Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([C@H:8]([N+:32]([O-])=O)[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].C([O-])=O.[NH4+]>C1COCC1.CO.[Pd].CCOCC>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([C@H:8]([NH2:32])[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](C1)[C@H]([N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](C1)[C@H](N)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 82.1 %

Procedure:
To a solution of 3β-acetoxy-6β-nitro-5α-cholestane (0.474 g, 0.001 mole) in THF (5 mL) and methanol (5 mL) was added 10% palladium on carbon (50 mg) followed by ammonium formate (0.315 g, 5 equivalents). The resulting mixture was stirred at room temperature for 50 minutes then diluted with Et2O, filtered and evaporated in vacuo. Flash column chromatography (SiO2, 4:1, hexane:Et2O) gave 3β-acetoxy-6β-amino-5α-cholestane (0.366 g, 82%).
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1.S(=O)(O)[O-].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl>[ClH:1].[F:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:9])=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(SC2CCNCC2)cc1
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S(c1ccc(F)cc1)C1CCNCC1
Reaction time: 0.75 h

Procedure:
3-Chloroperbenzoic acid (0.96 g) was slowly added to a stirred solution of 4-[(4-fluorophenyl)thio]piperidine hydrochloride (I.2g) in chloroform (60 ml) under ice-cooling over a period of 5 minutes and the mixture was stirred at the same temperature for 45 minutes. After being treated with sodium bisulfite solution under ice-cooling, the resultant mixture was adjusted to alkaline pH with 20% sodium hydroxide solution. The chloroform layer was separated and the aqueous layer was extracted three times with chloroform. The chloroform layers were combined and dried over magnesium sulfate. After removal of magnesium sulfate, the solution was treated with ethereal hydrochloric acid and concentrated to dryness in vacuo. The powdery residue was washed with isopropanol to give 4-[(4-fluorophenyl)sulfinyl]piperidine hydrochloride (1.10 g) as colourless powser.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.O.C(OCC)(=O)C.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:20]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)#[N:21]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of methyl 4-bromo-2-fluorobenzoate (9.1 mmol) in DMF (50 mL) was added zinc cyanide (641 mg, 5.5 mmol) followed by tetrakis(triphenyphosphine)palladium(0) (1.05 g, 0.91 mmol). The mixture was heated to 100° C. and stirred for 3 h. At that point, additional tetrakis(triphenyphosphine)-palladium(0) (500 mg, 0.43 mmol) was added. The mixture was stirred a further 30 min and was then cooled to room temperature. Water and ethyl acetate were added, and insoluble solids were removed by filtration through celite. The layers were then separated. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, washed with 10% aqueous lithium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (10% ethyl acetate in hexanes) to provide methyl 4-cyano-2-fluorobenzoate (1.36 g, 7.6 mmol, 84% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([N:31]=[C:32]=[O:33])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1([CH3:42])[O:39][C@@H:38]([CH2:40][OH:41])[CH2:37][O:36]1.N1C=CC=CC=1>C1COCC1.CCOC(C)=O.CC1(C)O[C@@H](CO)CO1>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:15][C:16]3[CH:17]=[C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:33])[O:41][CH2:40][C@H:38]5[CH2:37][O:36][C:35]([CH3:42])([CH3:34])[O:39]5)[CH:26]=4)[CH:19]=[CH:20][C:21]=3[CH2:22][CH2:23]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(N=C=O)c4)cc3C2)c1
