Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[CH2:8](OC(OCC)OCC)C.[C:18]([O:27][CH3:28])(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH2:21]>CC(O)C>[NH:4]1[C:3]([NH:2][CH:8]=[N:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]([O:27][CH3:28])=[O:26])=[N:7][N:6]=[N:5]1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1ccccc1N
Reactant: Nc1nnn[nH]1
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccccc1N=CNc1nnn[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 12.1 g of 5-aminotetrazole monohydrate, 42 g of triethoxymethane, 21 g of methyl anthranilate and 50 ml of 2-propanol was stirred at room temperature under nitrogen for 2 days. The white solid which formed was separated by filtration, washed with 2-propanol and vacuum oven dried to give N1 -(1H-tetrazol-5-yl)-N2 -(2-carbomethoxyphenyl)formamidine which was identical with authentic material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2C(O)=O)=[CH:4][CH:3]=1.[CH2:17]([N:19](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:41]([NH:49][NH2:50])(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O(Cl)Cl.[P+5]>C1(C)C=CC=CC=1.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:19][C:17]2[O:48][C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[N:49][N:50]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Reactant: NNC(=O)c1ccccc1
Reactant: CCN(CC)CC
Agent: ClOCl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [P+5]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (1 g, 3.6 mmol), triethylamine (1 mL, 7.2 mmol) and diphenylphosphoryl azide (1.98 g, 7.2 mmol) were placed in toluene (20 mL) and heated to 60° C. for 20 minutes. Benzoic acid hydrazide (0.98 g, 7.2 mmol) was added in a single portion and the reaction was heated and stirred for 2 hours. The reaction was cooled and submitted to aqueous workup. The crude material was dissolved in dioxane (100 mL), phosphorous(V) oxychloride was added and the reaction was heated to 100° C. overnight. The reaction was cooled and worked up and the residue was purified on silica gel (0-80% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [Na].[OH:2][CH:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O-:6])=[O:5].[OH-].[Na+]>>[CH3:9][CH:8]([CH2:7][C@H:3]([OH:2])[C:4]([OH:6])=[O:5])[CH3:10].[CH3:9][CH:8]([CH3:10])[CH2:7][C:3](=[O:2])[C:4]([OH:6])=[O:5]
Reactant: CC(C)CC(O)C(=O)[O-]
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: CC(C)CC(=O)C(=O)O
Product: CC(C)C[C@H](O)C(=O)O
Reaction time: 24 h

Procedure:
A 500 ml Erlenmeyer flask provided with a baffle and containing 90 ml of medium A was inoculated with Bacillus freudenreichii NRS-137KH20B (FERM-P No. 3169, ATCC 31301) from a slant culture. The incubation was carried out for 24 hours under the conditions described in Example 1. Thereafter, 3.17 g of sodium DL-2-hydroxy-4-methylvalerate were added and the fermentation was continued for 82 hours. The substrate remaining in the fermentation broth contained 15.2 mg/ml of free L-hydroxyacid (optical purity: 100%). The thus-obtained fermentation broth was then treated in an analogous manner to that described in Example 1 and there were obtained 1.18 g of crystalline L-2-hydroxy-4-methylvaleric acid of melting point 79.1° C. [[α]D25 =-26.8° (c=2 in 1-N sodium hydroxide)] and 0.7 g of 4-methyl-2-oxovaleric acid of boiling point 65°-75° C./10 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:11](=O)[CH2:12]Cl)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:11]1[N:16]=[C:17]([NH2:19])[S:18][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C(=O)CCl)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a solution of 2-(chloroacetyl)malonic acid diethyl ester in ethanol (8 parts) is added thiourea (1.9 equivalents). After stirring at room temperature for 2 hours, the mixture is let stand overnight. The reaction mixture is concentrated, diluted with water, and neutralized with aqueous sodium hydrogen carbonate to give 2-(2-amino-4-thiazolyl)malonic acid diethyl ester. Yield: 79.2%. mp. 99.5°-100.5° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:3].[H-].[Na+].[CH3:33][N:34]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35](=[O:38])[CH2:36]Br>O1CCCC1>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[N:11]([CH2:36][C:35]([N:34]([CH3:33])[CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])[CH3:1]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Reactant: CN(CCc1ccccc1)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1c(OCc3ccccc3)cccc1n2CC(=O)N(C)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
