Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH:21](Br)[CH3:22]>C(#N)C>[CH3:13][C:10]1[C:11]2[O:12][CH2:21][CH2:22][O:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1
Reactant: CC(Br)Br
Reactant: COC(=O)c1cc(C)c(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C)c2c(c1)OCCO2

Procedure:
A mixture of 34.0 g (0.19 mol) methyl 3,4-dihydroxy-5-methyl-benzoate, 77.12 g (0.56 mol) K2CO3 and 32.1 mL (0.37 mol) dibromoethane in 500 mL acetonitrile was refluxed for 6 h. The solid was filtered off, washed with 100 mL acetonitrile and the filtrate was evaporated to dryness i.vac. The residue was combined with 500 mL water and 500 mL EtOAc, the phases were separated, the organic phase was dried and evaporated to dryness i. vac. The residue was combined with 120 mL DIPE, the precipitate was suction filtered, washed with 50 mL DIPE and dried.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][N:6]=1)[CH3:3].[ClH:15]>>[ClH:15].[CH3:3][N:2]([CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1)[CH3:1]
Reactant: COC(=O)c1ccc(CN(C)C)nc1
Agent: Cl
Product: CN(C)Cc1ccc(C(=O)O)cn1

Procedure:
A mixture of methyl 6-(dimethylamino)methylnicotinate (256 mg) and 10N hydrochloric acid was refluxed overnight. After cooling, the reaction mixture was concentrated under reduced pressure to obtain 6-(dimethylamino)methylnicotinic acid hydrochloride (329 mg) as colorless powder.
Reaction SMILES: C(O)C.CC1[N:6]([C:11]2[CH:23]=[CH:22][C:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:13]([C:24]([F:27])([F:26])[F:25])[CH:12]=2)C(C)=CC=1.Cl.NO>C(N(CC)CC)C>[N:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:14]2[CH:22]=[CH:23][C:11]([NH2:6])=[CH:12][C:13]=2[C:24]([F:25])([F:26])[F:27])=[CH:17][CH:18]=1
Reactant: Cc1ccc(C)n1-c1ccc(Cc2ccncc2)c(C(F)(F)F)c1
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ccc(Cc2ccncc2)c(C(F)(F)F)c1
Reaction time: 18 h
Yield: 82.7 %

Procedure:
To 10 mL of an ethanol solution of 227 mg (0.69 mmol) of 4-[4-(2,5-dimethyl-pyrrol-1-yl)-2-trifluoromethyl-benzyl]-pyridine, 191 mg (2.75 mmol) of hydroxylamine hydrochloride and 200 μL of triethylamine were added and the mixture solution was refluxed with stirring for 18 hours. The reaction solution was partitioned between a saturated sodium bicarbonate solution and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The obtained residue was purified by a silica gel column (n-hexane:ethyl acetate=1:1) to obtain 144 mg (83%) of a target product as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH3:25])[C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
A solution of 3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B, 1.5 g, 5 mmol) in 50 mL of DMF was added to a suspension of sodium hydride (0.24 g, 5.9 mmol) in 20 mL of DMF and stirred for 30 minutes. Methyl iodide (3.1 mL, 49 mmol) was added, and the mixture was stirred at 25° C. for 18 hours. The reaction was quenched with 1 mL of water and concentrated to an oil. The residue was dissolved in chloroform, washed with water, brine, and dried over magnesium sulfate. The solution was concentrated to give 1.6 g of the title compound as a solid, mp 167-169° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[CH:21]=[C:20]([C:23]([OH:25])=O)[CH:19]=[CH:18]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:28])=O>>[C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[CH:21]=[C:20]([C:23]([Cl:28])=[O:25])[CH:19]=[CH:18]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NCCc1cccc2ccc(C(=O)O)cc12
Reactant: O=S(Cl)Cl
Product: O=C(Cc1ccccc1)NCCc1cccc2ccc(C(=O)Cl)cc12
Reaction time: 1 h

Procedure:
5 mmol of the product obtained in Step C are dissolved in 40 ml of thionyl chloride. After stirring under an inert atmosphere for 1 hour, the thionyl chloride is evaporated off under reduced pressure to yield the title product.
Reaction SMILES: Cl.[OH:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[CH2:13]([C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:24][N:23]([C:4](=[O:6])[C@H:3]([OH:2])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)[C@H](O)c1ccccc1
Yield: 26.7 %

