Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[CH2:23]([C@@H:30]1[CH2:35][C@@H:34]([N:36]([CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[CH:46][CH:45]=2)[C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])[CH2:33][CH2:32][NH:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[F:54][C:55]([F:70])([F:69])[C:56]1[CH:57]=[C:58]([CH:62]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:64]=1)[C:59](O)=[O:60]>C(Cl)Cl>[CH2:23]([C@@H:30]1[CH2:35][C@@H:34]([N:36]([CH2:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=[CH:46][CH:45]=2)[C:37](=[O:42])[C:38]([F:40])([F:41])[F:39])[CH2:33][CH2:32][N:31]1[C:59](=[O:60])[C:58]1[CH:62]=[C:63]([C:65]([F:66])([F:67])[F:68])[CH:64]=[C:56]([C:55]([F:54])([F:69])[F:70])[CH:57]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
143 mg (561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine are added to a solution of 200 mg (467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 113 mg (561 mmol) of 3,5-bis-(trifluoromethyl)-benzoic acid in 3 ml of methylene chloride, and the reaction mixture is left to stir at room temperature for 16 hours. It is then diluted with methylene chloride, and the organic phase is washed once each with 10% strength citric acid, 1N sodium bicarbonate solution and with brine, dried over magnesium sulfate and evaporated to dryness. The yellowish foam is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (1000:50:1). The title compound is obtained as yellow oil. TLC: methylene chloride/methanol/conc. ammonia (1000: 50:1) Rf =0.34, FD-MS: M+ =667.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:32][C:27]1[CH:26]=[C:25]([C:19]2([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=[C:16]([C:14]3[CH:13]=[CH:12][C:3]([C:4]([NH:6][CH2:7][C:8]([F:10])([F:9])[F:11])=[O:5])=[C:2]([NH:1][CH3:35])[CH:15]=3)[CH2:20]2)[CH:30]=[C:29]([Cl:31])[CH:28]=1
Reactant: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
In a solution of 0.25 g of 2-amino-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-(2,2,2-trifluoroethyl)benzoic acid amide (Compound of the present invention No. 5-329) synthesized in Synthetic Example 12 and 0.06 g of 36% formaldehyde aqueous solution in 7 ml of 1,2-dichloroethane, 1.00 g of sodium triacetoxy borohydride was added with stirring at room temperature in three portions at 1 hour-interval, and continued to stir at the same temperature for further 2 hours. After the completion of the reaction, the reaction mixture was poured to 5 ml of ice water, the organic phase was collected, and the solvent was distilled under reduced pressure. The residue was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (0:1 to 1:3 gradient), and 0.13 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylamino-N-(2,2,2-trifluoroethyl)benzoic acid amide was obtained as pale yellow crystal, and 0.13 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-dimethylamino-N-(2,2,2-trifluoroethyl)benzoic acid amide was obtained as pale yellow resinous substance.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[S:6][CH:7]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>O1CCCC1>[CH2:25]([N:28]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[S:6][CH:7]=1)[CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)cc2C1=O
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)n1
Reaction time: 12 h
Yield: 28.9 %

