Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].C([O:12][B:13](OC(C)C)[O:14]C(C)C)(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:7]([C:3]1[N:2]([CH3:1])[C:6]([B:13]([OH:14])[OH:12])=[CH:5][CH:4]=1)#[N:8]
Reactant: Cn1cccc1C#N
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(C#N)ccc1B(O)O
Temperature: 13 °C
Yield: 80.3 %

Procedure:
The solution of 1-methylpyrrole-2-carbonitrile (0.131 g, 1.23 mmol), triisopropylborate (250 μL, 1.08 mmol), and THF (4 mL) was cooled to about −4° C. and 2M LDA (0.6 mL, 1.2 mmol) was added dropwise from a syringe. The bath was removed and the suspension was allowed to warm to about 13° C. within about 2 hours. After cooling and quenching with water and 5% aqueous HCl, the product was extracted with diethylether. The organic layer was evaporated to give an oil which solidified upon standing to give 0.130 g (70% yield) of (5-cyano-1-methyl-1H-pyrrol-2-yl) boronic acid. 1H-NMR (DMSO-d6): δ 8.38, 6.87, 6.77, and 3.88.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]4[C:19]([C:20]5[C:21]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:22][O:23][C:24]=5[CH3:25])=[N:18][N:17]=[C:14]43)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:32][NH2:33]>O>[CH3:32][NH:33][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]4[C:19]([C:20]5[C:21]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:22][O:23][C:24]=5[CH3:25])=[N:18][N:17]=[C:14]43)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(-c3ccc(Cl)nn3)cc1-2
Solvent: O
Product: CNc1ccc(-c2ccc3c(c2)-c2nnc(-c4c(-c5ccccc5)noc4C)n2C3)nn1

Procedure:
8-(6-Chloropyridazin-3-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindole was heated in a sealed tube with methylamine (3 ml of 40% solution in water) for 16 h. The reaction mixture was cooled, poured into H2O and extracted into CH2Cl2, dried (MgSO4), and concentrated under reduced pressure.
Reaction SMILES: CC(C)([O-])C.[K+].[SH2:7].[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:23](=[O:24])[C:18]3[N:19]=[C:20]([CH3:22])O[C:17]=3[CH2:16][CH2:15][C:14]=2[CH:25]=1)[CH3:9].Cl>CN(C)C=O>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:23](=[O:24])[C:18]3[N:19]=[C:20]([CH3:22])[S:7][C:17]=3[CH2:16][CH2:15][C:14]=2[CH:25]=1)[CH3:9]
Reactant: S
Reactant: CCc1ccc2c(c1)CCc1oc(C)nc1C2=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc2c(c1)CCc1sc(C)nc1C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of potassium tert-butoxide (1.80 g) in dry N,N-dimethylformamide (20 ml) was cooled to 5° C. and saturated with hydrogen sulphide. The product from example 3 step (vi) (1.00 g) was added and the reaction stirred at room temperature for 1 hour. The mixture was poured into ice, acidified to pH4 with 2N hydrochloric acid and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO4) and evaporated to give an orange solid which was purified by chromatography eluting with 50% ethyl acetate in isohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].Cl[CH2:21][CH2:22][NH:23][C:24](=[O:28])[O:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:19][CH2:21][CH2:22][NH:23][C:24](=[O:28])[O:25][CH2:26][CH3:27]
Reactant: CCOC(=O)NCCCl
Reactant: Oc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)NCCOc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl
Temperature: 0 °C

Procedure:
To a solution of 0.5 g (1.73 mmol) of 2-chloro-4-(3-trifluoromethylphenoxy)phenol in 20 ml of N,N-dimethylfomamide, there are added 0.29 g (1.90 mmol) of ethyl 2-chloroethylcarbamate and 0.53 g (3.81 mmol) of potassium carbonate with stirring, and the resultant mixture is heated at 50° C. for 7 hours. The reaction mixture is poured into 100 g of ice-water and extracted twice with 100 ml of ethyl acetate. The extracts are combined together, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel chromatography to give ethyl 2-[2-chloro-4-(3-trifluoromethylphenoxy)phenoxy]ethylcarbamate.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19](Cl)=[O:20].[OH-].[Na+]>CC(C)=O>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)=[O:20]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O)c1c(Cl)cccc1Cl