Procedure:
Proceeding as in Example 1, but substituting (R)-2-hydroxy-2-phenylacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 40, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-((R)-2-hydroxy-2-phenylacetyl)pyrrolidine-2-carboxamide (8.4 mg, 26.7%). 1H-NMR (400 MHz, DMSO-D6): σ 10.03 (s, 1H), 7.56 (d, 2H), 7.27 (m, 11H), 6.97 (m, 5H), 5.20 (s, 1H), 4.44 (t, 1H), 2.86 (t, 2H), 2.71 (s, 1H), 2.45 (d, 2H), 1.80 (m, 2H). MS (EI) for C32H29FN2O4: 525.4 (MH+).
Reaction SMILES: C1([C@H](N)[C@H](C2C=CC=CC=2)N)C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([CH:32]1[CH2:34][CH2:33]1)=[O:31]>C(O)(C)C>[CH:32]1([C@H:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[OH:31])[CH2:33][CH2:34]1
Reactant: Cc1ccccc1C(=O)C1CC1
Agent: CC(C)(C)[O-]
Agent: N[C@@H](c1ccccc1)[C@@H](N)c1ccccc1
Agent: [K+]
Solvent: CC(C)O
Product: Cc1ccccc1[C@H](O)C1CC1
Reaction time: 60 h
Yield: 71.1 %

Procedure:
To a suspension of dichloro[(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]ruthenium(II) (851 mg), (1S,2S)-(−)-1,2-diphenylethylenediamine (191 mg) and potassium-tert-butoxide (270 mg) in isopropanol (90 ml) was added cyclopropyl 2-methylphenyl ketone (9.61 g) obtained in Step 2, and the mixture was hydrogenated at room temperature and at medium pressure (3.0 kgf/cm2) for 60 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to give the title compound (6.92 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]#[N:13])[CH2:4][CH2:3]1.[CH3:15]I>C(O)(C)(C)C>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:15])([C:12]#[N:13])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(C#N)c2ccccc21
Reactant: CI
Solvent: CC(C)(C)O
Product: CC1(C)CCC(C)(C#N)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
81.5 g of 1,1-dimethyl-4-cyano-tetralin are added dropwise to 49 g of potassium tert.butylate in 400 ml of tert.butanol and the mixture is stirred at room temperature for 1 hour. At 5° C. there are then added dropwise 72 g of methyl iodide and the mixture is stirred for 15 hours without cooling. The bulk of the tert.butanol is distilled off, the residue is taken up in ether and washed neutral with water, dried over sodium sulphate and evaporated. The residue is distilled in vacuo and there are obtained 61 g of 1,1,4-trimethyl-4-cyano-tetralin of boiling point 85° C./0.25 mmHg; melting point 46° C.; yield 70%. Odour: resembling (3), but more intensive, woody.
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([CH3:43])[CH:42]=1)[C:37]([OH:39])=O)=[O:33].[CH2:44]([C:46]1[CH:61]=[C:60]([C:62](=[NH:65])[NH:63]O)[CH:59]=[C:58]([CH3:66])[C:47]=1[O:48][CH2:49][C@@H:50]([OH:57])[CH2:51][NH:52][C:53](=[O:56])[CH2:54][OH:55])[CH3:45]>>[CH2:44]([C:46]1[CH:61]=[C:60]([C:62]2[N:65]=[C:37]([C:36]3[CH:40]=[C:41]([CH3:43])[CH:42]=[C:34]([CH:32]=[O:33])[CH:35]=3)[O:39][N:63]=2)[CH:59]=[C:58]([CH3:66])[C:47]=1[O:48][CH2:49][C@@H:50]([OH:57])[CH2:51][NH:52][C:53](=[O:56])[CH2:54][OH:55])[CH3:45]
Reactant: Cc1cc(C=O)cc(C(=O)O)c1
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCc1cc(-c2noc(-c3cc(C)cc(C=O)c3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Yield: 43.4 %