Procedure:
A suspension of 1.0 g (0.00275 mol) of 3-(4-chloromethylthiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 50 ml of tetrahydrofuran was treated with 4.5 ml (0.033 mol) of dipropylamine. After stirring at 50° for 12 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent and recrystallized from hot isopropyl ether. There was obtained 0.34 g (29%) of 3-(4-dipropylaminomethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p.134°-136°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[C:6]([O:14][CH3:15])=[N:5]2.[CH:16](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:16]=[N:13][N:12]=[C:7]1[C:6]([O:14][CH3:15])=[N:5]2
Reactant: COc1nc2cc(Cl)ccc2nc1NN
Reactant: CCOC(OCC)OCC
Product: COc1nc2cc(Cl)ccc2n2cnnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 1.4 g. (0.0062 mole) of 6-chloro-2-hydrazino-3-methoxyquinoxaline and 20 ml. of triethyl orthoformate was heated with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting mixture was then cooled to room temperature, and the precipitate which formed was subsequently recovered by means of suction filtration and washed with ethanol to ultimately afford 1.0 g. (69%) of pure 7-chloro-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 250°-252° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[NH2:5].Cl.O1CCOCC1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[F:35])[N:28]=[CH:27][N:26]=1>C(#N)C>[F:35][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:34]=1[C:25]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:2]([CH3:1])[CH:3]=1)=[N:26][CH:27]=[N:28]2
Reactant: Fc1cccc2ncnc(Cl)c12
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
3-Methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (6.42 g, 30 mmol) and 4N hydrogen chloride in dioxane (7.55 ml, 30 mmol) were added to a suspension of 4-chloro-5-fluoroquinazoline (5 g, 27.5 mmol; obtained as described in PCT Int. Appl. WO2001094341, AstraZeneca) in acetonitrile (100 ml). The mixture was stirred at 80° C. for 2 hours. After cooling, the precipitate washed with acetonitrile. This precipitate was partitioned between DCM and 5% aqueous sodium bicarbonate and the pH was adjusted to 8. The organic layer washed with brine and dried over MgSO4. Evaporation of the solvents gave 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (9.3 g, 94%) as a dark gum which crystallised on standing; NMR spectrum (CDCl3); 2.30 (s, 3H), 2.54 (s, 3H), 6.93 (d, 1H), 7.15-7.08 (m, 2H), 7.22 (m, 1H), 7.56 (d, 1H), 7.63 (s, 1H), 7.71 (m, 2H), 8.27 (s, 1H), 8.37 (d, 1H), 8.71 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH2:12]1)([O-:3])=[O:2].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][N:8]([CH2:7][C:6]1[CH:30]=[CH:31][CH:32]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:9][CH2:10][N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH2:12]1)[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN(CCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
106 mg of N-(3-nitrobenzyl)-2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 123-b), 40 mg of ethyl bromoacetate, and 33 mg of potassium carbonate were dissolved in 1 mL of acetonitrile, followed by stirring at room temperature for 3 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (chloroform:methanol=20:1) to obtain 97 mg (yield 76%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH2:21][CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:27]3[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][CH2:21][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(CCCc2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-phenylpropyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 73% overall yield. FDMS m/e=392 (M+ of free base). α[D]589 =-13.53 (c=0.58, methanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S@](C(C)(C)C)=O)[CH3:9])=[C:4]([F:17])[CH:3]=1.[ClH:18].O1CCOCC1>CO>[ClH:18].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([F:17])[CH:3]=1
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(Br)cc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccc(Br)cc1F
Reaction time: 4 h

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinic acid [(R)-1-(4-bromo-2-fluoro-phenyl)-ethyl]-amide (4.02 g, 12.5 mmol) in methanol (25 ml) was added a 4M HCl solution in dioxane (6.24 ml, 25.0 mmol) and the mixture was stirred for 4 h. The reaction mixture was then concentrated and diethyl ether was added. The resulting suspension was stirred for 2 h and then filtered to deliver the title compound as white solid (3.11 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39]2)[C:34]([F:50])=[CH:33][N:32]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:39]4)[C:34]([F:50])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 90 °C
Yield: 42 %