Reactant: CC1(C)OC[C@H](CO)O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1(C)OC[C@H](COC(=O)Nc2cc(Oc3ccc4c(c3)CC(C(=O)Nc3cccc(C(C)(C)C)c3)CC4)ccn2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A solution of N-(3-tert-butylphenyl)-7-[(2-isocyanatopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (250 mg, 0.56 mmol), [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (150 mg, 1.13 mmol) and pyridine (0.091 mL, 1.13 mmol) in THF (10 mL) was allowed to stir at rt. After 2 h, additional pyridine (0.14 mL) and [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (0.220 mg) were added. The reaction mixture was heated at 70° C. overnight and then another portion of pyridine (0.10 mL) and [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (0.150 mg g) were added. Heating continued for an additional 2 h and then the reaction mixture was subjected to MWI at 135° C. for 5 min. The reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl {4-[(7-{[(3-tert-butylphenyl)amino]carbonyl}-5,6,7,8-tetrahydronaphthalen-2-yl)-oxy]pyridin-2-yl}carbamate (290 mg, 89%) as a white solid. LCMS: (FA) ES+574.4.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[CH:13][C:12]=1[CH3:31]>C1COCC1>[F:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]4=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]4[CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)=[CH:13][C:12]=1[CH3:31]
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cc(Oc2ccc(-c3cccnc3N)cc2)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)ccc1F
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 245 mg) in THF (dry) (15 mL) was added 2-chloroethanesulfonyl chloride (0.386 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(4-fluoro-3-methylphenoxy)phenyl)pyridin-2-amine (360 mg) in THF (dry) (20 ml) was added at 0° C. and the mixture was stirred at room temperature for 5 hr. The mixture was quenched with water at 0° C. Water, EtOAc and IPE were added and the precipitates were collected, washed with water/EtOAc, dried in vacuo to give the title compound (359.2 mg) as a white solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: [CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:39][N:40]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[N:41]1>ClCCl>[CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([S:45]([C:42]2[CH:43]=[CH:44][N:40]([CH3:39])[N:41]=2)(=[O:47])=[O:46])[CH2:6][CH2:5]1
Reactant: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CN1CCN(S(=O)(=O)c2ccn(C)n2)CC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a mixture of 4-[1-(1-methyl-2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.1 g, 2.5 mmol) in dichloromethane (20 mL) was added triethylamine (0.52 mL, 3.7 mmol) followed by 1-methyl-1H-pyrazole-3-sulfonyl chloride (0.54 g, 3.0 mmol). The reaction was stirred at RT for 1 h, then quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. After being concentrated to dryness, the residue was purified on silica gel, eluting with 0 to 10% methanol in dichloromethane to provide the product (1.28 g, 87.7%). LCMS calculated for C26H40N9O3SSi (M+H)+: m/z=586.3; Found: 586.2. The product was separated on a ChiralCel OD-H column (3×25 cm, 5 μM), eluting with a gradient of ethanol in hexanes at flow rate 28 mL/min, to give the two enantiomers. First peak with retention time 20.76 min and second peak with retention time 24.72 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Product: O=CC=Cc1ccc(-c2ccccn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyridinyl)-benzaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.I[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>[Cu]=O>[C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:2]([CH3:1])=[N:3]1)([OH:19])=[O:18]
Reactant: O=C(O)c1ccccc1I
Reactant: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nn(-c2ccccc2C(=O)O)c2cc([N+](=O)[O-])ccc12
Yield: 97.2 %

