Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.O.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13](=[O:15])[CH3:14])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(C)c1cc(Br)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(Br)cc1C(C)C
Yield: 83 %

Procedure:
A solution of 4-bromo-2-iso-propyl-phenylamine (780 mg, 3.64 mmol) in acetic anhydride (4 mL) was stirred at room temperature over night. The reaction was poured into water and the resulting white precipitate was filtered off and dried under vacuum to give N-(4-bromo-2-iso-propyl-phenyl)-acetamide as a light pink solid (0.770 g, 83%); 1H NMR (300 MHz, DMSO-d6): δ 9.39 (s, 1H), 7.43 (d, 1H, J=2.4 Hz), 3.16 (m, 1H), 2.04 (s, 3H), 1.13 (d, 6H, J=7 Hz); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=dichloromethane; Rf=0.21
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C@@:17]12[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:20][C@@H:19]([N:25](C(=O)C(F)(F)F)[C@@H:26]1[C@H:31]([O:32][CH3:33])[CH2:30][O:29][CH2:28][CH2:27]1)[CH2:18]2)=[O:16])=[O:7])(C)(C)C.[BH4-].[Na+].O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(O)C>[C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C@@:17]12[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:20][C@@H:19]([NH:25][C@@H:26]1[C@H:31]([O:32][CH3:33])[CH2:30][O:29][CH2:28][CH2:27]1)[CH2:18]2)=[O:16])([OH:7])=[O:5]
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1C[C@H]2CCC[C@@]2(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CCC[C@@]2(C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)O)C1
Yield: 107.7 %

Procedure:
A solution of Example 11A (5.5 g, 9.8 mmol) and NaBH4 (1.1 g, 29.4 mmol) in dichloromethane/ethanol (20 mL/20 mL) was stirred at room temperature for 2 hours. Water was added and the resulting solution was adjusted to pH=10 with saturated Na2CO3 solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to result in the title compound (4.3 g, 95%).
Reaction SMILES: [CH2:1]1[C@H:9]([OH:10])[C@H:8]2[N:3]([CH2:4][C@H:5]([OH:13])[C@@H:6]([OH:12])[C@@H:7]2[OH:11])[CH2:2]1.[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C>N1C=CC=CC=1.O.CO>[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:13][CH:5]2[CH:6]([OH:12])[CH:7]([OH:11])[CH:8]3[N:3]([CH2:2][CH2:1][CH:9]3[OH:10])[CH2:4]2)=[O:20])=[CH:17][CH:16]=1
Reactant: O[C@H]1[C@H](O)[C@@H](O)CN2CC[C@H](O)[C@H]12
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OC2CN3CCC(O)C3C(O)C2O)cc1
Temperature: 25 °C
Yield: 12 %

