Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:19]([CH:25]1[CH2:27][CH2:26]1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C.O>[CH:25]1([CH:19]([O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:27][CH2:26]1
Reactant: Oc1cccc2ccccc12
Reactant: CCOC(=O)C(Br)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Oc1cccc2ccccc12)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of 1-naphthol (170 mg, 1.18 mmol) in anhydrous DMF (10 mL) was added K2CO3 (510 mg, 3.53 mmol) and ethyl α-bromocyclopropaneacetate (295 mg, 1.41 mmol). The mixture was stirred at room temperature for 2 h and then diluted with water (50 mL) and then extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography using a mixture of ethyl acetate and n-hexane (1:9) to furnish ethyl 2-cyclopropyl-2-(1-naphthalenyloxy)acetate (8, R=c-Pr, 296 mg, 93%) as a white solid. The ester (250 mg, 0.92 mmol) was dissolved in 20 mL THF: H2O (2:1) and then 3M NaOH (111 mg, 2.77 mmol) was added. The reaction was heated at 80° C. for 6 h. After cooling, the reaction mixture was quenched with 1N HCL to a pH ˜7 and then extracted with chloroform. The organic extract was dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography eluting with a mixture of ethyl acetate/n-hexane (a gradient of 2:1) to furnish 2-cyclopropyl-2-(1-naphthalenyloxy)acetic acid (41, R=c-Pr) (136 mg, 61%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=O.Cl.[C:14]([NH2:22])(=[NH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[K+]>O1CCCC1.O>[C:15]1([C:14]2[NH:21][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=3)[N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1Cl
Reaction time: 2 h

Procedure:
A solution of 68.0 g (0.254 mol) of the above-mentioned crude 2-bromo-3′,4′-dichloroacetophenone in 110 ml of tetrahydrofuran was added dropwise over 30 minutes, under reflux with heating, into a suspension of 39.8 g (0.254 mol) of benzamidine hydrochloride, 102.1 g (1.02 mol) of potassium bicarbonate in 400 ml of tetrahydrofuran and 100 ml of water. After the addition was complete, further refluxing with heating was carried out for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, to give a residual solid. This solid was successively washed with water and toluene, to give 45.5 g (62.0% crude yield) of crude crystals of the desired product. The crude crystals were recrystallized using acetonitrile, to give a purified white powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=O)[C:6]([C:10]([NH2:12])=O)=[N:5][N:4]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[N:8]=[C:3]([S:2][CH3:1])[N:4]=[N:5][C:6]=1[C:10]#[N:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nnc(C(N)=O)c(=O)[nH]1
Product: CSc1nnc(C#N)c(Cl)n1

Procedure:
A solution of 500 mg (2.7 mmol) of 3-methylsulfanyl-5-oxo-4,5-dihydro-[1,2,4]triazine-6-carboxylic acid amide (J. J. Huang, J. Org. Chem. 1985, 50, 2293-2298; H. Wang et al., Hua Hsueh Hsueh Pao 1964, 30 (2), 183-192; CA Vol. 61, 8311b) in 38 ml (408 mmol) of phosphorus oxychloride was heated to reflux during 1.5 h. After cooling the dark brown reaction mixture, the excess of phosphorus oxychloride was evaporated under reduced pressure. To destroy residues of phosphorus oxychloride and to neutralize the reaction mixture, the resulting red-brown oily residue was dissolved in 15 ml of toluene and the solution added to an ice-cold saturated aqueous solution of sodium hydrogencarbonate. The organic phase was diluted with 100 ml of dichloromethane, separated from the aqueous phase, dried over sodium sulfate, and evaporated under reduced pressure. The resulting 5-chloro-3-methylsulfanyl-[1,2,4]triazine-6-carbonitrile was obtained as a brown oil and was used in the following reactions without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](Cl)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15](Cl)=[O:16])[CH:8]=2)[CH:3]=1.[CH2:18]([NH2:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>O1CCCC1>[OH:1][C:2]1[C:11]([C:12]([NH:30][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([NH:30][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])[CH:8]=2)[CH:3]=1
Reactant: CCCCCCCCCCCCN
Reactant: O=C(Cl)c1ccc2cc(O)c(C(=O)Cl)cc2c1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCNC(=O)c1ccc2cc(O)c(C(=O)NCCCCCCCCCCCC)cc2c1
Temperature: 30 °C
Yield: 29 %