Procedure:
3-Methyl-6-nitroindazole (64.5 g), 46.0 g of 2-iodobenzoic acid, 40.8 g of potassium carbonate and 1.89 g of copper(II) oxide were subjected to reaction in the same manner as in Example 1 to obtain 53.6 g (69.4%) of 1-(2-carboxyphenyl)-3-methyl-6-nitroindazole.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([CH3:33])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CO>[CH3:32][O:31][C:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C@@H:19]([NH:18][CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:33])=[CH:23][CH:24]=1)=[O:30]
Reactant: COC(=O)Cc1ccc(OC[C@H](C)N)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(OC[C@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1

Procedure:
Following a procedure Similar to that described in Preparation 29, but using 750 mg of (R)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde (prepared as described in Preparation 25), 920 mg of methyl 4-[2(S)-amino-1-propoxy]phenylacetate (prepared as described in Preparation 28), 10 ml of absolute methanol and 500 mg of sodium cyanoborohydride, the title compound was obtained. [α]D23 -58.6° (c=0.998, chloroform).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.B(Br)(Br)Br.[OH-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NCCc2cc(O)ccc21
Reaction time: 12 h

Procedure:
To a solution of 6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (31.3 g, 177 mmol) in CH2Cl2 (300 mL) at -78° is added BBr3 (33.4 mL, 353 mmol). The reaction mixture is allowed to come to ambient temperature and is stirred for 12 hours. After this time the reaction mixture is cooled to 0° and is subsequently neutralized with 5N NaOH (150 mL) solution and saturated NaHCO3 solution. The resulting precipitate is extracted with hot acetone (4×500 mL) and the combined organics are concentrated in vacuo to give 6-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.FC(F)(F)C(O)=O.[C:30]1([C:36]2[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[C:44]([O:48][C:49]([NH:51][CH2:52][C:53]([NH:55][C@H:56]1[CH2:60][N:59]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[C@H:58]([C:68](O)=[O:69])[CH2:57]1)=[O:54])=[O:50])([CH3:47])([CH3:46])[CH3:45]>ClCCl.C(N(CC)CC)C>[C:30]1([C:36]2[CH:37]=[CH:38][C:39]([CH2:40][NH:41][C:68](=[O:69])[C@@H:58]3[CH2:57][C@@H:56]([NH:55][C:53](=[O:54])[CH2:52][NH:51][C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:50])[CH2:60][N:59]3[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[CH:42][CH:43]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)NCc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
Triethylamine (130 μL), 1-hydroxybenzotriazole (59 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89 mg) were added to a solution of the 4-phenylbenzylamine trifluoroacetate (B, 126 mg) and trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline (Compound D103 (B), 150 mg) in dichloromethane (10 mL) at 0° C. The mixture was stirred at room temperature for 16 hr and concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform:methanol=99:1 to 98:2, v/v) to give the title compound (178 mg) as a colorless foam:1H NMR (400 MHz, CDCl3) δ 1.45 (s, 18H), 1,67 (s, 2H), 2.01 (brs, 1H), 2.64 (br s, 1H), 3.27 (br s, 1H), 3.68-3.81 (m, 3H), 4.23-4.70 (m, 3H), 5.17 (br s, 1H), 6.43 (br s, 1H), 7.32-7.36 (m, 3H), 7.44 (t, J=7.6 Hz, 2H), and 7.53-7.57 (m, 4H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:8](=[O:20])[CH2:7]2.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[C:8](=[O:20])[CH:7]2[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: CCOC(OCC)N1C(=O)Cc2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCOC)c(OC)cc23)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Sodium hydride (95 mg of a 60% suspension in paraffin oil, 2.4 mmol) was added to a solution of 5-fluoro-1-diethoxymethyloxindole (520 mg, 2.05 mmol) and 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (220 mg, 0.82 mmol), (prepared as described for the starting material in Example 2), in THF (20 ml). After stirring for 2 hours at ambient temperature, the volatiles were removed by evaporation. The residue was partitioned beween methylene chloride and water, the organic layer was washed with water and then brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using an increasingly polar mixture of methylene chloride/ethyl acetate (100/0 to 0/100) as eluent to give 4-(5-fluoro-1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (300 mg, 68%) as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[C:26]([NH2:31])[C:25]=2[N+:32]([O-])=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C>[Zn]>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[C:26]([NH2:31])[C:25]=2[NH2:32])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2c(Cl)cnc(N)c2N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 90.2 %

Procedure:
N(4)-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)-silyl]oxy}methyl)cyclopentyl]-5-chloro-3-nitropyridine-2,4-diamine (0.875 g, 0.00165 mol) and zinc (0.431 g, 0.00659 mol) was added to acetic acid (40.0 mL, 0.704 mol) with stirring for 10 nm ins. The mixture was stirred for 10 min and the solid was filtered off. The filtrate was concentrated, dissolved in EtOAc (50 mL) washed with water (2×10). To the organic phase was added 2 ml Et3N and the mixture was washed with 10 mL water. The organic layer was concentrated and purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound (0.746 g, 90%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]#[N:19])=[CH:11][C:5]=2[N:4]=1.[CH3:20][NH:21][CH3:22].C(OCC)(=O)C>C1COCC1>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:3]([CH2:2][N:21]([CH3:22])[CH3:20])=[N:4][C:5]=2[CH:11]=1)#[N:19]
Reactant: CNC
Reactant: N#Cc1ccccc1-c1ccc2[nH]c(CCl)nc2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)Cc1nc2cc(-c3ccccc3C#N)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2-Chloromethyl-5-(2-cyanophenyl)-1H-benzimidazole (1.31 mole, 0.350 g) was dissolved in 2 ml THF and cooled to 0° C. Dimethylamine (1 ml) was added. The solution was stirred at room temperature for 20 minutes. Ethyl acetate was added. The organic phase was washed with water, dried over sodium sulfate, and concentrated to yield 270 mg of 5-(2-cyanophenyl)-2-dimethylaminomethyl-1H-benzimidazole. (MS)
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:7]([O:5][C:4](=[O:6])[CH2:3][C:1]#[N:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1ccccc1
Reactant: N#CCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#CCC(=O)OCc1ccccc1