Procedure:
To a suspension of 3 g of castanospermine in 30 ml of pyridine at 0° C. was added dropwise a solution of 3 g of 4-methylbenzoyl chloride. After the addition, the mixture was allowed to warm to room temperature and then heated at 55° C. for 24 hours. The reaction mixture was diluted with 10 ml of water and evaporated to dryness in vacuo. The resulting residue was stirred in 150 ml of a 1:2 mixture of water:methylene chloride. The insoluble material was separated by filtration to provide an amorphous off-white solid which was dissolved in 60 ml of hot methanol, treated with 0.5 g of activated charcoal and filtered. The colorless liltrate was cooled to give colorless crystals of [1S-(1α, 6β, 7α, 8β, 8αβ)]-octahydro-1,6,7,8-indolizine-tetrol 6-(4-methylbenzoate) melting at about 255°-258° C. with decomposition (580 mg, 12% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:22][C:23]([NH:25][C@H:26]([CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=S.[NH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:22][C:23]([NH:25][C@H:26]([CH3:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[NH:34]
Reactant: N
Reactant: COc1cc2c(NC(=S)N[C@H](C)c3ccccc3)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(NC(=N)N[C@H](C)c3ccccc3)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Using an analogous procedure to that described in Example 29, 1-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]-3-[(R)-(+)-α-methylbenzyl]thiourea was reacted with ammonia to give the title compound; NMR Spectrum: (CDCl3) 1.38-1.42 (m, 2H), 1.61 (d, 3H), 1.86-2.01 (q, 5H), 2.29 (s, 3H), 2.89 (d, 2H), 3.95 (m, 3H), 4.0 (d, 2H), 4.7 (q, 1H), 6.5 (br s, 1H), 7.12 (s, 1H), 7.29-7.31 (m, 5H), 7.79 (s, 1H), 8.53 (s, 1H); Mass Spectrum: M+H+ 449.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:15]([O:19][C:20]([CH2:22][NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:1]([N:26]1[CH2:27][CH2:28][CH:24]([NH:23][CH2:22][C:20]([O:19][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:21])[CH2:25]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)CNC1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(NCC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
Under nitrogen atmosphere, acetic anhydride (707 μl, 7.49 mmol) and triethylamine (1.39 ml, 9.98 mmol) were added to a dichloromethane (25 ml) solution of 3-(tert-butoxycarbonylmethylamino)pyrrolidine (1.00 g, 4.99 mmol) with cooling with ice, followed by stirring at room temperature for 17 hours. The solvent was evaporated away under reduced pressure, then the resulting residue was subjected to silica gel column chromatography, and the eluate with ethyl acetate gave the entitled compound (1.10 g, 91%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]1([C:37]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[N:38]2[CH:42]=[C:41]([CH2:43][CH2:44]O)[N:40]=[CH:39]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:52]1([C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:38]2[CH:42]=[C:41]([CH2:43][CH2:44][O:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=3)[N:40]=[CH:39]2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(OCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 0.08 h

Procedure:
15 ml of freshly distilled tetrahydrofuran, 340 mg (2.1 mmol) of 4-trifluoromethylphenol and 550 mg (2.1 mmol) of triphenylphosphine are added under nitrogen to 708 g (2 mmol) of 1-triphenylmethyl-4-(2-hydroxyethyl)-1H-imidazole. The resulting mixture is cooled and stirred for 5 min. 66 mg (2.1 mmol) of diethyl azodicarboxylate in 10 ml of tetrahydrofuran are then slowly added. Stirring is continued at room temperature for 2 hours under nitrogen. The solvent is then evaporated under reduced pressure and the residue is chromatographed on a column of silica gel, using diethyl ether as the eluent, to give 1-triphenylmethyl-4-[2-(4-trifluoromethylphenoxy)ethyl]-1H-imidazole.
Reaction SMILES: II.O[PH2]=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([CH:16]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][C:27]=3[F:28])[N:24]=[CH:23][CH:22]=[CH:21]4)O)=[CH:14][N:15]=2)[N:12]=1>C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([CH2:16][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][C:27]=3[F:28])[N:24]=[CH:23][CH:22]=[CH:21]4)=[CH:14][N:15]=2)[N:12]=1
Reactant: OC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Iodine (3.09 g, 12.17 mmol) and H3PO2 (1.673 mL of a 50% aqueous solution, 30.4 mmol) are added to a solution of (rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)methanol (Stage 174.3, 2 g, 6.08 mmol) in acetic acid (20 mL). The RM was heated under stirring at 110° C. for 18 h. The RM was then evaporated and taken into DCM and washed with NaHCO3 sol., and extracted with DCM/NaHCO3 sol. The combined organic layer were dried and concentrated. The residue was stirred in acetone and filtered. After 3 h drying under vacuum, it gave the title compound (tR 4.41 min (conditions 3), MH+=313).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:24])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCc2ccc(OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CCN2CCC(C(=O)O)(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid ethyl ester (5.0 g, 10.8 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.0 g (85%); off white powder; mp 205° C.; MS: 434.5 (M+H)+.
Reaction SMILES: [NH:1]1[C:6]2[S:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:5]=2[C:4](=[O:15])[NH:3][C:2]1=[O:16].[H][H].CCOC(/N=N/C(OCC)=O)=O.C1(=O)C=CC(=O)C=C1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O=O>C(#N)C>[N:1]1[C:2](=[O:16])[NH:3][C:4](=[O:15])[C:5]2[C:6]=1[S:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[N:10]=2
Reactant: O=c1[nH]c2c(c(=O)[nH]1)Nc1ccccc1S2
Reactant: [H][H]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C1C=CC(=O)C=C1
Solvent: CC#N
Product: O=c1nc2sc3ccccc3nc-2c(=O)[nH]1

