Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH3:9]I>>[OH:1][C@H:2]([CH3:8])[C@H:3]([CH3:9])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)C[C@@H](C)O
Product: COC(=O)[C@@H](C)[C@@H](C)O

Procedure:
This compound was prepared according to the procedure of Example 127, but the methyl 3-(R)-hydroxybutanoate was first alkylated with methyl iodide as described by Keck et al., (J. Org. Chem., 1985, 4317) to give methyl 3-(R)-hydroxy-2-(S)-methylbutanoate. The latter was transformed into the thiol according to the procedure of Example 127.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[S:5][C:6]=1[CH:7]([CH3:9])[CH3:8].CCN(CC)CC.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[S:5][C:6]=1[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)c1sc(CO)cc1Br
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1sc(CO[Si](C)(C)C(C)(C)C)cc1Br
Reaction time: 14 h

Procedure:
A solution of (4-bromo-5-isopropyl-thiophen-2-yl)-methanol (Example Q; 3.4 g, 14 mmol) in CH2Cl2 (4.0 mL) was treated with NEt3 (2.8 mL, 20 mmol), p-dimethylaminopyridine (0.050 g), and t-butyldimethylsilylchloride (2.41 g, 16.0 mmol). The mixture was stirred for 14 hours, then diluted with Et2O and washed with H2O. The organic layer was dried (MgSO4) and the solvent evaporated to provide the crude product, which was used without further purification.
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:5](=[CH2:6])[C:2]2([CH3:4])[CH3:3].[CH:11](=[O:13])[CH3:12].CC1C=CC(C)=CC=1C>>[CH3:3][C:2]1([CH3:4])[CH:1]2[CH2:10][CH:7]([CH2:8][CH2:9]2)[CH:5]1[CH2:6][C:11](=[O:13])[CH3:12]
Reactant: CC=O
Reactant: C=C1C2CCC(C2)C1(C)C
Agent: Cc1ccc(C)c(C)c1
Product: CC(=O)CC1C2CCC(C2)C1(C)C
Yield: 40.5 %

Procedure:
A 1 liter jacketed photochemical reaction vessel equipped with magnetic stirrer and pyrex immersion well is charged with 418 g camphene (807, Aldrich) and 372 g acetaldehyde and 30 g diacetyl (photochemical hydrogen abstractor). The mixture is irradiated with a 450 medium pressure mercury lamp (Hanovia) for 55 hours, during which time five 30 g portions of diacetyl are added at varying intervals. The reaction mixture is combined with 150 g of 1,2,4-trimethyl benzene and washed with water. The material is distilled without fractionation and then redistilled through a 5 foot Vigreux column to yield 224 g colorless product, b.p. 70° -72° (55 mm Hg).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[CH2:20]([OH:23])[CH:21]=[CH2:22].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>O.C1(C)C=CC=CC=1>[CH2:20]([O:23][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:21]=[CH2:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOCC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h
Yield: 109.4 %

Procedure:
Tetrabutylammonium hydrogenosulfate (470 g, 1.40 mol) is added to a solution of sodium hydroxide (6.6 Kg, 165 mol) in water (14 L) and toluene (14 L) at 20° C. Allyl alcohol (801.5 g, 13.8 mol) is added and the mixture is stirred at 20° C. for 1 h. The mixture is cooled to 5° C., and tert-butyl 2-bromoacetate (4 Kg, 20.5 mol) is added slowly maintaining the internal temperature below 15° C. The reaction mixture is stirred at room temperature for 16 h. The mixture is diluted with water (12 L) and hexanes (12 L) and the organic phase is separated. The aqueous phase is extracted with MTBE (5 L). The combined organic phase is dried over magnesium sulfate, filtered, and concentrated to afford the title compound as colorless oil (2.6 Kg, 100%). ES/MS m/e: 173 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[C:6]2([CH2:9][NH:8][CH2:7]2)[O:5][C:4](=[O:10])[NH:3]1.C(O)(=O)C.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].Cl>CO>[CH3:1][C@@H:2]1[C:6]2([CH2:9][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:7]2)[O:5][C:4](=[O:10])[NH:3]1
Reactant: C[C@H]1NC(=O)OC12CNC2
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H]1NC(=O)OC12CN(Cc1ccccc1)C2
Temperature: 0 °C

