Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:21]([O:20][C:18]([CH2:17][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Product: CC(C)(C)OC(=O)COc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
Prepared analogously to Example 13 from 4-cyano-4'-hydroxy-biphenyl and tert.butyl bromoacetate.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][CH:16]([F:35])[C:17]1[N:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:33][CH3:34])=[CH:25][CH:24]=2)[C:19]([SH:22])=[N:20][N:21]=1>ClCCl>[F:35][CH:16]([F:15])[C:17]1[N:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:33][CH3:34])=[CH:25][CH:24]=2)[C:19]([S:22][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:20][N:21]=1
Reactant: CCOC(=O)CBr
Reactant: CCc1ccc(-n2c(S)nnc2C(F)F)c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CSc1nnc(C(F)F)n1-c1ccc(CC)c2ccccc12
Reaction time: 2 h
Yield: 95.9 %

Procedure:
Triethylamine (0.11 mL, 0.786 mmol) and ethyl 2-bromoacetate (80 μL, 0.72 mmol) were added to a stirred solution of 5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (0.2 g, 0.655 mmol) in dichloromethane (2.6 mL). The resulting mixture was stirred for 2 h. The crude reaction mixture was purified by SGC (0-50% EtOAc/Hexanes) to afford ethyl 2-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate as an off-white solid (0.246 g, 96%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27]COC)=[CH:23][CH:22]=3)[N:18]=[C:17]3[N:31](C4CCCCO4)[N:32]=[C:33]([CH3:34])[C:16]=23)[CH2:8][C:7]1([CH3:42])[CH3:41])=[O:5].Cl>O1CCOCC1>[OH:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:18]=[C:17]3[NH:31][N:32]=[C:33]([CH3:34])[C:16]3=[C:15]([CH2:14][N:9]3[C:10]([CH3:13])([CH3:12])[CH2:11][N:6]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[C:7]([CH3:42])([CH3:41])[CH2:8]3)[CH:20]=2)=[CH:26][CH:25]=1
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)N(C(=O)COC)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COCC(=O)N1CC(C)(C)N(Cc2cc(-c3ccc(O)cc3)nc3[nH]nc(C)c23)CC1(C)C

Procedure:
93 mg of 2-Methoxy-1-{4-[6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,2,5,5-tetramethyl-piperazin-1-yl}-ethanone were dissolved in 2.5 ml of dioxane and reacted with 2 ml hydrochloric acid (4M in dioxane). The volatiles were removed after 16 h. After purification by preparative HPLC 25 mg of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][NH:13][NH2:14].C([O-])(=O)C.[Na+]>CC#N>[Cl:11][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[N:13]([CH3:12])[N:14]=[CH:9][CH2:8][C:7]=12
Reactant: CNN
Reactant: O=CCc1c(Cl)ncnc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1N=CCc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a stirred solution of 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (600 mg) in dry MeCN (10 mL), methyl hydrazine (154 mg) and sodium acetate (514 mg) were added. The reaction mixture was stirred at room temperature for 3 hours and solvents were removed under reduced pressure. The resulting oil was diluted with ethyl acetate (50 mL), washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was purified by column chromatography using EtOAc/CHCl3 (0.4:9.6) as eluent to afford 5-chloro-1-methyl-1,4-dihydropyridazino[3,4-d]pyrimidine (310 mg) as white solid. 1H NMR (DMSO-d6): δ 3.34 (s, 3H), 3.53-3.54 (d, 2H), 6.91-6.93 (t, 1H), 8.38 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:13]4[C:18]([C:10]=3[CH2:9][C:8](=[O:30])[NH:7][C:6]=2[CH:31]=1)=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=4.Cl[CH2:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[C:13]4[C:18]([C:10]=3[CH2:9][C:8](=[O:30])[N:7]([CH2:33][C:34](=[O:35])[N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:6]=2[CH:31]=1)=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=4
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2NC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2N(CC(=O)N2CCCCC2)C(=O)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a suspension of ethyl 3-chloro-12-cyclohexyl-6-oxo-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (772 mg, 1.77 mmol) in N,N-dimethylformamide (7.7 ml) were added a solution of 1-(2-chloroacetyl)piperidine (343 mg, 2.12 mmol) in N,N-dimethylformamide (2 ml) and potassium carbonate (488 mg, 3.53 mmol), and the mixture was stirred at 90° C. for 1 hr. Furthermore, a solution of 1-(2-chloroacetyl)piperidine (171 mg, 1.06 mmol) in N,N-dimethylformamide (1 ml) and potassium carbonate (244 mg, 1.77 mmol) were added, and the mixture was stirred at 90° C. for 1.5 hr. The mixture was allowed to cool to room temperature, water (10 ml) was added, and the precipitated solid was collected by filtration. The obtained solid was washed with water (10 ml) and dried in vacuo to give ethyl 3-chloro-12-cyclohexyl-6-oxo-5-[2-oxo-2-(piperidin-1-yl)ethyl]-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (911 mg, yield 92%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1.CO>[Pd].C(O)C.Cl>[ClH:1].[NH2:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][C:4]3[CH:19]=[C:20]([O:24][C:25]([O:27][CH3:28])=[O:26])[C:21]([CH3:23])=[CH:22][C:3]=3[F:2])=[N:7][CH:8]=[N:9]2)=[CH:14][CH:13]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c(F)cc1C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COC(=O)Oc1cc(Nc2ncnc3cc(N)ccc23)c(F)cc1C
Reaction time: 1.25 h
Yield: 97.5 %