Procedure:
When derivative compounds of formula (II) are desired, a solution or suspension of 1,5-dihydro-2H-pyrimido[4,5-b][1,4]benzothiazine-2,4(3H)-dione derivative of formula (I) wherein R4 is hydrogen in acetonitrile is prepared. To that solution or suspension at room temperature is added, dropwise, an oxidant such as diethylazodicarboxylate, 1,4-benzoquinone or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Alternatively, oxygen can be used as the oxidant. A preferred oxidant is diethylazodicarboxylate. The reaction mixture is stirred. When a precipitate results, the precipitate is collected an washed with diethylether to give a 2H-pyrimido[4,5-b][1,4]benzothiazine-2,4(3H)-dione derivative of formula (II). When no precipitate is obtained after oxidation, the solvent is removed from the reaction mixture, and the residue is triturated with diethylether and filtered to give a compound of formula (II).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9]C(=O)OC(C)(C)C)[CH:6]=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:9][C:7]1[N:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#N)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.7 %

Procedure:
To a round bottom flask charged with tert-butyl (6-cyanopyridin-2-yl)carbamate (0.5383 g, 2.455 mmol) in dichloromethane (9.82 ml) was added TFA (2.455 ml). The reaction mixture was stirred at room temperature 4 h. Excess TFA was removed in vacuo. The crude residue was taken up in methanol and free based using 2 parallel Phenomenex 5 g SCX columns. The columns were flushed with three column volumes methanol and three column volumes 3.5 N ammonia/methanol. The ammonia layers were concentrated in vacuo to provide 6-aminopicolinonitrile (0.312 g).
Reaction SMILES: [CH3:1][NH2:2].CO.[Cl:5][C:6]1[CH:11]=[C:10](I)[C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1>CCCCCC>[Cl:5][C:6]1[CH:11]=[C:10]([NH:2][CH3:1])[C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1
Reactant: CN
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Solvent: CO
Solvent: CCCCCC
Product: CNc1cc(Cl)ncc1C(F)(F)F
Temperature: 130 °C
Yield: 31 %

Procedure:
2 M Methylamine in MeOH (11.6 mL, 23.2 mmol) was added to 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (357 mg, 1.16 mmol) and the mixture was heated in a microwave reactor at 130° C. for 1 hour. The mixture was concentrated in vacuo. Preparative thin-layer chromatography, eluting with 20% EtOAc:hexane, gave 2-chloro-N-methyl-5-(trifluoromethyl)pyridin-4-amine (77 mg, 0.363 mmol, 31% yield).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[OH-].[Na+:14]>C(C(C)=O)C(C)C>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([O-:9])=[O:8])=[CH:4][CH:3]=1.[Na+:14]
Reactant: O=C(O)C(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: O=C([O-])C(O)c1ccc(O)cc1
Temperature: 20 °C

Procedure:
The procedure of Example 1 was repeated except that the organic phase containing p-hydroxymandelic acid was treated with a molar equivalent of sodium hydroxide as a 50% w/w aqueous solution. The caustic solution was added over one hour during which time the methyl isobutyl ketone solution was maintained at about 20° C. with cooling. The precipitate of sodium p-hydroxymandelate monohydrate was filtered off and suctioned as dry as possible before drying under vacuum at 40° C.
Reaction SMILES: C(OC([N:6]1[CH:15]=[C:14]([CH:16]=[O:17])[C:13]2[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:12]=2)[CH:7]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH3:37])[CH:30]=1)=O)C.[OH-].[K+].C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>CO>[C:23]([O:22][CH2:21][CH2:20][CH2:19][O:18][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:26][CH3:27])[CH:7]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH3:37])[CH:30]=1)[NH:6][CH:15]=[C:14]2[CH:16]=[O:17])(=[O:25])[CH3:24]
Reactant: CCOC(=O)N1C=C(C=O)c2cc(OCCCOC(C)=O)c(OC)cc2C1Cc1cccc(OCC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CCOc1cccc(CC2NC=C(C=O)c3cc(OCCCOC(C)=O)c(OC)cc32)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 109.2 %