Procedure:
A solution of (8R)-8-methyl-5-oxa-2,7-diazaspiro[3.4]octan-6-one (937 mg, 6.6 mmol), acetic acid (0.756 mL, 13.2 mmol), and benzaldehyde (1.0 mL, 9.9 mmol) in methanol (65 mL) was treated with sodium cyanoborohydride (829 mg, 13.2 mmol) at rt for 30 min. The mixture was then cooled to 0° C., and 3 N hydrochloric acid (100 mL) was added. The methanol was then removed in vacuo. The resulting aqueous solution was washed with ethyl acetate. The ethyl acetate wash was back extracted with 1 N hydrochloric acid, and the aqueous acidic phases were combined and basified with potassium carbonate. The organic phase was discarded. The aqueous mixture was then extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The desired (8R)-8-methyl-2-(phenylmethyl)-5-oxa-2,7-diazaspiro[3.4]octan-6-one was obtained in 93% purity as a milky colorless liquid (1.33 g, 5.73 mmol, 87% yield). MS (EI) for C13H16N2O2: 233 (MH+).
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: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
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: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][N:21]([CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[C:29]([F:32])([F:31])[F:30]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([N:21]([CH3:20])[CH:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CN1CCC(N(C)c2ccc(N)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(N(C)c2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-[methyl-(1-methyl-piperidin-4-yl)-amino]-3-trifluoromethyl-phenylamine. Title compound: ES-MS: 523.0 [M+H]+; single peak at tR=3.33 min (System 1); Rf=0.18 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: C([O:4][C@H:5]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=O)C>CO.N.C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:4][C@H:5]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: CC(=O)O[C@H](CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@H](O)CCc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 86.2 %

Procedure:
8.0 g of tert.butyl 2(R)-acetoxy-4-(4-nitrophenyl)butanoate were dissolved in 200 ml of methanol saturated with ammonia at 0° C. and the mixture was stirred for 16 hours. Evaporation of the mixture in vacuo gave 7 g of an almost colorless oil which was dissolved in an equal volume of diethyl ether/n-hexane (1;1) and eluted through a silica gel column with the same solvent mixture to give 6 g of tert.butyl 2(R)-hydroxy-4-(4-nitrophenyl)butanoate as a colorless crystalline solid having a melting point of 41°-42° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([N:11]([CH3:31])[C:12](=[O:30])[C:13]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)([CH3:15])[CH3:14])=[C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH:6]=1)(=[O:3])[CH3:2].[CH3:39][Si](C)(C)[N-][Si](C)(C)C.[K+].CI>O1CCCC1>[C:1]([N:4]([CH3:39])[C:5]1[N:10]=[CH:9][C:8]([N:11]([CH3:31])[C:12](=[O:30])[C:13]([C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=2)([CH3:15])[CH3:14])=[C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(=O)N(C)c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 60 mg (0.11 mmol) N-(6-acetylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 2 ml tetrahydrofuran at room temperature under argon were added dropwise 0.13 ml (0.12 mmol) of a 1 M solution of potassium hexamethyldisilazide in tetrahydrofuran. Stirring was continued for 1 h at room temperature and 17 mg (0.12 mmol) methyl iodide were added. After stirring overnight, the solvent was evaporated and the residue was purified by flash-chromatography to give 40 mg (65%) of the title compound as white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[O:10])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.[N+:47]([C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57](O)=[O:58])=[CH:52][CH:51]=1)([O-:49])=[O:48]>C(OCC)(=O)C.O.CN(C=O)C>[CH3:16][N:14]([CH3:15])[CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:57](=[O:58])[CH2:56][C:53]2[CH:52]=[CH:51][C:50]([N+:47]([O-:49])=[O:48])=[CH:55][CH:54]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCNC(=O)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)Cc1ccc(NC(=O)Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 4 h
Yield: 20.8 %