Procedure:
A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-nitroquinazoline hydrochloride (5.3 g, 13 mmol) and 10% palladium-on-charcoal catalyst (1 g) in ethanol (100 ml), ethanolic hydrogen chloride (1.8 ml of a 7M solution) and methanol (20 ml) was stirred under hydrogen at 1.7 atmospheres pressure for 75 minutes. The catalyst was removed by filtration through diatomaceous earth and the filter pad thoroughly washed with methylene chloride, methanol and ether and the solvent was removed from the filtrate by evaporation to give 7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (4.8 g, 97%) as a yellow solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[C:12]([O:16][C:17](=[O:45])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:39]3[C:38]4[CH:37]=[CH:36][C:35]([Br:40])=[CH:34][C:33]=4[N:32]=[CH:31][C:30]=3[N:29]=[C:28]2[CH2:41][O:42][CH2:43][CH3:44])=[CH:22][CH:21]=1)([CH3:15])([CH3:14])[CH3:13].[OH-].[NH4+:47].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[C:12]([O:16][C:17](=[O:45])[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][N:27]2[C:39]3[C:38]4[CH:37]=[CH:36][C:35]([Br:40])=[CH:34][C:33]=4[N:32]=[C:31]([NH2:47])[C:30]=3[N:29]=[C:28]2[CH2:41][O:42][CH2:43][CH3:44])=[CH:24][CH:25]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Reaction time: 1 h

Procedure:
3-Chloroperoxybenzoic acid (2.91 g, 9.3 mmol, 55% pure) was added to a solution of tert-butyl[4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-ylmethyl)benzyl]carbamate (3.2 g, 6.1 mmol) in chloroform (60 mL). The reaction was stirred for 1 hour and then cooled with an ice bath. Ammonium hydroxide (40 mL) was added and the reaction was stirred for 10 minutes. p-Toluenesulfonyl chloride (1.16 g, 6.1 mmol) was added in two portions. The cooling bath was removed and the mixture was stirred for an additional 16 hours. The layers were separated and the aqueous fraction was extracted with dichloromethane. The combined organic fractions were washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (CMA/chloroform) and subsequent recrystallization from acetonitrile yielded 1.15 g of tert-butyl[4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo [4,5-c]quinolin-1-ylmethyl)benzyl]carbamate as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1F.[CH3:17][O-:18].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[O:18][CH3:17]
Reactant: C[O-]
Reactant: CNc1cc(F)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(OC)c(C(=O)OC)cc1[N+](=O)[O-]
Yield: 57 %

Procedure:
2-Methoxy-4-methylamino-5-nitro-benzoic acid methyl ester (120 mg) was prepared by following General Procedure A starting from 2-Fluoro-4-methylamino-5-nitro-benzoic acid methyl ester (200 mg) and sodium methoxide (190 mg) in DMF.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:12][C:13]([S:15][CH3:16])=[NH:14])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24]([O:27][CH2:28][C:29](Cl)=[O:30])(=[O:26])[CH3:25]>ClCCl>[C:24]([O:27][CH2:28][C:29]([N:14]=[C:13]([NH:12][C:10]([NH:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:11])[S:15][CH3:16])=[O:30])(=[O:26])[CH3:25]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CSC(=N)NC(=O)NCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC(=NC(=O)COC(C)=O)NC(=O)NCc1ccc(Cl)cc1
Yield: 61.8 %