Procedure:
To a solution of 6-(3-acetoxy-propoxy)-1-(3-ethoxy-benzyl)-4-formyl-7-methoxy-1H-isoquinoline-2-carboxylic acid ethyl ester (130 mg, 0.25 mmol) in methanol (3.5 mL) was added powdered potassium hydroxide (85.5 mg, 1.53 mmol) at room temperature. The mixture was stirred at room temperature for 14 hrs. The solvent was evaporated and the residue was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (2×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane, 75% ethyl acetate/hexane, ethyl acetate) afforded 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (120 mg, 42% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:7]1([CH2:11][C:10](=[O:12])[NH:9][CH2:8]1)[CH2:6][C:5]2=[O:16].[BH4-].[Na+]>CO.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:7]1([CH2:11][C:10](=[O:12])[NH:9][CH2:8]1)[CH2:6][CH:5]2[OH:16]
Reactant: O=C1CC2(CN1)CC(=O)c1cc(Cl)ccc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CC2(CN1)CC(O)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
210 g of 5-chlorospiro[indane-1,3'-pyrrolidine]-3,5'-dione are dissolved in 2,5 liters of methanol, and a solution of 20 g of sodium borohydride in 250 cc of water and 5 cc of caustic soda solution is added at room temperature at such a rate that the temperature in the reaction vessel does not exceed 25°. The solution is stirred at room temperature for 2 hours, is then poured on ice and extracted several times with chloroform. The 5-chloro-3 -hydroxyspiro[indane-1,3'-pyrrolidin]-5'-one, obtained after concentrating the chloroform solution by evaporation, is a mixture of diastereoisomers, having a M.P. of 155°-180°, and containing approximately equal parts of the 1RS,3SR and the 1RS,3RS isomer. Pure (1RS,3SR)-5-chloro-3-hydroxyspiro[indane-1,3'-pyrrolidin]-5'-one, having a M.P. of 213°-216°, may be obtained by extracting repeatedly with chloroform and subsequently recrytallizing twice from methanol.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([O:13]C)=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(Cl)cccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c(Cl)cccc2s1
Temperature: 95 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
A mixture of methyl 4-chlorobenzo[b]thiophene-2-carboxylate (20 g), 5M aqueous sodium hydroxide solution (100 ml) and water (300 ml) was heated at 95° C. for 5 hours then poured into a mixture of concentrated hydrochloric acid (180 ml) and water (2000 ml) and stirred at ambient temperature for 2 hours. The resulting solid was collected by filtration, washed with water (3×500 ml), and dried in vacuo at 60° C. to give 4-chlorobenzo[b]thiophene-2-carboxylic acid (21.0 g) as an off-white solid, m.p. 246-248° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9]C)=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH2:13][CH2:12]1.B(Cl)(Cl)Cl.C(=O)=O.CC(C)=O.O>C(Cl)Cl>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][N:18]=2)[CH2:15][CH2:16]1
Reactant: COc1cc(Cl)c(Br)c(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1
Agent: ClB(Cl)Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: Oc1cc(Cl)c(Br)c(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A stirred solution of 0.38 gram (0.00084 mole) of 2-bromo-3-chloro-5-methoxy-1-{4-[5-(trifluoromethyl)(2-pyridyl)]piperazinyl}benzene and 0.78 gram (0.0021 mole) of n-tetrabutylammonium iodide in 30 mL of methylene chloride was cooled in a dry-ice/acetone bath and 2.1 mL (0.0021 mole, a 1.0M solution in methylene chloride) of boron trichloride was added dropwise. Upon completion of addition the reaction mixture was kept cold in the dry-ice/acetone bath for an additional 30-minute period, then it was allowed to warm to ambient temperature where it stirred during a three-hour period. After this time the reaction mixture was cooled in an ice/water bath and 15 mL of water was added. The organic layer was separated and the aqueous layer was extracted with one 15 mL portion of methylene chloride. The organic layer and the extract were combined and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using as eluants: 50% hexane in methylene chloride, then 100% methylene chloride, and finally 2% methanol in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.17 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=1.C(OC)(=O)C>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1ccc(Cl)nn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Solvent: COC(C)=O
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn1
Temperature: 25 °C