Procedure:
A dispersion of 5.4 g of 2-hydroxy-3,6-dichloro carbonylnaphthalene in 20.0 g of dry tetrahydrofuran was added with 14.8 g of n-dodecylamine solution in 30 g of dry tetrahydrofuran and reacted under reflux for 12 hours. To the reaction mixture, 50 g of water was added and the precipitates were collected by filtration, washed with water and thus obtained crystal was washed with 30 g of methanol under reflux. The obtained mixture was cooled to 30° C. and filtrated, washed with methanol and dried to provide 3.3 g of 2-hydroxy-3,6-di-n-dodecylaminocarbonylnaphthalene (decomposition point: 382.9° C.).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][O:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1>ClCCl>[N:25]([C:21]1[CH:20]=[C:19]([O:18][CH3:17])[N:24]=[CH:23][N:22]=1)=[C:1]=[S:2]
Reactant: COc1cc(N)ncn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (1.86 g, 7.99 mmol) in dichloromethane at room temperature was added 6-methoxypyrimidin-4-amine (1 g, 8 mmol). The orange solution was stirred at room temperature for 18 hours. The LC/MS showed the desired product as one of the major peaks. The deep orange solution was concentrated and the remaining residue was filtered. The filtrate was purified by silica gel chromatography (10-50% ethyl acetate/hexanes) to afford 4-isothiocyanato-6-methoxypyrimidine (0.72 g, 4.3 mmol, 54% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (1 H, d, J=5.79 Hz), 6.95 (1 H, d, J=5.79 Hz), 3.92 (3 H, s). MS (LC/MS) R.T.=3.15; [M+H]+=168.1.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39]C[CH2:37][CH2:36]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1CC[S:46](=[O:50])(=[O:49])CC1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][S:46](=[O:50])(=[O:49])[CH2:37][CH2:36]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCNCC1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCCCC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCS(=O)(=O)CC1
Yield: 23 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from Example 57B (200 mg, 0.37 mmol) and thiomorpholine 1,1-dioxide (150 mg, 1.11 mmol) to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-7-methoxy-quinazolin-4-ylsulfanyl}-phenyl)-urea (54.51 mg, 23%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.27 (m, 5H), 6.49 (s, 1H), 4.25-4.21 (m, 2H), 3.99 (s, 3H), 3.11 (bs, 4H), 2.95 (bs, 4H), 2.70-2.65 (m, 2H), 2.01-1.97 (m, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 641 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:25](=[O:27])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[O:21][C:20]=23)[CH:23]=1
Reactant: COCCN
Reactant: COc1cc(-c2cc3nccc(-c4cccc(C(=O)O)c4)c3o2)cc(OC)c1OC
Product: COCCNC(=O)c1cccc(-c2ccnc3cc(-c4cc(OC)c(OC)c(OC)c4)oc23)c1
Yield: 62 %