Procedure:
Concretely, 4-nitro-L-phenylalanine and 2,6-dichlorobenzoylchloride are condensed in a mixed solvent of a sodium hydroxide aqueous solution and acetone with keeping the reaction temperature at 5 to 15° C., and then crystallization is conducted to obtain a corresponding condensed substance, Nα-(2,6-dichlorobenzoyl)-4-nitro-L-phenylalanine almost quantitatively.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[NH2:15][C:16]1[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[CH:17]=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:15][C:16]2[N:20]([CH3:21])[N:19]=[C:18]([CH3:22])[CH:17]=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: Cc1cc(N)n(C)n1
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1Nc1cc(C)nn1C
Temperature: 80 °C
Yield: 79.7 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (4.6 g, 19.6 mmol) in ethanol (90 mL) is added 5-amino-1,3-dimethylpyrazole (4.4 g, 39.2 mmol). The mixture is heated for 22 hours at 80° C. The reaction is cooled to room temp and concentrated in vacuo. The solid which remains is dissolved in CHCl3 and washed with aqueous saturated NaHCO3 solution. The organic phase is dried (MgSO4), filtered and concentrated in vacuo and the resulting residue is purified over silica (50% EtOAc//hexanes, followed by 100% EtOAc) to afford 4.8 g of the desired product: 1H NMR (300 MHz, CDCl3) δ10.29 (s, NH), 8.82 (s, 1H), 6.30 (s, 1H), 4.43 (q, J=7.2 Hz, 2H), 3.77 (s, 3H), 2.53 (s, 3H), 2.30 (s, 3H), 1.45 (t, J=7.2 Hz, 3H); ESI+ MS: m/z (rel intensity) 308.0 (100, M++H).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[N-:27]=[N+:28]=[N-:29].[Na+].C(O)(=O)C>CN(C)C=O>[N:27]([CH2:2][C:3]1([OH:1])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1)=[N+:28]=[N-:29]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CN=[N+]=[N-])CC3)c(F)c2)C(=O)O1
Yield: 72 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with sodium azide (2.06 mmol) and glacial acetic acid (7.1 mmol) in dimethylformamide (15 ml) at a temperature 40° C. for 14 hours and by purifying the compound by silica gel column chromatography in 72% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH:6]([C:7](=[O:17])[N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]2[C:18](=[O:40])[CH:19]([NH:20]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:4]2[S:3]1.O.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>CC(C)=O>[C:43]1([CH3:53])[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:50])=[O:51])=[CH:47][CH:48]=1.[NH2:20][CH:19]1[C:18](=[O:40])[N:5]2[CH:6]([C:7](=[O:17])[N:8]([CH3:16])[CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:2]([CH3:41])([CH3:1])[S:3][C@H:4]12
Reactant: CN(Cc1ccccc1)C(=O)C1N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CN(Cc1ccccc1)C(=O)C1N2C(=O)C(N)[C@H]2SC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.3 %

Procedure:
To a solution of 2,2-dimethyl-6-(triphenylmethylamino)-3-(N-methyl-N-benzylcarbamoyl)penam (200 mg) in acetone (2 mL) was added p-toluenesulfonic acid monohydrate (70 mg). The solution was stirred at room temperature for 11/2 hours and the acetone was removed in vacuo. Trituration of the residue with ether and vacuum drying gave partially impure 6-Amino-2,2-dimethyl-3-(N-methyl-N-benzylcarbamoyl)penam p-toluenesulfonic acid salt (200 mg).
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.C[O:32][C:33]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39]([O:46]C)=[C:38]2[C:34]=1[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:61]=[CH:60][C:56]([C:57]([OH:59])=[O:58])=[CH:55][CH:54]=1)[CH2:37]2>O>[CH3:43][O:42][C:41]1[C:33](=[O:32])[C:34]2[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]3[CH:54]=[CH:55][C:56]([C:57]([OH:59])=[O:58])=[CH:60][CH:61]=3)[CH2:37][C:38]=2[C:39](=[O:46])[C:40]=1[O:44][CH3:45]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCOc1ccc(C(=O)O)cc1)C2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)O)cc3)C2)C1=O
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
A water (2.0 ml) solution of CAN (1.27 g, 2.32 mmols) was dropwise added to an acetonitrile (8.0 ml) solution of 4-[4-(4,5,6,7-tetramethoxyindan-2-yl)butoxy]benzoic acid (400 mg, 0.929 mmols), with cooling with ice, and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate) followed by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (200 mg) as crystals.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:6](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:3]1.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C.CCOC(C)=O.C(=O)(O)[O-].[Na+]>[N:28]([C@H:6]1[C@@H:2]([CH3:1])[CH2:3][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:5]1)=[N+:29]=[N-:30]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Yield: 60.1 %

