Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[C:31]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[C:34]([C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:33][CH:32]=[C:31]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(C(C)(C)C)ccc(C(C)(C)C)c5s4)cc3CC[C@@H]12
Yield: 17.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4,7-di(t-butyl)benzothiazole (130 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 33 mg (17%) of the title compound as an amorphous foam. FDMS: m/e=506.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].[S:28]1[CH2:34][C:32](=[O:33])[NH:31][C:29]1=[S:30]>C(O)(=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[C:34]4[S:28][C:29](=[S:30])[NH:31][C:32]4=[O:33])=[CH:17][CH:16]=3)[CH:10]=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(OCc2cccc(-c3ccccc3)c2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2cccc(-c3ccccc3)c2)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(3-phenylphenyl)methoxy]benzaldehyde (3.2 g, 10 mmol) was dissolved in acetic acid. To this solution, while stirring, were added sodium acetate (2.87 g, 35 mmol) and rhodanine (1.33 g, 10 mmol). This mixture was heated to reflux and maintained at this temperature. The progress of this reaction was monitored by thin layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].Cl[C:31]1[CH:36]=[CH:35][N+:34]([O-:37])=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:20][CH2:21][N:22]([C:31]4[CH:36]=[CH:35][N+:34]([O-:37])=[CH:33][CH:32]=4)[CH2:23][CH2:24]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCNCC1
Reactant: [O-][n+]1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCN(c2cc[n+]([O-])cc2)CC1
Temperature: 130 °C
Yield: 18 %

Procedure:
A mixture of (R)-3-(2-chlorobenzamido)-N-methyl-N-(piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide (see stage 2 illustrative compound H-214) (200 mg, 0.486 mmol, 1 eq), 4-chloropyridine N-oxide (63 mg, 0.486 mmol, 1 eq) and DIPEA (0.210 ml, 1.215 mmol, 2.5 eq) in ethanol (10 ml) was heated for 72 h at 130° C. in a pressure vessel. The reaction mixture was concentrated under reduced pressure and the crude product was then prepurified by column chromatography (Alox, 1% methanol/dichloromethane). It was then further purified by means of preparative TLC. The desired product was in the form of a white solid. Yield: 18% (90 mg, 0.178 mmol) The indicated yield is based on 2 combined batches of size 200 mg
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:17]1[C:25]2[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:21]=2[CH:20]=[CH:19][C:18]=1[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C.CCCCCC>[CH:17]1[C:25]2[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[O:22][C:21]=2[CH:20]=[CH:19][C:18]=1[N:30]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:18]3[CH:19]=[CH:20][C:21]4[O:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[C:25]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Brc1ccc(C=Cc2ccc(Br)cc2)cc1
Reactant: c1ccc(Nc2ccc3oc4ccccc4c3c2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C(=Cc1ccc(N(c2ccccc2)c2ccc3oc4ccccc4c3c2)cc1)c1ccc(N(c2ccccc2)c2ccc3oc4ccccc4c3c2)cc1

Procedure:
The Rf values of the object of the synthesis, 4,4′-dibromostilbene, and (dibenzofuran-2-yl)-phenylamine were respectively 0.37, 0.62, and 0.31, which were found by silica gel thin layer chromatography (TLC) (ethyl acetate:hexane (1:10) as the developing solvent).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=O)[CH2:13]2)=[N:6][CH:7]=1.Cl.[CH3:31][O:32][NH2:33]>CO.N1C=CC=CC=1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[C:20]([Cl:28])[CH:19]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=[N:33][O:32][CH3:31])[CH2:13]2)=[N:6][CH:7]=1
Reactant: CON
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CCC(CC(C(=O)Nc2cnc(Br)cn2)c2ccc(S(C)(=O)=O)c(Cl)c2)C1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionamide (prepared as in Example 49, 190 mg, 0.38 mmol) and methoxyamine hydrochloride (48 mg, 0.57 mmol) in methanol (0.90 mL) and pyridine (0.90 mL) was heated under reflux for 3 h. The reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layers were washed with a 1N aqueous hydrochloric acid solution (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 50% ethyl acetate/hexanes) afforded the N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-methoxyimino-cyclopentyl)-propionamide (61.2 mg, 78%) as a yellow foam: mp 91–97° C.; (ES)+-HRMS m/e calcd for C20H22BrClN4O4S (M+H)+ 529.0307 found 529.0310.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12]OC(=O)[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27]CC2C=CC=CC=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=O)[C:2]1C=CC=CC=1.NC1CC[O:41][CH2:40]C1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:26][C:25]1[CH:24]=[C:23]([OH:27])[CH:22]=[C:21]([Cl:35])[C:20]=1[CH2:19][C@@H:15]1[CH2:16][CH2:17][N:9]([CH:8]2[CH2:1][CH2:2][O:41][CH2:40][CH2:12]2)[C:14]1=[O:36]
Reactant: O=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: NC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1C1CCOCC1
Yield: 71.6 %