Procedure:
2-(4-Aminophenyl)-N-[2-(dimethylamino)ethyl]acetamide (221 mg), WSC (free form: 0.23 ml), 1-hydroxybenzotriazole (199 mg), and dimethylaminopyridine (244 mg) were added to a DMF (5 ml) solution of 4-nitrophenylacetic acid (181 mg), which was stirred for 4 hours. The reaction mixture was poured into water, and extraction was conducted using ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over sodium sulfate, and then concentrated. The residue was recrystallized from methanol, to give the titled compound (80 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[CH3:34][NH:35][O:36][CH3:37]>CN(C=O)C.O>[CH3:37][O:36][N:35]([CH3:34])[C:6](=[O:8])[C:5]1[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=1[O:12][CH3:13]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)N(C)OC
Reaction time: 0.25 h
Yield: 82 %

Procedure:
4-Amino-5-chloro-2-methoxybenzoic acid (10.1 g, 50 mmol) was dissolved in DMF (50 mL). Carbonyldiimidazole (8.9 g, 55 mmol) was added to the solution and the mixture was stirred for 15 minutes. Triethylamine (7 mL, 5.1 g, 50 mmol) and N,O-dimethylhydroxylamine hydrochloride (6.3 g, 65 mmol) were added and the mixture was stirred for 12 hours. The mixture was then diluted with water and extracted into ethyl acetate. The ethyl acetate extract was washed with 5% HCl, with water, and then with brine. The extract was dried over sodium sulfate and then evaporated. Crystallization from ethyl acetate gave N-methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide (10 g, 41 mmol), m.p. 134°-135° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][NH:8][CH2:9][CH2:10][OH:11])[CH2:4][O:3]1.[CH2:13]([O:20][CH2:21][N:22]1[C:30]2[C:29]([O:31][CH3:32])=[N:28][CH:27]=[N:26][C:25]=2[C:24]([CH:33]=O)=[CH:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:13]([O:20][CH2:21][N:22]1[C:30]2[C:29]([O:31][CH3:32])=[N:28][CH:27]=[N:26][C:25]=2[C:24]([CH2:33][N:8]([CH2:7][C@H:5]2[CH2:4][O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[CH2:9][CH2:10][OH:11])=[CH:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)OC[C@H](CNCCO)O1
Reactant: COc1ncnc2c(C=O)cn(COCc3ccccc3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ncnc2c(CN(CCO)C[C@H]3COC(C)(C)O3)cn(COCc3ccccc3)c12
Yield: 79.9 %