Procedure:
Starting from 3-[2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridin-7-yl]benzoic acid (0.062 mmol) and 2-methoxyethylamin (0.069 mmol) the product is prepared analogously to “A43” and obtained as colorless solid in a yield of 62%. HPLC (method A): Rt 2.53 min (purity 98.8%); LCMS (ESI+) (method E): Rt 1.78 min, M+H+ 463.2 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.84 (s, 1H), 8.79-8.72 (m, 1H), 8.60 (d, J=5.1, 1H), 8.28 (d, J=8.3, 1H), 8.03 (d, J=7.9, 1H), 7.78 (s, 1H), 7.75-7.70 (m, 2H), 7.35 (d, J=16.3, 2H), 3.93 (s, 6H), 3.74 (s, 3H), 3.54-3.43 (m, 4H), 3.28 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2].[NH2:28][CH2:29][C@H:30]1[CH2:34][CH2:33][C:32](=[O:35])[N:31]1[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:28][CH2:29][C@H:30]2[CH2:34][CH2:33][C:32](=[O:35])[N:31]2[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)CC[C@@H]1CN
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)c(NCCc2cccc(F)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1C(=O)CC[C@@H]1CNC(=O)c1ccc(-c2ccccc2C#N)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (110 mg, 0.30 mmol), (R)-tert-butyl 3-(2-(aminomethyl)-5-oxopyrrolidin-1-yl)propylcarbamate (125 mg, 0.46 mmol), HOBT (107 mg, 0.46 mmol), and HBTU (174 mg, 0.46 mg) in RB flask was added DMF and the mixture was stirred at r.t. for 1 h. LC/MS indicated the reaction was complete and the mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and water to give (R)-tert-butyl 3-(2-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)-5-oxopyrrolidin-1-yl)propylcarbamate (72 mg, 39%). LRMS (M+H+) m/z 615.2.
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:27])[C:13]2[C:18]([NH2:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([O:22][CH:23]([F:25])[F:24])[C:14]=2F)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].Cl>O1CCCC1>[NH2:19][C:18]1[C:17]([F:20])=[C:16]([F:21])[C:15]([O:22][CH:23]([F:25])[F:24])=[C:14]2[C:13]=1[C:12](=[O:27])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(N)c(F)c(F)c(OC(F)F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)c(N)c2c1=O
Reaction time: 0.5 h

Procedure:
The whole of the ethyl 3-cyclopropylamino-2-(6-amino-3-difluoromethoxy-2,4,5-trifluorobenzoyl)acrylate prepared as described above was dissolved in 340 ml of tetrahydrofuran, and 3.82 g (0.096 mole) of a 60% w/w dispersion of sodium hydride in mineral oil were added slowly to the resulting solution, whilst ice-cooling. The mixture was then stirred at the same temperature for 30 minutes, and then at room temperature for a further 1 hour. At the end of this time, the reaction mixture was acidified by the addition of 96 ml of 1N aqueous hydrochloric acid, whilst stirring vigorously. The resulting precipitate was collected by filtration and washed with water and with ethanol, in that order, to give 18.76 g of ethyl 5-amino-1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate [(XXII), R1 =--OCHF2, R17 =C2H5, X=F] as a colorless powder, melting at 295°-296° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:23][CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(S(C)(=O)=O)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (23 mg, 24%), MS (ISP) m/z=389.6 [(M+H)+], mp 321.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-methanesulfonyl-phenylboronic acid (65.0 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](Cl)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: COc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Reactant: O=C(Cl)Cc1cc(F)cc(F)c1
Product: COc1ccc(-c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3ccccc23)cc1

Procedure:
The product from Example 151A and 2-(3,5-difluorophenyl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.73 (s, 1H), 8.39-8.42 (m, 1H), 7.87-8.05 (m, 2H), 7.75-7.79 (m, 1H), 7.52-7.55 (m, 2H), 7.05-7.23 (m, 5H), 3.85 (s, 3H), 3.77 (s, 2H); MS (ESI+) M/Z 422 (M+H)+.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][C:21]([Br:26])=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[C:14]1[CH2:27][O:28][CH2:29][CH3:30])(C)(C)C>C(O)C>[Br:26][C:21]1[CH:22]=[CH:23][C:24]2[C:25]3[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])[C:14]([CH2:27][O:28][CH2:29][CH3:30])=[N:15][C:16]=3[CH:17]=[N:18][C:19]=2[CH:20]=1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCCN
Temperature: 25 °C
Yield: 93.9 %