Procedure:
To a mixture of cyanoacetic acid (VII) 2.34 g (27.5 mmol) and benzyl alcohol (VIIIa) 2.70 g (25 mmol) in 60 mL of toluene 50 mg of p-TsOH was added and the mixture was refluxed in a flask with a Dean-Stark trap for 24 h. The mixture was cooled down and toluene was washed with H2O and toluene was evaporated. The residue was distilled in vacuo (Kugelrohr apparatus, 0.1 mm Hg, T. oven 170-180° C.). Yield 3.36 g (77%), a colorless oil. MS (m/z, rel. intensity, %): 167.0 ([M+NH4−CN]+, 27), 193.0 ([M+NH4]+, 100).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:26])=[CH:21][CH:20]=2)[OH:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>O1CCCC1.CC(O)C.[OH-].[Pd+2].[OH-]>[C:31]([O:30][C:28](=[O:29])[NH:27][C@H:25]([C:22]1[CH:23]=[CH:24][C:19]([CH:17]([OH:18])[CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[CH:20][CH:21]=1)[CH3:26])([CH3:32])([CH3:33])[CH3:34]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.1 %

Procedure:
To a solution prepared by dissolving 2.98 g of the compound [25-1] in a mixed solvent of 30 mL of tetrahydrofuran and 10 mL of 2-propanol, 750 mg of a carbon catalyst of 20% palladium hydroxide was added, and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure, to obtain 2.3 g of tert-butyl((1S)-1-{4-[hydroxy(piperidin-4-yl)methyl]phenyl}ethyl)carbamate [33-3] (hereinafter, referred to as the compound [33-3]). The compound [33-3] was used in the subsequent reaction without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][S:12][CH:13]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[S:12]1[CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[N:10]=[N:11]1
Reactant: COc1ccc(-c2csnn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2csnn2)cc1
Temperature: -78 °C
Yield: 94.3 %

Procedure:
4-(4-methoxy-phenyl)-[1,2,3]thiadiazole (1.06 g, 5.50 mmol) was dissolved in methylene chloride (20 ml) and the solution was cooled to about −78° C. Boron tribromide (1.0 M in methylene chloride, 12.1 ml) was added dropwise to the solution to afford a brown-colored solution. The reaction mixture was allowed to stir for about fifteen minutes, the cooling bath was removed, and the mixture was allowed to stir at room temperature for about an additional twelve hours. The mixture was poured into water, and the resulting mixture was adjusted to about pH 6. The mixture was extracted with methylene chloride (3×100 ml), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 924 mg (94% yield) of the desired title compound as a tan solid. LRMS ([M+H]+)=179.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][N:25]1C(=O)C2=CC=CC=C2C1=O.C(=O)([O-])[O-].[K+].[K+].NN.[OH-].[Na+]>O1CCOCC1.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][NH2:25])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccn2)cc1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: NCCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Reaction time: 3 h
Yield: 40.9 %

Procedure:
7.50 g (24.77 mmol) of 4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine and 6.92 g (27.24 mmol) of N-(2-bromoethyl)phthalimide were dissolved in 60 ml of dioxane, and 4.11 g (29.74 mmol) of potassium carbonate was added. The mixture was stirred at an oil bath temperature of 90° to 100° C. for 3 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using a mixture of ethyl acetate and methanol in the volume ratio 25:1 as an eluent. The desired fraction was concentrated under reduced pressure, and 60 ml of ethanol and 1.61 g (32.16 mmol) of hydrazine (hydrate) were added to the residue, and the mixture was stirred under reflux. After 200 ml of 1N aqueous sodium hydroxide was added to the reaction mixture, the mixture was extracted twice with 200 ml of chloroform. The chloroform extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3.50 g (41%) of 2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]ethylamine as an oily product.