2.1 g of 5-benzyloxy-4-methoxymethyl-9H-pyrido-[3,4-b]indole-3-carboxylic acid-(1-methylethyl)ester is added to a suspension of 168 mg of sodium hydride (80% in mineral oil) in 25 ml of tetrahydrofuran at 0° C., it is stirred for 10 minutes at 0° C., then mixed with a solution of 1.6 g of N-methyl-N-2-phenylethyl-2-bromoacetamide and stirred for 18 hours at 24° C. Then, it is suctioned off on Celite, concentrated by evaporation in a vacuum, and the residue is purified by chromatography on silica gel. 2.8 g of 5-benzyloxy-4-methoxymethyl-9-{2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is obtained as weak, yellowish crystals with a melting point of 146°-147° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([Sn](CCCC)(CCCC)CCCC)[CH:4]=1.Br[C:23]1[CH:24]=[C:25]([C:30]2([C:41]3[CH:42]=[N:43][CH:44]=[N:45][CH:46]=3)[C:38]3[C:33](=[C:34]([F:39])[CH:35]=[CH:36][CH:37]=3)[C:32]([NH2:40])=[N:31]2)[CH:26]=[CH:27][C:28]=1[F:29]>CN(C=O)C.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>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:33]=1[C:32]([NH2:40])=[N:31][C:30]2([C:25]1[CH:26]=[CH:27][C:28]([F:29])=[C:23]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:24]=1)[C:41]1[CH:46]=[N:45][CH:44]=[N:43][CH:42]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(OC)ccn1
Reactant: NC1=NC(c2cncnc2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccnc(-c2cc(C3(c4cncnc4)N=C(N)c4c(F)cccc43)ccc2F)c1
Temperature: 110 °C
Yield: 14.9 %

Procedure:
4-Methoxy-2-(tributylstannyl)pyridine (265 mg, 0.67 mmol), 1-(3-bromo-4-fluorophenyl)-4-fluoro-1-(pyrimidin-5-yl)-1H-isoindol-3-amine (178.3 mg, 0.44 mmol) and tetrakis(triphenylphosphine)palladium(0) (138 mg, 0.11 mmol) were mixed in dry DMF (2.00 mL) and heated in a microwave reactor at 110° C. for 305 min. The resulting product mixture was filtered and purified by preparative-HPLC to give the title compound (28.2 mg, 12% yield):
Reaction SMILES: [N+]([O-])(O)=O.[Cl:5][C:6]1[C:7]([F:16])=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([OH:11])=[O:10].[Br:17]Br>C(O)(=O)C.O.[N+]([O-])([O-])=O.[Ag+]>[Br:17][C:13]1[C:14]([F:15])=[C:6]([Cl:5])[C:7]([F:16])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: BrBr
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: O=C(O)c1cc(Br)c(F)c(Cl)c1F
Reaction time: 14 h

Procedure:
In a mixture of 50 ml of acetic acid, 10 ml of water and 13 ml of nitric acid is dissolved 2 g (0.014 mole) of 3-chloro-2,4-difluorobenzoic acid and 3.64 ml (0.028 mole) of bromine. A solution of 3.52 g (0.0208 mole) of silver nitrate in 10 ml of water is then added slowly. After 14 hours at 20° C., the precipitate is filtered and rinsed with ether. The organic phase is washed with sodium bisulfite, then water and dried. Removal of the solvent affords the desired product.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:22])=[C:14]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[S:18])[CH:15]=1>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:22])=[C:14]([N:16]2[C:2](=[O:8])[C:3](=[O:5])[N:19]([CH2:20][CH3:21])[C:17]2=[S:18])[CH:15]=1
Reactant: CCNC(=S)Nc1cc(Cl)ccc1C
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCN1C(=O)C(=O)N(c2cc(Cl)ccc2C)C1=S
Yield: 83.1 %

Procedure:
Ethyl chlorooxoacetate (12.3 g; 0.09 mol) was added dropwise to the solution N-(5-chloro-2-methylphenyl)-N′-ethylthiourea (13.7 g; 0.06 mol) in chloroform (300 mL). The mixture was heated at reflux for 3 hour then evaporated to dryness. The residue was dissolved in ethyl acetate (400 mL) and washed with saturated sodium bicarbonate solution (300 mL), then with water (300 mL). ). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residual solid was slurried in ether and filtered. The solid was washed with ether and air dried to give 1-(5-Chloro-2-methylphenyl)-3-ethyl-2-thioxo-4,5-imidazolidinedione (14.1 g), m.p. 173–174° C. Mass spectrum; (El, M.+) m/z 382/384. 1 H-NMR (DMSO-d6; 300 MHz): δ 7.49–7.40 (m, 3H), 3.92 (m, 2H), 2.15 (s, 3H), and 1.23 ppm (t, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[OH-].[K+].O.[CH2:17]([SH:20])[CH2:18][CH3:19]>CO>[CH2:17]([S:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:18][CH3:19]
Reactant: O=C(O)CCCCCCCCCBr
Reactant: CCCS
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCSCCCCCCCCCC(=O)O
Temperature: 69 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
10-bromodecanoic acid (1.0 g, 3.98 mmol) was added to a solution of potassium hydroxide (0.893 g, 15.9 mmol) in 1-propanethiol (30 mL) and methanol (30 mL) and stirred at 69° C. for 18 hrs. The reaction was allowed to cool to room temperature after the addition of 20 mL water. After acidification to pH=1 and extraction into ethyl acetate, the organic phase was dried over sodium sulfate and solvent removed at reduced pressure to yield a white crystalline powder. The product was purified by silica column chromatography in 8% ethyl acetate/hexane/0.3% formic acid and recrystallization from hexane to yield 10-(propylthio)decanoic acid (210 mg, 21%), mp 42°-43.5° C.; 1H NMR (300 MHz, CDCl3) δ0.96 (t, 3H, J=7.3, CH3) 1.15-1.40 (bm, 10H, methylene envelope), 1.49-1.64 (bm, 6H, CH3CH2CH2SCH2CH2, CH2CH2COOH), 2.32 (t, 2H, J=7.6, CH2COOH), 2.40-2.55 (bm, 4H, CH3CH2CH2SCH2), 10.93 (Br, 1H, COOH); 13C NMR (75.4 MHz, CDCL3) δ 13.64, 23.09, 24.71, 28.96, 29.07, 29.13, 29.24, 29.36, 29.77, 32.16, 34.10, 34.28, 179.98; m/z 247 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:26])C(=O)C1.C(=O)(O)[O-].[Na+]>C(#N)C>[NH2:1][C:2]1[C:3]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[N:4][C:5]([Br:26])=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nccnc2N)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Reaction time: 1 h
Yield: 96 %

Procedure:
To a suspension of methyl 4-(3-aminopyrazin-2-yl)-2-fluorobenzoate (31.5 g, 127 mmol) in acetonitrile (430 mL) at 0° C. was added NBS (23.9 g, 134 mmol). The reaction mixture was stirred in ice bath for 1 h, sat. sodium bicarbonate was added, stirred 30 min and product was extracted with ethylacetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was recrystallized in EtOAc and heptane to give methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate as brown color solid in 96% yield. LCMS (m/z): 326.0/328.0 (MH+), 0.87 min.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:26][NH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([O:36][C:37](=[O:51])[NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:32][CH2:31]1>C(Cl)Cl>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([CH2:26][NH:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([O:36][C:37](=[O:51])[NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:32][CH2:31]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
To a three-necked 1-L flask was added 4-carboxybenzaldehyde (4.77 g, 31.8 mmol), EDC (6.64 g, 34.7 mmol), HOBT (1.91 g, 31.8 mmol), and DCM (200 mL). When the mixture was homogenous, a solution of biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (10 g, 31.8 mmol; prepared as in Preparation 4) in DCM (100 mL) was added slowly. The reaction mixture was stirred at room temperature for 16 hours and then washed with water (1×100 mL), 1N HCl (5×60 mL), 1N NaOH (1×100 mL) brine (1×50 mL), dried over sodium sulfate, filtered and concentrated to afford 12.6 g of the title compound (92% yield; 85% purity based on HPLC). MS m/z: [M+H+] calcd for C29H31N3O4, 486.2; found, 486.4. Rf=3.12 min (10-70 ACN:H2O, reverse phase HPLC).