Procedure:
The title compound (407 mg) was prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide starting from 3-formyl-5-methyl-benzoic acid (340 mg, 2.07 mmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (674 mg, 2.07 mmol). LC-MS: tR=0.85 min; [M+1]+=454.11; 1H NMR (D6-DMSO): δ 1.23 (t, J=7.5 Hz, 3H), 2.36 (s, 3H), 2.55 (s, 3H), 2.74 (q, J=7.5 Hz, 2H), 3.20-3.29 (m, 1H), 3.39-3.48 (m, 1H), 3.70-3.81 (m, 2H), 3.84 (d, J=4.8 Hz, 2H), 3.93-4.00 (m, 1H), 5.32 (d, J=4.8 Hz, 1H), 5.56 (t, J=5.0 Hz, 1H), 7.71 (t, J=5.8 Hz, 1H), 7.82 (s, 2H), 8.06 (s, 1H), 8.34 (s, 1H), 8.50 (s, 1H), 10.15 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([N+:13]([O-])=O)=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([C:16](=[O:21])[CH2:17][N:18]([CH3:20])[CH3:19])[CH2:3]1.O.NN>[Fe](Cl)(Cl)Cl>[CH3:20][N:18]([CH2:17][C:16]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[C:7]([NH2:13])[CH:6]=2)[C:2]([CH3:22])([CH3:1])[CH2:3]1)=[O:21])[CH3:19]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CC2(C)C
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Product: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2(C)C
Temperature: 65 °C
Yield: 71 %

Procedure:
A suspension of {2-[3,3-dimethyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}dimethylamine (2.20 g, 7.16 mmol), hydrazine hydrate (2.81 mL, 57.3 mmol), iron(III)chloride (0.232 g, 1.432 mmol), and activated carbon (2 g, 7.16 mmol) was warmed at 65° C. for 16 hours. The solution was filtered while still warm through celite, taken to a residue under reduced pressure, and partitioned between chloroform and saturated sodium bicarbonate. The organic layer was washed with saturated sodium chloride (aq), dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 1-[(dimethylamino)acetyl]-3,3-dimethyl-5-(methyloxy)-2,3-dihydro-1 H-indol-6-amine (1.41 g, 71% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (s, 1 H), 6.69 (s, 1 H), 4.62 (s, 2 H), 3.82 (s, 2 H), 3.73 (s, 3 H), 3.12 (s, 2 H), 2.23 (s, 6 H), 1.22 (s, 6 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]#[N:25])=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C@@H:7]([NH:10]C(=O)OCC1C=CC=CC=1)[CH2:8][CH3:9].O=[C:27]([CH3:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[NH2:25][C:24]1[C:3]2[C:2](=[CH:23][CH:22]=[CH:21][C:4]=2[O:5][CH2:6][C@@H:7]([NH2:10])[CH2:8][CH3:9])[N:1]=[C:27]([CH3:34])[C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CC[C@@H](COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N

Procedure:
Prepared as in Example 2a from (S)-benzyl 1-(3-amino-2-cyanophenoxy)butan-2-ylcarbamate (Example 97c) and ethyl 3-oxobutanoate as brown solid (75%). MS 318 (MH+).
Reaction SMILES: C([N:8]1[C:13](=[O:14])[CH2:12][O:11][C:10]2[N:15]=[CH:16][C:17]([Br:19])=[CH:18][C:9]1=2)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Br)C1C=CC=CC=1>CN(C=O)C>[Br:19][C:17]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][C:13](=[O:14])[NH:8][C:9]=2[CH:18]=1
Reactant: O=C1COc2ncc(Br)cc2N1Cc1ccccc1
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1COc2ncc(Br)cc2N1

