procedure:
After dissolving 1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-ol (50 mg, 0.073 mmol) in anhydrous dimethylformamide (2 ml), tetrabutylammonium fluoride (0.5 ml, 1.0 M tetrahydrofuran solution) was added and the mixture was stirred at 100° C. for 13 hours. Ethyl acetate and water were added, after which the aqueous layer was adjusted to pH 11 and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by thin-layer silica gel chromatography (ethyl acetate/methanol=4/1). The purified product was further purified by preparative HPLC to obtain 1-{2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazol-5-yl}-propan-1-ol.