Procedure:
The product from Example 14.1 (0.048 g, 0.274 mmol) was reductively aminated with 5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (0.081 g, 0.274 mmol) and sodium triacetoxyborohydride (0.075 g, 0.356 mmol) in the same way as described for the R-enantiomer in Example 13.2. to give (S)-2-(((5-(benzyloxymethyl)-4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)amino)ethanol (100 mg, 80%) as a colourless gum which slowly turned pale yellow. The 1H and 13C NMR were as described for the R-enantiomer in Example 13.2. +ESMS Found 457.2469 C24H33N4O5 (M+H)+ requires 457.2451.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH3:27])[C:10]2=[O:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[S:30]([C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([OH:38])=[O:37])(=[O:32])=[O:31].C(=O)(O)[O-].[Na+]>CC(C)=O.O>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C@H:18]2[C@:12]3([N:11]([CH3:27])[C:10](=[O:28])[N:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]3=[O:14])[CH2:15][N:16]([S:30]([C:33]3[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=3)[C:36]([OH:38])=[O:37])(=[O:32])=[O:31])[CH2:17]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(S(=O)(=O)c1cccc(C(=O)O)c1)C[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a mixture of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile (Example 15a) (0.11 g, 0.26 mmol) and (3-(Chlorosulfonyl)benzoic acid (0.058 g, 0.26 mmol) in acetone and water (1:1 mL) was added sodium bicarbonate at room temperature. The reaction mixture was stirred at room temperature for forty minutes, quenched by the slow addition of 1N hydrochloric acid (1 mL) and partitioned between DCM (2×20 mL) and brine (25 mL). The DCM layer was dried over sodium sulfate, concentrated and column purified using silica gel chromatography using DCM and MeOH to yield the titled compound (0.12 g). Retention time: 3.39 min. YMC S5 Combiscreen ODS 4.6×50 mm (4 minute gradient). Solvent A=10% MeOH, 90% water and 0.2% phosphoric acid. Solvent B=90% MeOH, 10% water and 0.2% phosphoric acid.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([I:11])[CH:10]=1)[NH2:7])=[N+:2]=[N-:3].[CH:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](OC2C=CC=CC=2)=[N:20][C:21]#[N:22])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[N:1]([C:4]1[CH:5]=[C:6]([NH:7][C:19](=[N:20][C:21]#[N:22])[O:18][C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)[CH:8]=[C:9]([I:11])[CH:10]=1)=[N+:2]=[N-:3]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: [N-]=[N+]=Nc1cc(N)cc(I)c1
Solvent: ClC(Cl)Cl
Product: N#CN=C(Nc1cc(I)cc(N=[N+]=[N-])c1)Oc1ccccc1
Yield: 94.6 %

Procedure:
CHART B, Step B-1. To a solution of 3-azido-5-iodoaniline (A-4, 2.42 g, 9.31 mmol) in chloroform (8 mL) is added diphenyl cyanocarbonimidate (2.21g, 9.31 mmol). The solvent is allowed to evaporate at a temperature of 70° C. overnight. The resulting solid is washed with ether, filtered and dried to afford 3.558 g of N-(3-azido-5-iodophenyl)-N'-cyanocarbamimidic acid, phenyl ester (B-1) which is used without further purification. A small analytical sample is recrystallized from ethyl acetate in hexane. Mp=195° C. (dec). IR (mull) 3094, 3078, 2954, 2925, 2867, 2854, 2208, 2121, 2106, 1652, 1600, 1590, 1565, 1504, 1491, 1446, 1433, 1401, 1302, 1219, 1195, 833 cm -1 ; 1H NMR (DMSO) δ10.57 (bs (1 H), 7.50 (t, 1 H, J=2 Hz), 7.28 (m, 2 H), 7.10 (m, 5 H); 13C NMR (DMSO) δ151.4, 141.3, 138.6, 129.9, 128.2, 126.4, 124.6, 120.8, 113.6, 95.0; Mass Spec (70eV, EI) m/z 404 (parent), 376, 249 (base), 222, 207, 194, 155, 145, 128, 118, 103, 94, 77, 65, 51; Exact mass calculated for C14H9IN6O: 403.9884. Found: 403.9877. Melt solvate: 3.6% ethyl acetate; Analysis calculated for C14H9IN6O plus 3.6% C4H8O2 : C, 42.07; H, 2.49; N, 20.04; Found; C, 41.95; H, 2.25; N, 19.76.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]#[CH:4].N1C=CN=C1.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>CCCCCC>[F:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH:2]([O:1][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]#[CH:4])=[CH:12][CH:11]=1
Reactant: C#CC(O)COc1ccc(F)cc1
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Product: C#CC(COc1ccc(F)cc1)O[Si](C)(C)C
Temperature: 0 °C
Yield: 87.9 %