Procedure:
(+/−)-(trans)-benzyl 3-methyl-4-(tosyloxy)pyrrolidine-1-carboxylate (5.00 g, 12.84 mmol) and sodium azide (2.087 g, 32.1 mmol) in DMF (10 mL) was heated under argon at 85° C. for 18 h. The resulting mixture was cooled and diluted with EtOAc and sat. sodium bicarbonate, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give a tan oil which was purified via preparative chromatography using Hexanes/EtOAc mixtures as the eluant and 40 g silica cartridge. Fractions containing the major product were combined and concentrated to afford the title compound as a near colorless oil (2.01 g, 7.72 mmol, 60%). HPLC (method B) retention time=3.30 min. LCMS (m+Na)=283.2. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.41-7.30 (m, 5H), 5.15 (d, J=6.2 Hz, 2H), 4.00 (t, J=4.3 Hz, 1H), 3.76-3.55 (m, 3H), 3.16-3.02 (m, 1H), 2.47-2.30 (m, 1H), 1.13 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:11]([OH:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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:13][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2)=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[C:11]=1[OH:12]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1ccc2c(Br)c(O)c(Cl)cc2n1
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: [K+]
Solvent: COCCOC
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c(O)c(Cl)cc2n1
Temperature: 80 °C
Yield: 46.5 %

Procedure:
Pd(PPh3)4 (120 mg, 0.1 mmol) was added to a mixture of 5-bromo-7-chloro-2-methylquinolin-6-ol (1D) (345 mg, 1.04 mmol), 4-chlorophenylboronic acid (326 mg, 2.09 mmol) and K2CO3 (2.3 mL 2 M in water, 4.7 mmol) in 1,2-dimethoxyethane (10 mL). The reaction mixture was flushed with nitrogen, heated at 80° C. for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with a NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide 1E as a white solid (147 mg, 47%). LCMS-ESI+ (m/z): 304.2, 306.2 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.C([O-])(O)=O.[Na+].C(N1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35])(OCC)=O.OP(O)(O)=O>CC(C)=O.O>[C:26]1(=[O:35])[N:1]([CH:2]2[C:13](=[O:14])[N:4]3[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]23)[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1=C(C(=O)O)N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Reaction time: 3 h

Procedure:
To a suspension of 181 g. of 7-amino-3-methyl-3-cephem-4-carboxylic acid (7-ADCA) in 1700 ml. of water, 142 g. of NaHCO3 were slowly added followed by a solution of 186 g. of N-carbethoxyphthalimide in 1 liter of acetone added dropwise over a 30 minute period. After stirring for 3 hrs. the solution was cooled in an ice-water bath and acidified to pH 2.1 by addition of 600 ml. of 42.5% of H3PO4. The resulting precipitate was filtered, washed with water, and vacuum dried to give 227 g. of a mixture of the starting material and the desired phthalimido compound. The mixture was separated by extraction with warm acetone and ethyl acetate, recovering 105 g. of 7-ADCA. The yield of the phthalimido compound was 114 g. A sample (1 g.) of product was crystallized from acetone (15 ml.); colorless crystals, m.p. 223°-225°; [α]D + 428.02° (MeCN); ir (nujol) 1810, 1785, 1740 and 1710 cm-1 ; nmr (CDCl3) δ 2.38 (s, 3, CH3), 3.0 and 3.75 (ABq, 2, J=14 Hz), 5.13 (d, 1, J=4.5 Hz), 5.71 (d, 1, J=4.5 Hz), and 7.82 (m, 4, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[N:11]([O-])=O.[Na+].O.O.Cl[Sn]Cl>C1COCC1.O.Cl>[ClH:10].[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][NH2:11])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(NN)cc1Cl
Temperature: -5 °C
Reaction time: 2 h