Procedure:
In concentrated hydrochloric acid (8 mL) was stirred intermediate 65 (1.0 g, 3.43 mmol) which was then cooled to 0° C. This was then treated, in parts, with tin dust (0.92 g, 7.8 mmol) and then warmed to 80° C. for 1 hour. The mixture was cooled to room temperature and diluted with water (100 mL). The mixture was stirred to form a precipitate. The solid was collected by filtration, washed with water (10 mL), and dried at 65° C. for 3 hours under a vacuum to give the title compound. MS: M++1=230.9 Da. Intermediate 67: 1-Benzyl-7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2-one. In DMF (30 mL) was stirred intermediate 66 (650 mg, 2.83 mmol) and cesium carbonate (3.9 g, 12 mmol). To this was added, dropwise, benzyl bromide (513 mg, 3.0 mmol) and the mixture was stirred overnight at room temperature. The mixture was filtered free of insolubles and the DMF was evaporated at reduced pressure to give a crude oil which was purified by MPLC (90 g silica gel column, 9:1 (methylene chloride/ethyl acetate). The appropriate fractions were combined and evaporated at reduced pressure to give the title compound. MS: M++1=321.0 Da.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]1(C)C=CC(S(O)(=O)=O)=C[CH:12]=1.C(OCC)(OCC)(OCC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]=[C:11]([CH3:12])[NH:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1
Product: Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 8 h

Procedure:
A mixture of 4,5-dichloro-1,2-phenylenediamine (25 g, 0.14 mol) and a catalytic amount of p-toluenesulfonic acid suspended in toluene (200 mL) is heated to reflux in a 500 mL three-necked flask fitted with a reflux condenser and addition funnel. Triethyl orthoacetate (23 g, 0.14 mol) is added dropwise over the course of 2 hours. The reflux condenser is then replaced with a distillation head and approximately 50 mL of solvent (mixture of ethanol and toluene) is collected. The remaining reaction mixture is allowed to stand at room temperature overnight. The resulting solid is collected by suction filtration and dried under vacuum for 24 hrs. The product is used without further purification.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[C:9]1([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18](OC)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C>CO.O>[ClH:1].[C:9]1([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18]([N:4]=[C:3]([NH2:5])[NH2:2])=[O:19])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(-c2ccccc2)c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: NC(N)=NC(=O)c1cccc(-c2ccccc2)c1
Reaction time: 0.25 h
Yield: 17.6 %

