Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[N:3]=1.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(O[C@@H:32]1[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:64])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C@@H:43]([O:44][C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@H:33]1[O:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=O)C>ClCCCl.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]2[N:11]([C@@H:32]3[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:64])[C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C@@H:43]([O:44][C:45](=[O:52])[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C@H:33]3[O:34][C:35](=[O:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: Nc1nc2nccn2c(=O)[nH]1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Nc1nc(=O)n2ccn([C@@H]3O[C@H](COC(=O)c4ccccc4)[C@@H](OC(=O)c4ccccc4)[C@H]3OC(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of dry 2-aminoimidazo[1,2-a]-s-triazin-4-one (V) 3.02 g, 0.020 mol), freshly distilled hexamethyldisilazane (15.0 mL), and a few crystals of ammonium sulfate (25 mg) was heated at reflux temperature for 15 h. with the exclusion of moisture. The clear, slightly brown solution was fractionated by distillation to remove excess of hexamethyldisilazane and the residual gum was presumed to be the bis(trimethylsilyl) derivative which was used without further prification. To a solution of the above trimethylsilyl derivative in anhydrous 1,2-dichloroethane (100 mL) was added 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (10.09 g, 0.02 mol) followed by stannic chloride (7.0 g, 0.027 mol). The reaction mixture was protected from moisture and stirred for 30 h. at ambient temperature. The brown reaction solution was then poured into 200 mL of chloroform, with efficient stirring and keeping the mixture basic at all times. The resulting emulsion was filtered through a Celite pad which was washed with chloroform (3×25 mL). The combined organic layer was washed with water (2×100 mL) before it was dried over anhydrous sodium sulfate. The solvent was evaporated to a light brown foam which was chromatographed on an open-bed, silica gel column (5×75 cm) prepacked in ethyl acetate and eluted with ethyl acetate-water-1-propanol (4:2:1, v/v, upper phase). The band containing the requisite product was collected and the solvent evaporated to leave 6.8 g (56.30%) of a light yellow, chromatographically homogeneous foam: [α]25D -32.0° (cl.O.Me2SO); UVλmax (pH 1) 233 nm (ε=45800), 268 (18800); UVλmax (pH 7) 235 nm (ε=39400), 263 sh (24700); UVλmax (pH 11) 234 nm (ε=42300), 260 sh (20600). Anal. (C31H25N5O8.0.5H2O, 604.57) C, H, N.
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11][C:12]([OH:14])=[O:13])[CH2:2]1.[CH2:16](O)[CH3:17]>C1C=CC=CC=1>[CH2:16]([O:13][C:12](=[O:14])[CH2:11][CH:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:15])[CH2:2]1)[CH3:17]
Reactant: CCO
Reactant: O=C(O)CC1CC(=O)c2ccccc2C1
Solvent: c1ccccc1
Product: CCOC(=O)CC1CC(=O)c2ccccc2C1
Yield: 100 %

Procedure:
A solution of 28.3 g of 2-(1,2,3,4-tetrahydro naphthalene 1-one 3-yl) acetic acid (VIII) in 150 ml of ethanol, 30 ml of 7 N hydrochloric ethanol and 150 ml of benzene is brought to reflux for 8 hours. Then the solvents are evaporated, the residue is taken up in ether, washed with water, dried on sodium sulfate, filtered and the filtrate evaporated. 38 g (Yield ~100%) of 2-(1,2,3,4-tetrahydro naphthalene 1-one 3-yl) acetic acid ethyl ester are obtained, the NMR spectrum of which has the following characteristics: δ ppm=7.8 to 8.1, m (aromatic H at 8); 7.2 to 7.6, m (aromatic H at 5, 6 and 7); 4.15, q (COO--CH2); 2.4 to 3, m (7 H: protons at 2,3,4 and CH2 --CO--O--); 1.25, t (CH3).
Reaction SMILES: C([O:8][C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])C1C=CC=CC=1.[ClH:18]>C(O)C.C(OCC)(=O)C.[Pd]>[ClH:18].[OH:8][C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12]
Reactant: N#Cc1ccc(F)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCc1ccc(F)cc1O
Yield: 74.3 %