Procedure:
5 g of 4-amino-2-chlorobenzonitrile and 40 ml of concentrated HCl in 30 ml of THF are mixed at -5° C.; 2.26 g of NaNO2 in 30 ml of water are added and the mixture is left stirring for 2 hours, 30 g of SnCl2.2H2O in 30 ml of concentrated HCl are then added and stirring is maintained at -5° C. for 30 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH3:18].[OH:19]O>C(O)(=O)C>[Cl:1][C:2]1[C:15]2[S:14](=[O:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:16])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1ccc2c(c1Cl)Sc1ccccc1N2C
Reactant: OO
Solvent: CC(=O)O
Product: COc1ccc2c(c1Cl)S(=O)c1ccccc1N2C
Temperature: 50 °C

Procedure:
To 4-chloro-3-methoxy-10-methyl-10H-phenothiazine (0.5 g) (see Example 5) was added acetic acid (12 ml) and hydrogen peroxide (2 ml). The reaction mixture was heated at 50° C. for 15 minutes and then, evaporated to dryness. The corresponding sulfoxide (0.5 g) (4-chloro-3-methoxy-10-methyl-5-oxo-10H-phenothiazine) was obtained by crystallization (m.p. decomposed at 141° C.).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Li]CCCC.[N+:15]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20](OC)=[O:21])([O-:17])=[O:16]>C1COCC1>[N+:15]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([C:5]1[S:4][C:3]([Si:2]([CH3:9])([CH3:8])[CH3:1])=[N:7][CH:6]=1)=[O:21])([O-:17])=[O:16]
Reactant: C[Si](C)(C)c1nccs1
Reactant: COC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ncc(C(=O)c2ccccc2[N+](=O)[O-])s1
Reaction time: 0.5 h

Procedure:
To a solution of 2-trimethylsilylthiazole (2.0 g, 12.7 mmol) in THF at −78 C was added BuLi (5.08 mL, 2.5 M, 12.7 mmol). The reaction was stirred at −78 C for 0.5 hr and methyl 2-nitrobenzoate (2.69 mL, 19.1 mmol) was added. The suspension was stirred at room temperature for 2 hr and quenched with ammonium chloride solution. The mixture was extracted with ethyl acetate and the combined organic layer was dried over sodium sulfate, concentrated and purified by column chromatography to give 2H (680 mg)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[NH2:14][CH:15]1[C:19](=[O:20])[N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH:16]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH:14][C@H:15]2[C:19](=[O:20])[N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][C@H:16]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:13])=[CH:2]1
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)Cc1c[nH]c2ccccc12
Reaction time: 18 h
Yield: 81.6 %

Procedure:
To a solution of indole-3-acetic acid (248 mg, 1.42 mmol) in DMF (3 ml) was added 1,1-carbonyldiimidazole (230 mg, 1.42 mmol). After stirring for 2 h a solution of the aminopyrrolidinone of Example S (352 mg, 1.42 mmol) in DMF (1 ml) was added. After stirring for an additional 18 h the solvent was evaporated to give an oil which was chromatographed on silica gel eluting with EtOH/CH2Cl2 (2%-5%) to give 470 mg (91%) of the title compound as a solid. NMR (DMSO) 400 MHz : 3.25δ, m, 1H; 3.59δ, d, 2H; 3.88δ, t, 1H; 4.01δ, t, 1H; 4.65δ, q, 1H; 6.98δ, t, 1H; 7.08δ, t, 1H; 7.15δ, t, 1H; 7.24δ, d, 1H; 7.37, m, 3H; 7.56δ, d, 1H; 7.78δ, d, 2H; 8.62δ, d, 1H.
Reaction SMILES: C(O)=O.C(OC([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[CH:13]=[C:12]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2([CH3:34])[N:32]=[C:31]([NH2:33])[CH2:30][O:29][CH2:28]2)[CH:22]=1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:20].[Cl:20][C:17]1[CH:18]=[C:19]2[C:14]([CH:13]=[C:12]([C:21]3[CH:22]=[C:23]([C:27]4([CH3:34])[CH2:28][O:29][CH2:30][C:31]([NH2:33])=[N:32]4)[CH:24]=[CH:25][CH:26]=3)[NH:11]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cccc(C3(C)COCC(N)=N3)c2)cc2ccc(Cl)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: O=CO
Product: CC1(c2cccc(-c3cc4ccc(Cl)cc4[nH]3)c2)COCC(N)=N1
Reaction time: 7 h