Procedure:
Concentrated hydrochloric acid (15.6 mL, 0.194 mol) was added to a solution of tert-butyl[4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (23.2 g, 48 mmol) in ethanol, and the reaction was heated at reflux for 20 minutes. A precipitate formed, and the reaction was allowed to cool to ambient temperature overnight. The solid was isolated by filtration, washed with ethanol, and dissolved in water. The solution was washed with dichloromethane and then made basic with the addition of 50% aqueous sodium hydroxide. The basic solution was extracted with dichloromethane (3×300 mL), and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 17 g of 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH:7]=[N:8][C@H:9]([C:11]([O-:13])=[O:12])[CH3:10])=[CH:5][CH:4]=1.[Na+].[O:17]([CH2:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:7]2[N:8]([C:25](=[O:26])[CH2:24][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:9]([CH3:10])[C:11](=[O:13])[O:12]2)=[CH:14][CH:15]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: COc1ccc(C=N[C@@H](C)C(=O)[O-])cc1
Agent: [Na+]
Product: COc1ccc([C@@H]2OC(=O)[C@H](C)N2C(=O)COc2ccccc2)cc1

Procedure:
(2S,4S)-2-(4'-Methoxyphenyl)-4-methyl-N-phenoxyacetyl-1,3-oxazolidin-5-one (18) was prepared from sodium N-(para-methoxybenzylidene)-(L)-alaninate (2.29 g, 10.0 mM) and phenoxyacetyl chloride (1.37 mL, 10.0 mM) following general procedure D and obtained as a colourless oil after purification by flash column chromatography, using 20% ethyl acetate/petroleum ether as eluant (1.87 g, 55%, mixture of two diastereomers in a ratio of 4:1 by 1H-NMR). Upon trituration with diethyl ether 18 was obtained as very fine white needles and as a single diastereomer by 1H NMR: [α] D20 +224 (c 1.0, CHCl3); mp 95-97° C.; IR (KBr): 1795, 1715, 1670 cm-1 ; 1H NMR (500 MHz, d8 -toluene, 90° C.): δ 6.45-7.09 (m, 9H), 6.44 (s, 1H), 4.50 (q, J=7 Hz, 1H), 4.06 (d, J=14 Hz, 1H), 3.81 (d, J=14 Hz, 1H), 3.31 (s, 3H), 1.41 (d, J=7 Hz, 3H); 13C NMR (50.3 MHz, CDCl3): δ 172.1, 167.3, 161.4, 156.7, 129.0, 128.5, 128.1, 122.1, 114.6, 114.0, 89.6, 67.8, 55.4, 52.7, 16.1; LRMS (NH3): 342 (MH+). Anal. Calcd for C19H19NO5 : C, 66.86; H, 5.57; N, 4.10; found: C, 66.69; H, 5.59; N, 4.01.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](O)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH3:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccccc1C1(O)CCN(C(=O)OCc2ccccc2)CC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 18 h
Yield: 67.7 %