Procedure:
A solution of intermediate 134, 2-(benzyloxy)-4-fluorobenzonitrile, (9.03 g, 39.7 mmol) in ethanol (100 mL) and ethyl acetate (100 mL) was stirred with 10% palladium on carbon (1.67 g,) and concentrated hydrochloric acid (12 mL, 144 mmol) under a hydrogen atmosphere (60 psi) for four days. The catalyst was removed by filtration through Celite, and the filtrate was concentrated. The crude product was triturated with ether and the resulting solid collected by filtration to give the title compound (5.24 g, 74% yield) as a pale orange solid. 1H NMR (500 MHz, DMSO-D6) δ ppm: 10.81 (1H, s), 8.18 (3H, s), 7.36 (1H, t, J=7.3 Hz), 6.79 (1H, dd, J=10.8, 2.6 Hz), 6.66 (1H, dt, J=8.5, 2.3 Hz), 3.90 (2H, d, J=5.2 Hz).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:9]2[N:14]3[N:15]=[C:16]([CH3:26])[C:17]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4Cl)=[C:13]3[N:12]=[C:11]([CH3:27])[CH:10]=2)[CH2:6][CH2:7][CH3:8])[CH2:3][CH2:2]1.[CH3:28]C1C=C(Cl)C=CC=1C1C(C)=NN2C(N(CCC)CCC)=CC(C)=NC=12>>[CH:1]1([CH2:4][N:5]([C:9]2[N:14]3[N:15]=[C:16]([CH3:26])[C:17]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[CH3:28])=[C:13]3[N:12]=[C:11]([CH3:27])[CH:10]=2)[CH2:6][CH2:7][CH3:8])[CH2:3][CH2:2]1
Reactant: CCCN(CCC)c1cc(C)nc2c(-c3ccc(Cl)cc3C)c(C)nn12
Reactant: CCCN(CC1CC1)c1cc(C)nc2c(-c3ccc(Cl)cc3Cl)c(C)nn12
Product: CCCN(CC1CC1)c1cc(C)nc2c(-c3ccc(Cl)cc3C)c(C)nn12

Procedure:
cyclopropylmethyl-[3-(2,4-di-chloro-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-propyl-amine, [3-(2-methyl-4-chloro-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-di-propyl-amine;
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][N:6]([CH2:8][C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH:10]=1)[CH3:7]>FC(F)(F)C(O)=O>[NH:11]1[C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]([CH2:8][N:6]([CH3:7])[CH3:5])[CH2:10]1
Reactant: CN(C)Cc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC1CNc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
1.1 g of sodium cyanoborohydride is gradually added to a solution of 1 g of gramine in 20 ml of trifluoroacetic acid, under argon, cooled in an ice bath, and stirred for half an hour at 0° C. and then for 2 h at ambient temperature. The reaction medium is plunged into 50 g of ice and alkalinized using 30% sodium hydroxide, and is then extracted with four times 30 ml of ethyl acetate. The organic phase is washed with 20 ml of water, dried over anhydrous magnesium sulphate, filtered, and then concentrated to dryness under reduced pressure. After a silica column purification, eluent: 85/15 v/v CH2Cl2/MeOH, 660 mg of (2,3-dihydro-1H-indol-3-ylmethyl)dimethylamine are obtained in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][C:22]([CH3:24])=[CH:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]([O:37][CH2:38][CH3:39])(=[O:36])[C:32]#[C:33][CH2:34][CH3:35]>CN(C)C=O.O>[CH2:34]([C:33]1[C:32]([C:31]([O:37][CH2:38][CH3:39])=[O:36])=[C:16]2[C:17]3[CH:23]=[C:22]([CH3:24])[O:21][C:18]=3[CH:19]=[CH:20][N:15]2[N:14]=1)[CH3:35]
Reactant: Cc1cc2c[n+](N)ccc2o1
Reactant: CCC#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CC)nn2ccc3oc(C)cc3c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 38.3 %

Procedure:
A mixture of 5-amino-2-methylfuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (1.44 g, 4.33 mmol), potassium carbonate (838 mg, 6.06 mmol) and ethyl 2-pentynoate (628 μL, 4.76 mmol) in dimethylformamide (20 mL) was stirred at room temperature for 14 hr. The reaction solution was diluted with water, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (451 mg, yield 38%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:42]=[CH:41][C:34]([C:35]([O:37][CH2:38][CH2:39][OH:40])=[O:36])=[CH:33][C:32]=2[O:43][CH3:44])=[O:29])[CH:5]=[CH:6][CH:7]=1.[C:46]([O:50][C:51]([NH:53][CH:54]([CH3:58])[C:55](O)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CN(C1C=CC=CN=1)C>CN(C)C=O>[C:46]([O:50][C:51]([NH:53][C@H:54]([CH3:58])[C:55]([O:40][CH2:39][CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:41]=[CH:42][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:45])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:43][CH3:44])[CH:33]=1)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(C(=O)OCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)OCCOC(=O)[C@@H](C)NC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 90 %