Procedure:
A solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (2.41 g, 5.60 mmol) and tert-butyl (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]pyrrolidine-1-carboxylate, 7a, (1.69 g, 5.30 mmol) in DME (34 mL) and 2M Na2CO3 (8.5 mL) was degassed with nitrogen (5 min) then treated with Pd(PPh3)4 (0.31 g, 0.27 mmol) then heated at 90° C. overnight. The resulting dark solution was filtered through florisil, washed with EtOAc then concentrated in vacuo. The resulting residue was purified by silica-gel chromatography (0-100%) petroleum ether: EtOAc gradient. Removal of the solvent under reduced pressure afforded 1.33 g (42% yield) of a white solid after vacuum drying.
Reaction SMILES: C(S([NH:7][CH:8]([C:10]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:11]=1[CH2:12][OH:13])[CH3:9])=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH:8]([C:10]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:11]=1[CH2:12][OH:13])[CH3:9]
Reactant: CC(NS(=O)C(C)(C)C)c1ccc(Cl)cc1CO
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(N)c1ccc(Cl)cc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(1-tert-butylsulfinamidylethyl)-5-chlorobenzyl alcohol from step 2 of the L-519,502 synthesis (isomer 2, 0.654 g, 2.23 mmol) in MeOH (10 mL) at ambient temperature was added 4M HCl in dioxane (1.12 mL, 4.46 mmol). The resulting solution was stirred at ambient temperature for 0.5 h, then concentrated in vacuo. The residue was partitioned between EtOAc and water basified to pH=8 with saturated NaHCO3 solution. The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure. 2-(1-aminoethyl)-5-chlorobenzyl alcohol was obtained as a pink oil that crystallizes on sitting (0.3 g; HPLC RT=2.07 min, method A; 1H NMR, 400 MHz, CDCl3, 7.32 ppm (d, 1H), 7.29 ppm (d, 1H), 7.24 ppm (dd, 1H), 4.76 ppm (d, 1H), 4.65 ppm (d, 1H), 4.34 ppm (q, 1H), 3.4 ppm (br s, 3H), 1.7 ppm (d, 3H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:9](=O)[CH2:8][CH2:7]1)=[O:5].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCl.CC(O)=O>[CH2:2]([O:3][C:4]([C@H:6]1[CH2:12][CH2:11][C@H:9]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](NNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-cyclohexanonecarboxylic acid ethyl ester (5.0 g, 29.0 mmol) and tert-butyl carbazate (3.9 g, 29.4 mmol) in dichlorometane (250 mL) and AcOH (4 mL) was added NaBH(OAc)3 (18.7 g, 88.0 mmol) gradually at 0° C. After addition, the mixture was stirred at the same temperature for 3 h, then allowed to warm to room temperature and stirred for 20 h. The reaction mixture was poured into saturated aqueous Na2CO3 solution and extracted with DCM. The DCM extracts were washed with brine×2 and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound D1-1 (3.0 g, 36%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[I-].[Na+].[C:34](=[O:37])([O-])[O-:35].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:7]([C:11]([O:13][CH:14]([O:35][C:34](=[O:37])[C:25]([CH3:30])([CH3:26])[CH3:24])[CH:15]([CH3:23])[CH3:16])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(C(=O)OC(OC(=O)C(C)(C)C)C(C)C)n1Cc1cccc2c1ccn2-c1ccccc1C#N

Procedure:
A mixture containing 2-butyl-4-chloro-1-[[1-(2-cyanophenyl)-1H-indol-4-yl]methyl]-1H-imidazole-5-carboxylic acid (550 mg, 1.27 mmol, prepared as described in part C of Example 9), the title A compound (979 mg, 5.08 mmol), sodium iodide (381 mg, 2.54 mmol) and cesium carbonate (1.86 g, 5.72 mmol) in 2.5 mL of dimethylformamide was heated at 60° C. for 7 hours in a stoppered flask. Upon cooling the reaction mixture was diluted with 110 mL of ethyl acetate and filtered. The organic extract was rinsed with three 15 mL portions of pH 4 buffer, 20 mL of 1:1, water:brine and 30 mL of brine, then dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 1.3 g of crude product. Chromatography on 75 g of silica gel eluted with 4:1, hexanes:ethyl acetate yielded 567 mg of the title B compound.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:21]=[CH:20][C:11]3[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=3[CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].[NH4+].[OH-]>CO.O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6](=[N:25][OH:26])[C:8]2[CH:21]=[CH:20][C:11]3[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Nc1nc2cc(C(=O)c3ccc(F)cc3)ccc2[nH]1
Reactant: NO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)Nc1nc2cc(C(=NO)c3ccc(F)cc3)ccc2[nH]1
Temperature: 25 °C