Procedure:
The product of Step 2 (5.1 g) in CH2Cl2 (50 mL) was treated sequentially with trifluoroacetic acid (8.9 mL) and triethylsilane (34.5 mL). After 18 h, the solution was treated with saturated NaHCO3 (150 mL). After a further 1 h, the organic layer was separated and the aqueous extracted with CH2Cl2 (100 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography, eluting with EtOAc/hexane mixtures to give 1-benzyloxycarbonyl-4(2-methylthiophenyl)piperidine (3.3 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=2)=[CH:29][CH:28]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:25][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=2)=[CH:31][CH:32]=1
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Reactant: CC1Cc2ccccc2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC1Cc2ccccc2N1Cc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
To a solution of 2-methylindoline (21 μL, 0.16 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (88 mg, 0.415 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 20 mg, 0.093 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with CHCl3 (3×25 mL). The organic layer was washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (11-20% acetone/CH2Cl2) to give 3-[4-(2-methyl-2,3-dihydro-indol-1-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (25 mg, 54%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (br. s., 1H), 7.98 (br. s., 1H), 7.85 (d, J=8.2 Hz, 2H), 7.56 (s, 1H), 7.48 (d, J=7.8 Hz, 2H), 6.99 (d, J=7.2 Hz, 1H), 6.84-6.94 (m, 1H), 6.53 (t, J=7.4 Hz, 1H), 6.31 (d, J=7.8 Hz, 1H), 4.45 (d, J=16.3 Hz, 1H), 4.14-4.27 (m, 1H), 3.57-3.76 (m, 1H), 3.12 (dd, J=15.8, 8.6 Hz, 1H), 2.56 (dd, J=16.0, 9.4 Hz, 1H), 1.25 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][Si:3]([O:10][CH3:11])([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7].[CH:12]([N:15]=[C:16]=[N:17][CH:18]([CH3:20])[CH3:19])([CH3:14])[CH3:13]>>[CH:18]([NH:17][C:16]([NH:7][CH2:6][CH2:5][CH2:4][Si:3]([O:8][CH3:9])([O:10][CH3:11])[O:2][CH3:1])=[N:15][CH:12]([CH3:14])[CH3:13])([CH3:20])[CH3:19]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: CC(C)N=C=NC(C)C
Product: CO[Si](CCCNC(=NC(C)C)NC(C)C)(OC)OC

Procedure:
A mixture of 11.74 g of (3-(trimethoxysilyl)propyl)amine (0.0654 mol) and of 9.9 g of diisopropylcarbodiimide (0.0785 mol, 20% excess) was heated for 6 h 30 min at 80° C. Analysis by GC then showed an amine conversion of greater than 97%. The final colorless mixture was evaporated to dryness at 100° C. under 2 mbar for 2 h to give 22.5 g of a colorless, low-viscosity liquid corresponding to the expected guanidine.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[C:6]([Cl:18])=[CH:7][C:8]([NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:9][C:10]=1[NH2:11]>C(O)C>[CH2:16]([O:15][C:13](=[O:14])[NH:12][C:8]1[N:9]=[C:10]2[NH:11][C:2]([NH2:1])=[N:4][C:5]2=[C:6]([Cl:18])[CH:7]=1)[CH3:17]
Reactant: CCOC(=O)Nc1cc(Cl)c(N)c(N)n1
Reactant: N#CBr
Solvent: CCO
Product: CCOC(=O)Nc1cc(Cl)c2nc(N)[nH]c2n1
Reaction time: 3 h
Yield: 38 %

Procedure:
Cyanogen bromide (0.55 g, 5.2 mmol) was added to a stirred solution of ethyl 5,6-diamino-4-chloro-2-pyridinecarbamate (intermediate for the preparation of 1, 1.00 g, 4.3 mmol) in 20 mL of ethanol at room temperature. The solution was stirred for 3 h and then at 60° C. for 3 h. The precipitate was filtered and washed with diethyl ether to give (2-amino-7-chloro-3H-imidazo[4,5-b]pyridin-5-yl)-carbamic acid ethyl ester (0.55 g, 38%) as a yellow powder. 1H NMR confirmed the structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:30]#[N:31])[CH:26]=3)[C:21]2=[O:32])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[OH:38][C:36]([C:35]([F:40])([F:39])[F:34])=[O:37].[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:30]#[N:31])[CH:26]=3)[C:21]2=[O:32])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(N2C(=O)c3ccc(C#N)cc3C2=O)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(N2C(=O)c3ccc(C#N)cc3C2=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of 4-(5-cyano-1,3-dioxo-2H-isoindol-2-yl)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (1.33 mmol, 0.6 g) in dichloromethane (12 mL) was added trifluoroacetic acid (3 mL) at room temperature. The reaction mixture was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. The solvent was removed under vacuum and the residue was azeotrophed with toluene (2×10 mL) and dried under high vacuum to afford 0.46 g (100%) of a yellow solid. HR MS (C19H15N3O4): Obs mass, 350.0156. Calcd mass, 350.0183 (M+H).