Procedure:
In a manner similar to the method described in Example 3, chiral 2-hydroxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 1, 105.2 mg, 0.159 mmol) was reacted with (R)-(2-(tert-butoxycarbonylamino)propanoic acid (Chem-Impex, 75 mg, 0.398 mmol), HATU (Bachem, 151 mg, 0398 mmol), N,N-diisopropylethylamine (104 mg, 0.14 mL, 0.802 mmol) and dimethylaminopyridine (Aldrich, 10.8 mg, 0.088 mmol) in dimethyl formamide (8 mL) to give chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-((R)-2-tert-butoxycarbonylamino-propionyloxy)-ethyl ester as a white solid (119 mg, 89% yield). MS (ES+) m/z calcd. for C41H47Cl2F2N4O8 [(M+H)+]: 831. found: 831.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][N:11]=[C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=12.[Br:19]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:18][C:17]1[C:12]2[C:13](=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[O:10][N:11]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c(-c3ccc(Cl)cc3Cl)onc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2onc3c(CBr)cccc23)c(Cl)c1
Yield: 71.8 %

Procedure:
A mixture of 10.9 g (0.039 mole) of 3-(2,4-dichlorophenyl)-7-methyl-2,1-benzisoxazole, 7.1 g (0.040 mole) of N-bromosuccinimide, 0.1 g of dibenzoylperoxide and 200 ml of carbon tetrachloride was heated at reflux under illumination of a flood lamp for 2 hr. The mixture was filtered and the filtrate was washed once with a saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to give a solid as residue. The solid was recrystallized from 2-propanol to yield 10.0 g (71%) of tan solid, m.p. 108°-110° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[O:24]1[C:28]2[CH:29]=[CH:30][C:31](B(O)O)=[CH:32][C:27]=2[O:26][CH2:25]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([C:2]3[CH:3]=[C:4]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([N:18]5[CH2:22][CH2:21][CH2:20][CH:19]5[CH3:23])[N:13]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=3)=[CH:32][C:27]=2[O:26][CH2:25]1
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc4c(c3)OCO4)nn3ccnc23)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (66 mg, 0.2 mmol), benzo[d][1,3]dioxol-5-ylboronic acid (60 mg, 0.24 mmol), Pd2(dba)3 (12 mg, 0.02 mmol), X-phos (39 mg, 0.08 mmol) and Na2CO3 (64 mg, 0.6 mmol) in dioxane (5 mL) and water (0.5 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=20:1) to give crude product as a yellow oil, which was then purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 6-(benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (62 mg, 75%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.58 (s, 1H), 8.69 (s, 1H), 8.14 (s, 1H), 7.61 (s, 1H), 7.44-7.39 (m, 3H), 7.06-7.04 (m, 1H), 6.70 (d, 1H, J=7.5 Hz), 6.11 (s, 2H), 6.05 (d, 1H, J=8.1 Hz), 4.27-4.20 (m, 1H), 3.58-3.53 (m, 1H), 3.41-3.36 (m, 1H), 2.07-1.99 (m, 3H), 1.71-1.68 (m, 2H), 1.14 (d, 1H, J=6.0 Hz). LC-MS: [M+H]+, 415, tR=1.965 min, HPLC: 99.31% at 214 nm, 99.64% at 254 nm, tR=6.821 min.
Reaction SMILES: C(O)CCC.C(O)(=O)C.[C:10]([C:13]1[CH:18]=[C:17]([NH:19][C:20]([NH2:22])=[NH:21])[CH:16]=[CH:15][C:14]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25])(O)=[O:11].P(Cl)(Cl)(Cl)(Cl)Cl>O.N1C=CC=CC=1>[NH:19]([C:17]1[CH:18]=[C:13]2[C:14]([CH:23]=[C:24]([O:26][CH3:27])[O:25][C:10]2=[O:11])=[CH:15][CH:16]=1)[C:20]([NH2:22])=[NH:21]
Reactant: COC(=O)Cc1ccc(NC(=N)N)cc1C(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCCCO
Product: COc1cc2ccc(NC(=N)N)cc2c(=O)o1
Yield: 71.5 %