Procedure:
Methyl [5-(4-fluorobenzoyl)-1H-benzimidazol-2-yl]carbamate, (581.6 g, 1.86 mole) (Janssen Pharmaceutica, U.S. Pat. No. 3,657,267, Apr. 18, 1972) was suspended in MeOH (15 L) in which hydroxylamine hydrochloride (508.1 g, 7.32 mole) was dissolved. The mixture was heated at reflux (80 hrs) until a clear solution was obtained and the starting material was no longer detected at TLC. After cooling to room temperature, the mixture was filtered to remove undissolved material, and the solvent was removed under reduced pressure to give a solid residue. This material was suspended in H2O (5 L) and adjusted to pH 12 with conc. NH4OH. The title product that was obtained as a precipitate was collected by filtration, washed with H2O, then dried under reduced pressure at 70° C. for 16 hrs. Yield: 620.8 g. TLC Rf=0.4-0.6 (2nd spot), 0.0 (base line material). Mp:>315° C.; 3405, 1725, 1660-1640, 1600, 835, 760 cm-1, 1H NMR (DMSO-d6): δ 3.78 (s, 3 H, OCH3), 6.70-8.00 (m, 7 H, Ar--H), 11.20 (bs, 1 H, NH), 11.90 (bs, 1 H, OH).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][C:3]=1[C:4]([NH2:6])=O.[CH2:21]([O:23]C(OCC)OCC)C>>[CH3:12][O:11][C:9]1[CH:10]=[C:2]2[C:3]([CH:4]=[N:6][C:21](=[O:23])[NH:1]2)=[CH:7][C:8]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(N)c(C(N)=O)cc1OCc1ccccc1
Product: COc1cc2[nH]c(=O)ncc2cc1OCc1ccccc1

Procedure:
2-Amino-4-methoxy-5-benzyloxybenzamide (JMC, 20, 146) (5 g) was mixed with triethylorthoformate (15 ml) and refluxed overnight. The reaction solution was cooled and triturated with EtOAc (40 ml) then filtered to give 7-methoxy-6-benzyloxyquinazolone (3.2 g). This product was mixed with DIPEA (15 ml) and to the solution was added POCl3 (3 ml) slowly. The reaction mixture was refluxed for 30 minutes and cooled, then poured into a stirred mixture of ice and CHCl3. The solution was further extracted with CHCl3 three times and washed with H2O followed by brine, dried over Na2SO4 and evaporated to give a light brown solid as the chloride for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.CC(C)([O-])C.[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4C)c3O2)cc1
Yield: 69.5 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-methylphenylboronic acid (0.266 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium tert-butoxide (0.366 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.358 g (70%) of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 98-100° C.; Anal. calcd. for C23H22O4S: C, 70.03; H, 5.62. Found: C, 69.83; H, 5.61.
Reaction SMILES: [CH:1]1([C:6](O)([CH2:23][C:24]2[O:25]C(C)(C)[O:27][C:28](=[O:30])[CH:29]=2)[C:7]#[C:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])=[C:11]([F:22])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C(C)(C)C#N)=C(F)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]([CH3:20])([CH3:21])[C:18]#[N:19])=[C:11]([F:22])[CH:10]=3)[CH2:23][C:24]([OH:25])=[CH:29][C:28](=[O:27])[O:30]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(C)(C)C#N)c(F)cc1C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Product: COc1cc(C(C)(C)C#N)c(F)cc1CCC1(C2CCCC2)CC(O)=CC(=O)O1

Procedure:
The desired product was prepared analogously to Example A (97), step 4, substituting 2-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-5-methoxy-phenyl}-2-methyl-propionitrile (2.0 g, 4.39 mmol) from Step 6 below in place of 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile. Yield: 0.87 g, 49%. 1H NMR (CDCl3) δ: 1.39–1.48 (m, 2H), 1.59–1.68 (m, 5H), 1.79 (s, 6H), 1.83–1.95 (m, 3H), 2.30–2.37 (m, 1H), 2.54–2.69 (m, 4H), 3.83 (s, 3H), 5.30 (s, 1H), 6.86 (d, J=11.9 Hz, 1H), 6.95 (d, J=6.6 Hz, 1H). MS (ESI): 400 (M−1).