Procedure:
To a solution of guanidine hydrochloride (2.7 g) in methanol (12 ml) was added sodium methoxide (5.13 g, 28% in methanol) and the mixture was stirred for 15 minutes under nitrogen. To this mixture was added a solution of methyl 3-phenylbenzoate (1.20 g) in methanol (2 ml) and the mixture was stirred for 6 hours. The reaction mixture was poured into a mixture of ethyl acetate (100 ml) and water (50 ml). The organic layer was successively washed with 5N-sodium hydroxide aqueous solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on alumina (100 ml) and eluted with chloroform-methanol (10:1). The fractions containing the desired product were collected and evaporated in vacuo. The residue was crystallized from 4N-hydrogen chloride-ethyl acetate. The crystalline was recrystallized from ethanol to afford 2-[3-phenylbenzoyl]guanidine hydrochloride (274.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[NH:7][N:6]=1.[CH2:17]=[O:18]>CO>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:17][OH:18])[N:6]=1
Reactant: COC(=O)Cc1n[nH]c(=O)c2ccccc12
Reactant: C=O
Solvent: CO
Product: COC(=O)Cc1nn(CO)c(=O)c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of methyl-4-oxo-3-H-phthalazin-1-ylacetate (2.18 g), methanol (50 ml) and aqueous formaldehyde (37% concentration, 10 ml) was refluxed for 40 hours. The reaction mixture was cooled to room temperature and then poured onto water (50 ml). The resulting solid was collected and crystallized from methanol (yield: 0.5 g; m.p. 154°-155° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:12])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of the crude carboxylic acid (652 mg, 3.00 mmol) and NMM (0.50 ml, 4.5 mmol) in THF (12 ml) was added isobutyl chloroformate (0.45 ml, 3.5 mmol) and the resulting mixture was stirred at 0° C. for 5 minutes. A solution of aniline (0.45 ml, 4.9 mmol) in THF (3 ml) was then added dropwise. The reaction was warmed to room temperature and stirred for 66 hours. The reaction was diluted with 1M HCl (30 ml) and was extracted with Et2O (25 ml×3). The organic solution was washed with brine (50 ml), was dried (Na2SO4), filtered and concentrated under reduced pressure, giving crude ((R)-1-phenylcarbamoyl-butyl)-carbamic acid tert-butyl ester as an oily, light yellow foam.
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[CH3:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[CH2:12][CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:22]=1.Cl>O.C(O)(C)C.C1CCCCC1.CC(C)=O>[OH:14][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:22][C:10]=1[CH:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:12][CH2:13][OH:15]
Reactant: Cc1ccc2c(c1)C(c1ccccc1)CC(=O)O2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCCCC1
Solvent: O
Product: Cc1ccc(O)c(C(CCO)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
A basic aqueous solution of sodium borohydride prepared beforehand by dissolving 23.8 g (0.630 moles) of NaBH4 at ambient temperature in 170 ml of H2O and 3.5 ml of 30% wt./vol. NaOH was added dropwise to a suspension of 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one of the formula (II) (100 g, 0.420 moles) in isopropanol (200 ml). Once addition was complete, the temperature was adjusted to 60° C. and the course of the reaction was monitored by TLC (eluent: cyclohexane/acetone: 70/30) until the substrate had completely disappeared. After 5 h, the reaction mixture was cooled to ambient temperature and HCl (2N) was added until a final pH of 7.0 was obtained. Stirring was continued for 30 min at ambient temperature, then the resultant suspension was filtered through a Buchner filter. The filtered solution was concentrated under reduced pressure and the crude residue was crystallised from toluene (280 ml) to yield 87.4 g (yield 86%) of 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanol (VIII) as a white solid.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH:11]([CH2:13][CH3:14])[C:10]2=[N:15][C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[CH:17][C:18](=[O:19])[N:9]2[CH2:8][CH2:7]1)=O)C.[BrH:26]>C(O)(=O)C>[BrH:26].[CH2:13]([CH:11]1[C:10]2=[N:15][C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[CH:17][C:18](=[O:19])[N:9]2[CH2:8][CH2:7][NH:6][CH2:12]1)[CH3:14]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(CC)C1
Agent: Br
Solvent: CC(=O)O
Product: CCC1CNCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To a solution of 0.075 g (0.22 mmol) of (+/−)-9-ethyl-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4-a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester (example 10) dissolved in 0.8 mL of glacial acetic acid was added 0.77 mL (4.37 mmol) of hydrobromic acid (33 wt % solution in glacial acetic acid). The resulting mixture was stirred at 90° C. for 4 hours, cooled and evaporated to dryness. Methanol was added to the residue and evaporated. Toluene was added to the residue and evaporated. The crude was triturated with diethyl ether and filtered to afford 0.068 g of the product as a white powder (88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Cl.O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)OCc1ccccc1
Yield: 69.5 %

Procedure:
2-Amino-5-chlorobenzoic acid methyl ester (5 g, 27 mmol) was dissolved in 36 mL pyridine. CBz-Cl (4.2 mL, 29.6 mmol) was then added and the resultant solution was stirred at 60° C. overnight. The following day, LCMS analysis indicated the reaction was complete. The reaction mixture was subsequently poured in a slow stream into 200 mL of rapidly stirring 2 M HCl/H2O. The mixture was transferred to a separatory funnel and extracted with 2×50 mL of EtOAc. The aqueous phase was discarded and the combined organics were dried over sodium sulfate and concentrated in vacuo to provide 6 g of 2-benzyloxycarbonylamino-5-chloro-benzoic acid methyl ester (pale yellow oil, 70% yield): HPLC retention time=3.15 minutes; MS (ES) M+H expected 320.0, found 320.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)([O-:3])=[O:2].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:37][CH2:38][CH2:39][NH2:40].Cl>CN(C)C=O>[Cl:37][CH2:38][CH2:39][NH:40][C:13]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[O:15]
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: NCCCl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(NCCCl)c1cc2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Nitro-1H-indole-2-carboxylic acid (371 mg, 3.2 mmol) prepared in Step A was dissolved in N,N-dimethylformamide (10 mL). Triethylamine (0.6 mL, 4.3 mmol), EDC (614 mg, 3.2 mmol) and HOBT (433 mg, 3.2 mmol) were added, 2-chloroethylamine (252.8 mg, 3.2 mmol) was added, and the mixture was stirred for 8 h at room temperature. 1N-hydrochloric acid solution was added, and the reaction mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give the title compound.