Procedure:
To a dichloromethane solution (2.0 mL) of methyl N-({[(4-chlorobenzen-1-yl)methyl]amino}carbonyl)-carbamimidothioate (257 mg, 1.00 mmol) synthesized in Reference Synthesis Example 326, triethylamine (279 μL, 2.00 mmol) and 2-chloro-2-oxoethyl acetate (162 μL, 1.50 mmol) were added and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (221 mg, yield 62%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH:4]=O.[NH2:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O.C(=O)(O)[O-].[Na+]>CC(O)=O>[CH3:12][C:2]([C:3]1[CH:4]=[N:13][C:14]2[C:15]([C:24]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:1]
Reactant: Nc1c(C(=O)c2ccccc2)cccc1C(F)(F)F
Reactant: CC(C)(CC=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 200 °C
Yield: 33.9 %

Procedure:
3,3-Dimethyl-3-phenylpropionaldehyde (0.272 g, 1.67 mmol) and [2-amino-3-(trifluoromethyl)phenyl](phenyl)methanone (0.138 g, 0.52 mmol) are dissolved in AcOH (3 mL) and treated with 1:20H2SO4/AcOH solution (0.10 mL). The mixture is heated in a microwave at 175° C. for 15 min and a further 5 min at 200° C. The reaction is carefully poured into saturated aq sodium bicarbonate and extracted with ethyl acetate. The extracts are washed with saturated aq sodium bicarbonate and dried (MgSO4). The product is chromatographed eluting with 5:95 ethyl acetate:hexane. The partially purified is further purified using Prep HPLC with a gradient of 10-100% acetonitrile/water to afford the title compound (0.069 g). HRMS: calcd for C25H20F3N+H, 392.16261; found (ESI, [M+H]+), 392.1637.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: COC1(c2cc(F)cc(Cl)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: COC1(c2cc(F)cc(Cl)c2)CCNC1
Yield: 51.9 %

Procedure:
Preparation according to Example 1: (+1-benzyl-3-(3-chloro-5-fluorophenyl)-3-methoxypyrrolidine (0.265 g, 0.83 mmol), 1,2-dichloroethane (20 ml), 1-chloroethyl chloroformate (0.47 g, 3.31 mmol). Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound 0.099 g (52%). [a]D=−2.8° (methanol). MS m/z (relative intensity, 70 eV) 229 (M+, 1), 214 (53), 199 (bp), 187 (81), 133 (56).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32]C)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+]>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([OH:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1cccc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2cccc(CC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
To a mixture of methyl 2-[3-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-2-pyridyl]methoxy]phenyl]acetate (1.10 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5.0 mL) and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated, and water and dilute hydrochloric acid were added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (0.85 g, 80%) of 2-[3-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-2-pyridyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 97-98° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O.O1CCOCC1>[C:1]1([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(Nc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Methyl 4-(phenylamino)benzoate (0.080 g; 0.352 mmol) was added to a mixture of NaOH in water (0.6 mL; 2M) and dioxane (0.6 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated in vacuo and extracted with dichloromethane. The aqueous layer was acidified with a solution of hydrogen chloride 6M and the precipitated product was collected by filtration and used without further purifications to yield 0.048 g (64%) of the title compound as a white solid which was used without further purifications.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:5]=1.[OH-].[Na+]>>[N:20]1([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([OH:25])=[O:2])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(N2CCCC2)c(Oc2ccccc2)c([N+](=O)[O-])c1

Procedure:
50 g of 3-(1-pyrrolidinyl)-4-phenoxy-5-nitrobenzoic acid methyl ester (preparation cf Example 34, step b) are saponified under heating with dilute sodium hydroxide solution.
Reaction SMILES: [CH3:1][S:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14](N)=[O:15])=[C:7]2[N:6]=[N:5]1.N([O-])=[O:18].[Na+]>C(O)(C(F)(F)F)=O.O>[CH3:1][S:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]([OH:15])=[O:18])=[C:7]2[N:6]=[N:5]1
Reactant: CSCn1nnc2c(C(N)=O)ncn2c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CSCn1nnc2c(C(=O)O)ncn2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 3-(methylthiomethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (12.43 mmol, 3 g, 1 eq.) in TFA (12 mL) was added sodium nitrite (43.5 mmol, 3 g, 3.5 eq.) dissolved in water (6 mL) portion-wise keeping exothermic effervescence under control and the mixture was stirred at room temperature for over 3 hours. The reaction mixture was poured into ice and it was gently stirred until the ice melted. The resulted suspension was filtered, washed with water and ether and dried under vacuum to give the title compound. Yield=61%. δH (DMSO-d6) 8.85 (1H, s), 5.44 (2H, s), 2.25 (3H, s).
Reaction SMILES: CO.[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([C:17](=[O:19])[CH3:18])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Br-:20].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C.C(=O)([O-])O.[Na+]>O>[Br:20][CH2:18][C:17]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7]2)[CH:10]=1)=[O:19]
Reactant: COc1ccc(C(C)=O)cc1OC1CCCC1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)CBr)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 41.7 %