Procedure:
Methyl 2-carboxy-4-nitrophenyl acetate was prepared from 2-carboxy-4-nitrophenylacetate and methanol by the procedure described above. Hydrogenation of this nitro compound gives methyl 4-amino-2-carboxy-phenylacetate (yield 90%). The guanidination of the amino compound with 3,5-dimethylpyrazole-1-carboxamidine nitrate (ADMP) was performed by a standard method described previously (Tsunematsu & Makismi, J. Biochem. 88, pp 1773-1783, (1980)). 2.2 g of amino compound (10 mmole), 1.9 g of triethylamine (19 mmole) and 3.0 g of ADMP (15 mmole) was heated in 20 ml of THF and refluxed for 18 hrs. The white precipitate was filtered and washed with cold methanol to give 1.5 g of methyl 2-carboxy-4-guanidinophenylacetate, (yield 46%). One spot on TLC, Rf=0.6 (Butanol:acetic acid:pyridine:water=4:1:1:2), it shows an orange color when sprayed with Sakaguchi reagent. NMR spectrum (CF3COOH), δ 8.4, 7.7 (b, 4H), 6.6 (b, 4H) 4.4 (s, 2H), 4.1 (s, 3H). Anal. Calc. for C11H13N3O4. 1/2 H2O: C, 50.77; H, 5.42; N, 16.15. Found: C, 51.03; H, 5.38; N, 16.19. 0.9 g of methyl 2-carboxy-4-guanidinophenylacetate (3 mmole) was heated with 1.5 g of PCl5 (7.2 mmole) at 70°-80° C. for 2 hrs, white solid precipitated out during the heating. The solid was filtered off and purified by silica gel column chromatography with methylene chloride and methanol (5:1) as an eluent to give 0.5 g of 7-guanidino-3-methoxyisocoumarin (yield 59%). One spot on TLC, Rf=0.7 (Butanol:acetic acid:pyridine:water=4:1:1:2); m.p. 185°-186° C. (dec);, NMR spectrum (d6 -DMSO): δ 7.9, 7.6 (b, 3H), 7.7 (b, 4H), 6.1 (s, 1H), 3.9 (s, 3H); mass spectrum (FAB+), m/e=234 (M+ -Cl). Anal. Calc. for C11H12N3O3Cl1. 1/2 H2O: C, 47.40; H, 4.67; N, 15.08; Cl, 12.75. Found: C, 47.42; H, 4.74; N, 15.05; Cl, 12.68.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]1([C:18](=O)[C:19]([O:21]C)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:19]([OH:21])=[O:20]
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: O=C(O)C(=C1C(=O)Nc2ccc(Br)cc21)c1ccccc1
Yield: 45.2 %

Procedure:
5-Bromooxindole (640 mg) was reacted with methyl phenylglyoxylate (540 mg) using method A to give 470 mg (45%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:16]#[N:17])=[CH:4][CH:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[C:16]([C:10]1[CH:11]=[C:12]([NH:15][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([N:22]3[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]3)=[CH:26][CH:27]=2)[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N:22]3[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]3)=[CH:33][CH:32]=2)=[CH:3][CH:4]=1)#[N:17]
Reactant: N#Cc1cc(N)ccc1Nc1ccc(N)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: N#Cc1cc(NC(=O)c2ccc(N3CCC(O)CC3)cc2)ccc1Nc1ccc(NC(=O)c2ccc(N3CCC(O)CC3)cc2)cc1