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=O)=[O:13])=[CH:8][CH:7]=1)#[N:2].[OH2:23].[NH2:24][NH2:25]>>[NH2:2][C:1]1[NH:25][N:24]=[C:4]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([S:12]([NH2:15])(=[O:13])=[O:23])=[CH:10][CH:11]=2)[N:3]=1
Reactant: N#CN=C(Nc1ccc(S(N)(=O)=O)cc1)Oc1ccccc1
Reactant: NN
Reactant: O
Product: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)n[nH]1
Temperature: 70 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
To a solution of 4-(3-cyano-2-phenyl-isoureido)-benzenesulfonamide (1.35 mmol) in TBF (5 ml), was added a solution of hydrazine monohydrate (2 mmol; 1.5 equivalents). The solution was stirred at 70° C. for 16 hours. The reaction mixture was allowed to cool to room temperature. A white solid precipitated out. It was removed by filtration and was washed with ethanol to afford the title compound (300 mg; 87% yield). 1H NMR (400 MHz, DMSO-d6) 5.95-6.00 (2H, s), 7.00-7.05 (2H, s), 7.55-7.65 (4H, m), 9.15-9.20 (1H, s); MS (ES+) m/e=255
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:24][CH:23]2[NH2:25])[CH:19]=[CH:20][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([NH:25][CH:23]2[CH2:24][CH:22]2[C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Reactant: COc1cccc(C2CC2N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C2CC2NC(=O)C(C)(C)c2nccnc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
A mixture of Intermediate 29 (0.2 g, 0.997 mmol), 2-(3-methoxyphenyl)cyclopropanamine (FSSI, mixture of cis/trans, 0.163 g, 0.997 mmol), HATU (GenScript Corporation, 0.455 g, 1.196 mmol), hunig's base (Aldrich, 0.696 ml, 3.99 mmol) in DMF (0.997 ml) and DCM (0.997 ml) was stirred at room temperature overnight. Reaction mixture was diluted with DCM and washed with water and brine. The organic layer was loaded onto a Biotage samplet (25 g). Purification (0-100% EtOAc/hexane) produced 2-(3-chloropyrazin-2-yl)-N-(2-(3-methoxyphenyl)cyclopropyl)-2-methylpropanamide (0.183 g, 0.529 mmol, 53%). M+1: 346.0.
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:16][C:17](=[O:21])[CH2:18][NH:19][OH:20])=[CH:11][N:12]([CH3:15])[C:13]=1[CH3:14])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22]>C(O)(C)C>[Cl-:22].[OH:20][N:19]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2=[C:13]([CH3:14])[N:12]([CH3:15])[CH:11]=[C:10]2[NH2+:16][C:17](=[O:21])[CH2:18]1
Reactant: Cc1c(C(=O)c2ccccc2)c(NC(=O)CNO)cn1C
Reactant: Cl
Solvent: CC(C)O
Product: Cc1c2c(cn1C)[NH2+]C(=O)CN(O)C2c1ccccc1
Product: [Cl-]
Temperature: 0 °C

Procedure:
The compound of example 1 (79.4 g) was suspended in isopropanol containing 2.1% of HCl (3700 ml) and refluxed for 2 hours with stirring. The reaction mixture was then cooled to 0° C. and a first crop (61 g) of the compound of the title which crystallized out was recovered by filtration. A second crop (9 g) was obtained by concentrating the mother liquors to a small volume. M.p. 220°-223° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH2:29][CH2:30][NH2:31]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:31][CH2:30][CH2:29][NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: NCCNc1ccccn1
Solvent: CS(C)=O
Product: Nc1c(F)c(NCCNc2ccccn2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 75.4 %

Procedure:
A solution of 7 (270 mg, 0.91 mmol) and N-2-pyridinyl-1,2-ethanediamine (250 mg, 1.82 mmol) in DMSO (7 mL) was stirred at 80° C. for 1 h. The reaction mixture was cooled and freeze-dried overnight. The crude product was taken up in methanol (75 mL) and the resulting precipitate was removed by filtration, washed with cold methanol and dried to yield 8 (285 mg, 75%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[C:7]([O:21][C:22](=O)C)[CH:6]=1)C.CC(C)([O-])C.[K+].C(=O)([O-])[O-].[K+].[K+].IC>CO>[CH3:1][O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[C:7]([O:21][CH3:22])[CH:6]=1