Procedure:
Treat a solution of 4-(4-(R)-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (Preparation 27) (10.4 g, 20 mmol) and 4-aminotetrahydropyran (2 g, 20 mmol) in dichloromethane (100 mL) with acetic acid (1 mL, 20 mmol). Stir the reaction 1 hr at room temperature then add sodium triacetoxyborohydride (12.6 g, 60 mmol) and stir for an additional 4 hr at room temperature. Quench with water and separate the organic layer. Wash with brine, dry over magnesium sulfate, filter, and remove the solvent under vacuum. Purify by silica gel column chromatography using hexanes:ethyl acetate to afford 4.93 g (57%) of desired product: MS (m/z): 434 (M+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=3)[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chlorophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 7.22 (d, 2H), 6.83 (d, 2H), 4.99 (s, 2H), 3.77 (m, 2H), 3.72 (m, 2H), 3.19 (m, 2H), 3.16 (m, 2H), 2.28 (s, 3H) ppm; MS (ES) M+Na expected=443.0, found 443.0.
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]([F:20])([F:19])[C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10].C([O-])(=O)C.[Na+].Cl.[CH3:27][O:28][C:29](=[O:39])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:31]>>[CH3:27][O:28][C:29](=[O:39])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:31][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9](=[O:10])[C:8]([F:20])([F:19])[F:7]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1C[C@H](NC(=O)C(F)(F)F)C(=O)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)C(F)(F)F
Yield: 78.5 %

Procedure:
In 84.4 g of ethyl acetate 21.1 g (0.1 mole) of N-trifluoroacetyl-L-aspartic anhydride was suspended, and 9.2 g (0.11 mole) of sodium acetate was added at -5 - 0° C. with stirring, and 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride was added at the same temperature. The mixture was reacted for 3 hours with stirring at the same temperature and concentrated under reduced pressure. Thereafter 63.3 g of acetic acid was added and stirred for an hour at 15°-20° C. Precipitated crystals were filtered, washed and dried. Crystals of N-trifluoroacetyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained in a yield of 30.6 g (78.5% yield on L-phenylalanine methyl ester hydrochloride). The crystals obtained were analyzed by high performance liquid chromatography to give a ratio of α-isomer:β-isomer of 99.0:1.0.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[C:32]([F:31])=[CH:39][C:38]([F:40])=[CH:37][C:36]=3[F:41])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cc(F)c(CBr)c(F)c1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2c(F)cc(F)cc2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2,4,6-trifluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.41 (s, 1 H), 7.20 (d, J=10.0 Hz, 1 H), 7.08 (t, J=4.0 Hz, 1 H), 6.91 (dd, J=5.6, 8.3 Hz, 1 H), 6.71 (t, J=8.1 Hz, 2 H), 6.23-6.16 (m, 1 H), 5.61-5.42 (m, 3 H), 4.31-4.24 (m, 2 H), 2.94-2.76 (m, 2 H), 2.72 (s, 3 H), 2.13-2.05 (m, 2 H), 0.96 (s, 9 H); LC/MS (m/z) ES+=539.33 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:25][C:26]3[CH:33]=[CH:32][CH:31]=[C:28]([CH3:29])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Cc1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Cc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1