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-chloro-6-methylpyridazine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.118, m/z=446; 1H NMR (CD3OD) 0.96 (s, 3H), 1.26 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.26 (m, 1H), 2.50 (m, 2H), 2.69 (s, 3H), 3.08 (m, 1H), 5.59 (m, 1H), 7.11 (m, 2H), 7.25-7.40 (5H), 7.63 (m, 1H), 7.82 (m, 2H), 7.98 (d, 1H). The compound was dissolved in refluxing methyl acetate and allowed to cool slowly to rt to afford a solid with mp 149.5-151.5° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH3:17])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18](I)[CH3:19].[Li].C(NC(C)C)(C)C>>[C:1]1([CH2:7][CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH2:17][CH2:18][CH3:19])[CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cnccc1C(C)CCc1ccccc1
Reactant: CCI
Agent: [Li]
Solvent: CC(C)NC(C)C
Product: CCCc1cnccc1C(C)CCc1ccccc1
Yield: 15.6 %

Procedure:
2.1 g (9.35 mmol) of 1-phenyl-3-(3-methyl-4-pyridyl)butane, 1.46 g (9.35 mmol) of ethyl iodide and 2 equivalent of lithium-diisopropylamine were reacted in the same manner as in Example 1. The reaction product was purified to obtain 0.37 g of the desired compound (yield: 15.6%).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[Br:9]Br>[OH-].[Na+]>[Br:9][N:3]1[C:2]([CH3:8])([CH3:1])[CH2:6][O:5][C:4]1=[O:7]
Reactant: BrBr
Reactant: CC1(C)COC(=O)N1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)COC(=O)N1Br
Reaction time: 0.25 h

Procedure:
12.3 g (0.11 mol) 4,4-dimethyl-2-oxazolidinone was dissolved in 180 ml of 1 M sodium hydroxide and the resulting solution was cooled to 0°. 19.2 g (0.012 mol) bromine was added dropwise with stirring over 0.25 hr and the reaction mixture was stirred at 0° for an additional 0.75 hr. The N-bromamine separated from the reaction mixture as an orange colored solid. The solid was isolated by filtration and thoroughly washed with cold water. Trituration of this material in petroleum ether (30°-60°) gave 16.2 g (0.084 mol), 76%, 3-bromo-4,4-dimethyl-2-oxazolidinone (NBDMO), mp 118°-120°; uv (H2O) λmax 274 nm, ε= 201 M-1 cm-1 ; ir (KBr): 2985, 1725, 1370, 1290, 1200, 1165, 1040 and 740 cm-1 ; pmr (CDCl3) δ 4.27 (s, 2H) and 1.33 (s, 6H) ppm.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[C:21]([CH3:24])=[N:22][O:23][C:13]=3[CH2:12][N:11]=2)=[CH:6][CH:5]=1.CC(C1C=C(C(C)C)C(S([N:40]=[N+:41]=[N-:42])(=O)=O)=C(C(C)C)C=1)C.CCOCC>CN(C=O)C>[N:40]([CH:12]1[N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]2[C:21]([CH3:24])=[N:22][O:23][C:13]1=2)=[N+:41]=[N-:42]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a round bottom flask was added sodium hydride (0.13 g, 3.3 mmol, 60% in mineral oil). The flask was then purged with nitrogen, DMF (10 mL) was then added and the flask was cooled to 0° C. 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine (930 mg, 3.0 mmol) in DMF (5 mL) was added and the reaction was allowed to stir for 45 min. Trisyl azide (1.40 g, 4.5 mmol) in DMF (5 mL) was added and the reaction was mixed at 0° C. for 1 h. The reaction poured into ether (100 mL) and washed with brine (3×). The organic layer was dried over Na2SO4, filtered, concentrated to afford crude 4-azido-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepine, which was used directly in the following reaction. LC/MS m/z 350 [M+H]+.