Reactant: CCOC(=O)c1ccc(OCCc2cccc(C)c2)c(OC(C)=O)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CI
Product: COC(=O)c1ccc(OCCc2cccc(C)c2)c(OC)c1
Reaction time: 8 h

Procedure:
The compound of step 2 (150 mg, 0.438 mmol) was dissolved in methanol (3 ml), potassium tert-butoxide (73 mg, 0.657 mmol) was added and the mixture was stirred overnight under reflux. Potassium carbonate (60 mg, 0.44 mmol) and iodomethane (124 mg, 0.876 mmol) were then added repeatedly, at intervals of 1 h, with stirring under reflux until completion of the reaction. The volatiles were evaporated in vacuo, the residue was partitioned between EA and 2 N hydrochloric acid, and the aqueous phase was extracted with EA. The combined organic phases were dried over sodium chloride, decanted and evaporated to dryness to yield the title compound.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH:11](OCC)=[O:12].Cl>CO.C(Cl)Cl.O>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][CH:11]=[O:12]
Reactant: Nc1ccccn1
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=CNc1ccccn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a solution of sodium methoxide (176 mL, 25 wt %, 0.81 mol) in 500 mL of methanol was added 2-aminopyridine (30.0 g, 0.32 mol) and the resulting solution was stirred at 40° C. for 30 minutes. Ethyl formate (220 mL, 2.76 mol) was then added dropwise and the reaction mixture was stirred overnight at 40° C. After cooling to room temperature, 250 mL of H2O and 250 mL of CH2Cl2 were added and conc. HCl (˜40 mL) was added dropwise until pH ˜5. Most of the methanol was evaporated and the resulting mixture was extracted with 3×150 mL of CH2Cl2. The combined organic portions were washed with 250 mL of H2O and 150 mL of brine and dried over Na2SO4. After evaporation of the solvent, 20.2 g of crude solid was obtained and distilled on a Kugelrohr at an oven temperature of 140° C. to yield 18.98 g of a white solid as the product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][C:7]2=[O:18])(=[O:3])[CH3:2].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH2:16][CH3:17])[N:8]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=1)[C:7]2=[O:18])(=[O:3])[CH3:2]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1nc2ccc(C(C)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
A suspension of 0.250 g of 6-acetyl-2-butyl-4(1H)-quinazolinone, 0.685 g of 5-[4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl) -1H-tetrazole and 0.424 g of anhydrous potassium carbonate in 25.0 ml of dry acetone is heated at reflux for 16 hours. The reaction mixture is alowed to cool to room temperature, filtered and the filtrate evaporated in vacuo to a residue. The residue is purified by column chromatography on silica gel using 1:3 ethyl acetate-hexanes to give 0.43 g of the desired product as a solid, m.p. 104°-105° C.
Reaction SMILES: [C:1]([O:4][C:5]1[N:6]=[C:7]([CH3:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=[O:3])[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:45])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:4][C:5]1[N:6]=[C:7]([CH2:19][Br:45])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2cc(OC(C)=O)nc(C)c2cc1OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2cc(OC(C)=O)nc(CBr)c2cc1OC
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-yl acetate SIL 32158 (261 mg, 1.00 mmol) in dry CCl4 (5 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added benzoyl peroxide (12 mg, 0.05 mmol) followed by NBS (178 mg, 1.00 mmol) and the mixture was stirred for 15 min at 130° C. under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2 (20 mL), washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 75:25) gave 1-(bromomethyl)-6,7-dimethoxyisoquinolin-3-yl acetate SIL 32162 as a yellow solid (140 mg, 41% yield).