Procedure:
To a 0° C solution of 10 g (55 mmoles) of 3-hydroxy-4-p-fluorophenoxy-1-butyne (Example 157) in 75 ml of dry dimethylformamidee and 88 g (130 mmoles) of imidazole is added dropwise, with stirring, 7.5 g (68 mmoles) of chlorotrimethylsilane. The mixture, while under an argon atmosphere, is stirred at room temperature for 18 hours, and then poured into 150 ml of hexane and 100 ml of ice-water. Thhe organic phase is separated, washed with 50 ml of a brine solution, dried with magnesium sulfate, and evaporated under vacuum. This crude product is distilled under vacuum at 0.1 mm (bp 73°-75° C), to give 12.2 g (91%) of the subject compound as a colorless oily liquid.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]([O:24][C:25]([CH2:27][C:28]([O-:30])=O)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Li+].CCN=C=NCCCN(C)C.Cl.Cl.[Br:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1)=[O:53]>CN(C=O)C.O>[C:20]([O:24][C:25](=[O:26])[CH2:27][C:28]([N:57]1[CH2:56][CH2:55][N:54]([C:52](=[O:53])[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[Br:45])[CH2:59][CH2:58]1)=[O:30])([CH3:21])([CH3:22])[CH3:23]
Reactant: O=C(c1ccccc1Br)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
HOBt (585 mg, 4.3 mmol) and DIEA (933 mg, 7.2 mmol) were added to a stirred solution of lithium tert-butoxycarbonyl-acetate (600 mg, 3.6 mmol) in DMF (6 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (830 mg, 4.3 mmol) followed by (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride (1.3 g, 4.3 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using neutral alumina (3% methanol in chloroform) to afford 530 mg (31%) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid tert-butyl ester. LCMS: 412.08 (M+)+, 52.6%, 1H NMR: (DMSO-d6): δ 7.7 (d, 1H), 7.5 (m, 1H), 7.4 (m, 2H), 3.7-3.4 (m, 8H), 3.2-3.1 (m, 2H), 1.4 (s, 9H).
Reaction SMILES: [I-].[Na+].N12CCCN=C1CCCCC2.CS(O[CH2:19][CH:20]1[CH2:23][CH:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]1)(=O)=O.C(OCC)C>C(COC)OC.O>[CH2:19]=[C:20]1[CH2:23][CH:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]1
Reactant: CS(=O)(=O)OCC1CC(OCc2ccccc2)C1
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: C=C1CC(OCc2ccccc2)C1

Procedure:
Sodium iodide (0.45 gm, 3 mmol) and 1,8-diazabicyclo (5.4.0)undec-7-ene (0.304 gm, 2 mmol) were added to a stirred solution of [3-(benzyloxy)cyclobutyl]methyl methanesulfonate (0.27 gm, 1 mmol) (step b) in dimethoxyethane and the reaction mixture was refluxed for about 2 hours. It was allowed to come to room temperature and then was stirred with diethyl ether and water for about 10 minutes. The ether layer was separated and aqueous layer was washed with ether. The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude compound was purified over silica gel.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCOCC1>[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=3)[CH2:25][CH2:26]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(C(c2ccccn2)N2CCNCC2)cc1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(CN2CCN(C(c3ccccc3)c3ccccn3)CC2)cc1
Yield: 51.9 %

Procedure:
Using 2.8 g of methyl 4-bromomethylphenylacetate, 2.9 g of 1-[phenyl-(2-pyridyl)methyl]piperazine, 2 ml of triethylamine, and 100 ml of dioxane, the reaction procedure of Example 1 was otherwise repeated and recrystallized from benzene-hexane to provide 2.47 g of methyl 4-[[4-[phenyl-(2-pyridyl)methyl]-1-piperazinyl]methyl]phenylacetate melting at 122° C.-123° C.
Reaction SMILES: Cl[Sn]Cl.[N+:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[CH:10]2)([O-])=O.[OH-].[K+]>Cl>[NH2:4][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[CH:10]2
Reactant: O=[N+]([O-])c1ccc2ncncc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Product: Nc1ccc2ncncc2c1

Procedure:
SnCl2 (8.5 g) dissolved in 8.5 mL of conc. HCl was added to the solution of 6-nitroquinazoline in 42.5 mL of 6 N HCl at 0° C. The reaction mixture was neutralized with KOH 10 minutes later and then extracted with diethyl ether (Et2O) and EtOAc. The product 6-aminoquinazoline was obtained (0.67 g) after the removal of the solvent.