Procedure:
A mixture of 2-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-6-chloro-indole-1-carboxylic acid tert-butyl ester formate (12 mg, 0.02 mmol) and hydrochloric acid in dioxane (4M) was left at room temperature for 7 hours. For the workup, the solution was evaporated at reduced pressure and the residue dried at high vacuum to yield the (RS)-5-[3-(6-chloro-1H-indol-2-yl)-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine hydrochloride as an amorphous brown material. MS (ISP): m/z=340.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:15])=[N-]>CCOC(C)=O.CCOCC>[CH3:15][O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)/C=C/c1ccc(O)cc1

Procedure:
To a solution of 4-hydroxycinnamic acid (0.407 g, 2.48 mmol) in EtOAc, a solution of diazomethane in Et2O was added until the yellow color persisted. Excess diazomethane was quenched by the addition of AcOH and the reaction mixture was evaporated to dryness. The residue was dissolved in EtOAc and washed with 10% aqueous HCl, saturated NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography, using a gradient from 10%-20% EtOAc in hexane, to give E-3-(4-hydroxyphenyl)acrylic acid methyl ester as a white solid (0.362 g).
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4]Cl.C(=O)([O-])[O-].[K+].[K+].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>CC(C)=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:2]2([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)[CH2:4][CH2:3]2)=[O:7])=[CH:9][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Yield: 82.9 %

Procedure:
A solution of 150 g of 4-chlorophenyl 1-bromo-3-chloropropyl ketone in 200 ml of acetone is added drop-wise to a boiling solution of 100 g of potassium carbonate and 110 g of 1,2,4-triazol in 400 ml of acetone, and the mixture is then stirred under reflux for 8 hours. Thereafter, it is evaporated down in vacuo, and the residue is stirred in 500 ml of water. The precipitate which separates out is filtered off under suction, washed several times with water and dried. 104 g (82% of theory) of 1-(4-chlorobenzoyl)-1-(1,2,4-triazol-1-yl)-cyclopropane of melting point 78° C. are obtained. ##STR56##
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:7]=[C:6]([C:20]([O:22]C)=[O:21])[C:5]=1[C:24]([O:26][CH3:27])=[O:25].O.Cl>CO>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]([C:24]([O:26][CH3:27])=[O:25])=[C:4]([Cl:3])[C:9]2=[O:10])=[CH:17][CH:16]=1
Reactant: COC(=O)c1cn(Cc2ccc(OC)cc2)c(=O)c(Cl)c1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(C(=O)O)cn(Cc2ccc(OC)cc2)c(=O)c1Cl
Reaction time: 12 h
Yield: 95.9 %

Procedure:
Lithium hydroxide (1.884 g, 44.8 mmol) was added to a solution of compound (9) (8.2 g, 22.42 mmol) in MeOH (150 ml)/water (100 ml). The reaction was stirred for about 12 h at r. t. and the reaction solution was adjusted to pH=2 with diluted aqueous HCl. The solid was filtered and washed with cold ether to give the title compound (8.4 g, 21.49 mmol, 96% yield). LC-MS (ESI+): m/e 352(M+H)+, Rt: 1.73 min; 1H-NMR (DMSO-d6, 400 MHz): δ=3.75 (s, 3H), 3.83 (s, 3H), 5.20 (s, 2H), 6.93 (d, 2H, J=8.8 Hz), 7.33 (d, 2H, J=8.8 Hz), 8.68 (s, 1H), 13.39 (br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=2)[CH:17]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:23])=[CH:20][N:19]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4F)nnn3C)c2)nc1
Yield: 61 %

Procedure:
As described for example 22, 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (75 mg, 0.194 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (51 mg, 61%) which was obtained as an off white foam. MS: m/e=406.3 [M+H]+.