Procedure:
To 200 ml of methanol solution containing 11.6 g (49.5 mmol) of 1-(3-cyclopentoxy-4-methoxyphenyl)ethanone (see Bioorg. Med. Chem. Lett. 2003, 13, 2355) was added 20.47 g (54.5 mmol) of trimethylphenylammonium tribromide at room temperature, and the mixture was stirred at room temperature for 40 minutes. After completion of the reaction, water was added to the reaction mixture, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and then extracted with chloroform. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the obtained concentrate was added 50 ml of a mixed solvent (diisopropyl ether/hexane=1/2 (V/V)), and precipitated solid was collected by filtration. The obtained solid was washed with diisopropyl ether, and dried under reduced pressure to obtain 6.47 g of the title compound as a white solid. (Yield: 41%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C@H:5]([CH3:10])[CH2:6][C:7]([OH:9])=[O:8].Cl[C:13]([O:15][CH3:16])=[O:14]>>[CH3:1][O:2][C:3](=[O:11])[CH:4]([C:13]([O:15][CH3:16])=[O:14])[C@H:5]([CH3:10])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)C[C@H](C)CC(=O)O
Reactant: COC(=O)Cl
Product: COC(=O)C(C(=O)OC)[C@H](C)CC(=O)O

Procedure:
Scheme 1 illustrates an exemplary method for making a compound of the formula 1.3. Starting from (R)-5-methoxy-3-methyl-5-oxopentanoic acid, reaction with methyl chloroformate gives (R)-5-methoxy-4-(methoxycarbonyl)-3-methyl-5-oxopentanoic acid, which can be esterified with, for example, trimethylsilyl chloride and methanol to give compound 1.3, (R)-trimethyl 2-methylpropane-1,1,3-tricarboxylate.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:22][CH2:21][CH:20]([C@H:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[OH:24])[CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:35]([CH3:37])[CH3:36])[CH:12]=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:39]1[CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41][CH2:40]1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:22][CH2:21][CH:20]([C@H:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[OH:24])[CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:35]([CH3:37])[CH3:36])[CH:12]=[C:11]([C:42]3[CH2:43][CH2:44][O:39][CH2:40][CH:41]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)c1cc(I)c2c(n1)CC1(CCC([C@@H](O)c3ccc(C(F)(F)F)cc3)C1)C[C@@H]2O[Si](C)(C)C(C)(C)C
Product: CC(C)c1cc(C2=CCOCC2)c2c(n1)CC1(CCC([C@@H](O)c3ccc(C(F)(F)F)cc3)C1)C[C@@H]2O[Si](C)(C)C(C)(C)C

Procedure:
Obtained by starting from (R)—((S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclopentane-1,7′-quinoline]-3-yl)(4-(trifluoromethyl)phenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The crude product is used directly in the next step.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][N:2]1[C:12]1[CH:21]=[C:20]([NH2:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.N12CCCN=C1CCCCC2.[Cl:34][CH2:35][C:36](Cl)=[O:37]>C(OCC)(=O)C>[Cl:34][CH2:35][C:36]([NH:22][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH:21]=1)=[O:37]
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
To the solution of 2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine (500 mg, 1.73 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.52 mL, 3.48 mmol) followed by chloroacetyl chloride (0.21 mL, 2.64 mmol) at room temperature. The resulting solution was heated with stirring at 70° C. for 2 hours under nitrogen. After cooled to room temperature, the reaction was diluted with ethyl acetate (50 mL), and then washed with water (50 mL×3). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:4) to give 140 mg of product as an off-white solid (yield was 22.1%). MS obsd. (ESI+) [(M+H)+] 366.