Procedure:
The title compound (0.004 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3-methylbenzyl chloride (0.6 mL) in place of benzyl chloride. MS (ESI): exact mass calculated for C21H22ClN3, 351.15. found, m/z 352.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.31-7.26 (m, 2H), 7.26-7.21 (m, 2H), 6.99 (t, J=7.5 Hz, 1H), 6.88 (d, J=7.1 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J=7.1 Hz, 1H), 5.13 (s, 2H), 2.79-2.73 (m, 4H), 2.69-2.65 (m, 2H), 2.63-2.60 (m, 2H), 2.09 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[CH:7]([NH:22][CH:23]=[O:24])[CH2:6][CH:5]1[CH3:25])(=[O:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(=O)C.C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:22][CH:23]=[O:24])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2C(NC=O)CC1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](NC=O)C[C@@H]1C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of [1-acetyl-6-(4-formylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (for a preparation see Intermediate 48) (95 g, 0.25 mol) and piperidine (31 g, 0.3 mol) in solution in dichloroethane (2 L) were added at room temperature triacetoxysodiumborohydride (70 g, 0.33 mol) and acetic acid (33 g). After stirring 2 hours a t.l.c monitoring indicated the completion of the reaction and the mixture was poured into a saturated solution of NaHCO3. The organic phase was extracted after addition of DCM (500 mL) and washed with brine (100 mL), dried over Na2SO4, filtered and evaporated to dryness. Trituration of the residue in a mixture of DCM/hexane afforded the title compound (109 g, 95.6%) as an off white solid. LC/MS (Method E) m/z 406 [M+H]+, Rt=2.22 min;
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[C:10]([F:16])[CH:9]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])=[C:10]([F:16])[CH:9]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N,N-Dimethylcarbamoyl chloride (101 μL, 1.1 mmol) was added to a solution of 1-(4-bromo-2-fluorophenyl)methanamine (0.204 g, 1.0 mmol) and triethylamine (148.1 μL, 1.10 mmol) in methylene chloride (5 mL) at 0° C., followed by 4-dimethylaminopyridine (0.012 g, 0.1 mmol). After 10 min, the ice-water bath was removed and the mixture was stirred overnight at RT. The mixture was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue (253 mg, 91.9%) was directly used in next step without further purification. LCMS: (M+H)=276.9/274.9.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][N:45]1[CH:49]=[C:48]([NH2:50])[CH:47]=[N:46]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:50][C:48]3[CH:47]=[N:46][N:45]([CH3:44])[CH:49]=3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: Cn1cc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)cn1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 1-methyl-1H-pyrazol-4-amine (26 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C15H18ClN7O2, 364.13. found 364.2.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH:4]1[CH2:13][C:12]2[CH:11]=[C:10]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5]1)[CH3:2].C(N(CC)CC)C.[CH:35]([N:38]=[C:39]=[O:40])([CH3:37])[CH3:36]>C(Cl)Cl>[CH:35]([NH:38][C:39]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:3]([CH2:1][CH3:2])[CH:4]2[CH2:5][CH2:6][C:7]3[C:12](=[CH:11][C:10]([NH:14][C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])=[CH:9][CH:8]=3)[CH2:13]2)[CH2:27][CH2:26]1)=[O:40])([CH3:37])[CH3:36]
Reactant: CCN(CC1CCNCC1)C1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Reaction time: 20 h
Yield: 79.1 %

Procedure:
To a solution of N-[7-(ethyl-piperidin-4-ylmethyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-2,2,2-trifluoro-acetamide (1.7 mmol) in methylene chloride (20 mL) under an inert atmosphere was added triethylamine (1.0 mL, 6.6 mmol) and isopropyl isocyanate (230 μL, 2.3 mmol). The reaction was stirred for 20 h and then concentrated in vacuo. This material was partitioned between 5% KOH and water. The organic layer was dried (MgSO4) and concentrated to afford 4-({ethyl-[7-(2,2,2-trifluoro-acetylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid isopropylamide as a clear oil (630 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][NH2:11].C(N(CC)CC)C.[F:26][C:27]([F:40])([F:39])[O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][NH:11][S:35]([C:32]1[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:39])[F:40])=[CH:34][CH:33]=1)(=[O:37])=[O:36]
Reactant: NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(OC(F)(F)F)cc1
Yield: 59.6 %

Procedure:
To a solution of 0.20 g of 3,5-dichloro-4-(2-aminoethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene and 0.10 g of triethylamine dissolved in 5 ml of dichloromethane was added dropwise a solution of 0.16 g of 4-trifluoromethoxybenzenesulfonyl chloride dissolved in 5 ml of dichloromethane, while stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.20 g of 3,5-dichloro-4-(2-(4-trifluoromethoxybenzenesulfonamido)ethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (60% yield), nD23.0 1.5470.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O.CCCCCC>[Si:18]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([Br:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)c2occc2c1
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)c2occc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 231 %

Procedure:
A mixture of 0.12 gm (0.52 mmol) 5-hydroxymethyl-7-bromobenzofuran 0.070 gm (1.03 mMol) imidazole, and 0.078 gm (0.52 mMol), 0.070 gm (1.03 mMol) imidazole, and 0.078 gm (0.52 mMol) tert-butyldimethylsilyl chloride in 1 mL dimethylformamide was stirred at room temperature for 18 hours. The reaction mixture was diluted with hexane and washed well with water. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure to provide 0.41 gm (82%) of 5-tert-butyldimethylsilyloxymethyl-7-bromobenzofuran. This material was reacted essentially as described in EXAMPLE 1 to provide 0.085 gm (24%) 1-(5-tert-butyldimethylsilyloxy-methylbenzofur-7-yl)-2-aminopropane. This material was treated with tetrabutylammonium fluoride in tetrahydrofuran for 1 hour at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated and the organic phase washed well with water. The remaining organics were concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with dichloromethane containing 2% methanol saturated with ammonia. Fractions containing product were combined and concentrated under reduced pressure to provide 0.028 gm (50%) of 1-(5-hydroxymethylbenzofur-7-yl)-2-aminopropane. The title compound was prepared by reacting this amine with hydrochloric acid.