Procedure:
Compound 834 was prepared according to the procedure described in Scheme IV from N1-(4-aminophenyl)-2-cyanobenzene-1,4-diamine and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C37H38N6O4: 631.30; found: 631.11.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CCN(CC)CC.CS(Cl)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[N:26]([CH2:2][C@H:3]1[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[N+:27]=[N-:28]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]1CN=[N+]=[N-]
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
To a mixture of (R)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (32.5 g, 173 mmol) and Et3N (27 mL, 191 mmol) in THF (650 mL) at 0° C. was added methane sulfonylchloride (14.9 ml, 191 mmol) dropwise. The mixture was stirred for 10 min. The precipitation was filtered off and the filtrate was concentrated. The residue was then dissolved with DMF (200 mL). Sodium azide (34 g, 519 mmol) was then added. The mixture was stirred at 65° C. for 6 hours. 300 mL EtOAc and 300 mL brine were then added to the reaction mixture. The organic layer was dried and concentrated. The residue was purified by Biotage silica gel chromatography (EtOAc:Hexane 1:4) to give (R)-tert-butyl 2-(azidomethyl)azetidine-1-carboxylate as a colorless oil (32 g, 87% yield). LRMS (M−100+H+) m/z 113.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([N+]([O-])=O)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5].N([O-])=O.[Na+].B(O)(O)O.[FH:30]>O>[Cl:1][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:30])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5]
Reactant: CC(O)(CCCl)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: F
Agent: O=N[O-]
Agent: OB(O)O
Agent: [Na+]
Solvent: O
Product: CC(O)(CCCl)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
3 ml. of concentrated hydrochloric acid are added, at 0°, to 2.78 g. of 1-chloro-3-(4'-amino-4-biphenylyl)-butan-3-ol [which can be obtained by nitrating 1-chloro-3-(4-biphenylyl)-butan- 3-ol and reducing the resulting 1-chloro-3-(4'-nitro-4-biphenylyl)-butan-3-ol] and a solution of 1.4 g. of NaNO2 in 6 ml. of water is then added at 0°, while stirring. After adding a solution of 0.7 g. of boric acid in 1.5 g. of 60% hydrofluoric acid, the mixture is stirred for 40 minutes and filtered and the product is washed with water, methanol and ether and dried and the resulting diazonium fluoborate is heated to about 150° until decomposition is complete to give 1-chloro-3-(4'-fluoro-4-biphenylyl)-butan-3-ol, m.p. 78° - 79°.
Reaction SMILES: [CH3:1][SiH:2]([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].S(Cl)([Cl:12])(=O)=O.Cl.S(=O)=O>>[CH3:1][Si:2]([CH:6]([CH3:8])[CH3:7])([CH:3]([CH3:5])[CH3:4])[Cl:12]
Reactant: CC(C)[SiH](C)C(C)C
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Agent: O=S=O
Product: CC(C)[Si](C)(Cl)C(C)C

Procedure:
73 g (3.0 mol) magnesium was introduced into a 2 L four-neck flask equipped with a reflux condenser, stirring rod, thermometer, and addition funnel, and was dried under nitrogen. 1,000 mL dry THF was then added. A Grignard reagent was prepared by slowly dripping in 235.6 g (3.0 mol) isopropyl chloride from the addition funnel. 166.8 g (1.45 mol) methyldichlorosilane was then dripped in from the addition funnel. After completion of this addition, the reaction was brought to completion by continuing to stir for 2 hours at the reflux temperature of THF, followed by the addition of 350 mL water, with cooling, for hydrolysis. The reaction solution was recovered by decantation, and the THF was distilled out through a 30 cm Widmer precision distillation column. Continuing with distillation at ambient pressure afforded 160 g (1.2 mol) methyldiisopropylsilane (bp= 122 degrees Centigrade). 26.1 g (0.2 mol) of the methyldiisopropylsilane thus obtained was placed in a 50 mL three-neck flask equipped with a reflux condenser, thermometer, and addition funnel. 27 g (0.2 mol) sulfuryl chloride was carefully dripped in at 60 degrees Centigrade while stirring with a magnetic stirring bar. An exothermic reaction developed with the production of hydrogen chloride and sulfur dioxide. After addition of the entire quantity, the reaction was maintained for 1 hour at 70 degrees Centigrade and then distilled in vacuo. 27 g (0.16 mol) of the target methyldiisopropylchlorosilane (bp=64 degrees Centigrade32 mmHg) was obtained.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:23][CH2:22][C:9]2([O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>CO.O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:11]2[CH2:10][C:9]3([CH2:22][CH2:23][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)[O:13][N:12]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1CCC2(CC1)CC(c1cccc(OC)c1)=NO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(C2=NOC3(CCC(C(=O)O)CC3)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-methoxyphenyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid ethyl ester (51 g, 161 mmol) in MeOH (1000 ml) and lithium hydroxide monohydrate (18 g, 241 mmol) in H2O (145 ml) was stirred overnight at RT.