Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:18][CH:19]([F:21])[F:20])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].C(O)(=O)C>CO.O>[F:21][CH:19]([F:20])[O:18][C:8]1[C:9]2[O:17][C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[C:10]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC(F)F)c2oc3ccncc3c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OC(F)F)c2oc3ccncc3c12
Yield: 89.1 %

Procedure:
A solution of Methyl-6-difluoromethyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (6.5 g, 0.0221 moles), sodium hydroxide (4.0 g, 0.110 moles) and water (10.0 mL) in methanol (60.0 mL) was refluxed for 1-1.5 hrs. Methanol was removed under reduced pressure. The residue obtained was diluted with water (50.0 mL) and acidified with acetic acid. The solid separated was filtered, washed with water (2×100 mL) and dried to get 5.5 g of product as off-white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[O:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>[O:1]1[C:11]2([CH2:12][CH2:13][O:8][CH2:9][CH2:10]2)[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1
Reactant: O=C1CCOCC1
Reactant: OCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: OCC1COC2(CCOCC2)OC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
A mixture of 2-(hydroxymethyl)-1,3-propanediol (3.3 g, 31.1 mmol), tetrahydro-4H-pyran-4-one (3.12 g, 31.2 mmol), p-toluenesulfonic acid monohydrate (268 mg, 1.41 mmol) and benzene (68.3 ml) was refluxed in a round bottom flask equipped with a cooling tube and Dean-Stark for 6 hours. After cooled to room temperature, triethylamine (1 ml) was added to the reaction mixture and the mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel: 200 g, elution solvent: heptane, heptane/ethyl acetate=1/1, 1/3) to obtain the title compound (3.80 g, yield: 64.9%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])/[CH:5]=[CH:6]/[CH:7]([CH3:9])[CH3:8])[CH3:2].[CH2:11]([N:18]([CH2:22][Si](C)(C)C)[CH2:19]OC)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:1]([O:3][C:4]([CH:5]1[CH:6]([CH:7]([CH3:9])[CH3:8])[CH2:22][N:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19]1)=[O:10])[CH3:2]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C/C(C)C
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1C(C)C

Procedure:
104.1 In analogy to example 101.1 (E)-4-methyl-pent-2-enoic acid ethyl ester and N-benzyl-N-(methoxymethyl)tri-methylsilylmethylamine (CAS 93102-05-7) were reacted to give (3RS,4RS)-1-benzyl-4-isopropyl-pyrrolidine-3-carboxylic acid ethyl ester. Light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:12][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH:7]=[CH:6][C:5]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: COc1ccccc1B(O)O
Reactant: Nc1cc(Br)ccc1S(N)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1ccc(S(N)(=O)=O)c(N)c1
Yield: 99.4 %

Procedure:
A mixture of 4-bromo-2-aminobenzenesulfonamide (140 mg, 0.56 mmol), 2-methoxyphenylboronic acid (106 mg, 0.70 mmol), Pd(PPh3)2Cl2 (20 mg, 5 mol %) in 1,2-dimethoxyethane (30 ml) and Na2CO3 (2M, 3 ml, 6 mmol) was refluxed under N2 for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO3 (20 ml) and extracted with EtOAc (2×40 ml). The organic layer was washed with brine (20 ml), dried (Na2SO4) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 155 mg (100%) of 2-amino-4-(2-methoxyphenyl)-benzenesulfonamide as colorless powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 219–221° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:26]=[CH:25][C:13]3[CH2:14][CH2:15][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:4](=[O:27])[CH:3]=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35]O)=[N:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[CH2:14][CH2:15][N:16]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:17][CH2:18][C:12]=4[CH:11]=3)[C:4](=[O:27])[CH:3]=2)=[N:33][CH:34]=1
Reactant: OCc1ccc(F)cn1
Reactant: O=C(N1CCc2ccc(CCn3ccc(O)cc3=O)cc2CC1)C(F)(F)F
Product: O=C(N1CCc2ccc(CCn3ccc(OCc4ccc(F)cn4)cc3=O)cc2CC1)C(F)(F)F

Procedure:
4-(5-Fluoro-pyridin-2-ylmethoxy)-1-{2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one is prepared following example 23.9 from 500 mg (1.32 mmol) 4-hydroxy-1-{2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one (preparation 21b) and 251 mg (1.97 mmol) (5-fluoro-pyridin-2-yl)-methanol.
Reaction SMILES: C([O:3][C:4]([C:6]([CH3:17])([C:12]([O:14]CC)=[O:13])[CH:7]([CH:9]=[CH:10][CH3:11])[CH3:8])=[O:5])C.[OH-].[K+]>C(O)C>[CH3:17][C:6]([C:12]([OH:14])=[O:13])([C:4]([OH:5])=[O:3])[CH:7]([CH:9]=[CH:10][CH3:11])[CH3:8]
Reactant: CC=CC(C)C(C)(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC=CC(C)C(C)(C(=O)O)C(=O)O
Yield: 134 %

Procedure:
A mixture of 77.7 g of methyl 2-propenylpropane dicarboxylic acid diethyl ester, 123 g of potassium hydroxide and 625 ml of ethyl alcohol is heated at reflux for 53 hours. The reaction is cooled, concentrated in vacuo and the residue partitioned between water and diethyl ether. The aqueous layer is separated, made acidic with concentrated hydrochloric acid, saturated with solid sodium chloride and extracted with diethyl ether. The combined diethyl ether layers are dried and concentrated in vacuo to give 80 g of methyl 2-propenylpropane dicarboxylic acid as colorless crystals; MP 89°-90° C.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].CC#N.[C:13]1([C@@H:19]([CH3:22])[CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C1COCC1.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:21][CH2:20][C@@H:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:22])[N:7]=1
Reactant: C[C@@H](CN)c1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CNc1nc(Cl)nc(Cl)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of cyanuric chloride (677 mg, 3.67 mmol, 1.00 equiv) in 1:1 CH3CN:H2O (6.1 mL) at 0° C. was added a solution of (2R)-2-phenyl-1-propanamine (0.52 mL, 3.7 mmol, 1.0 equiv) in THF (1.8 mL). The reaction mixture was treated with 1 N NaOH to maintain a pH of 9-10 and stirred for 10 min at 0° C. The resulting suspension was used in the next step without workup or purification. MS (ES+): m/e 282.9 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]=[C:20]([C:23]([OH:25])=O)[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:51][CH2:52][C:53]([N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:71])([F:70])[F:69])[CH:63]=2)[CH2:57][CH2:56]1)=[O:54]>CN(C=O)C.O>[O:54]=[C:53]([N:55]1[CH2:56][CH2:57][CH:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:71])([F:69])[F:70])[CH:63]=2)[CH2:59][CH2:60]1)[CH2:52][NH:51][C:23]([C:20]1[CH:19]=[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([F:10])([F:27])[F:26])[NH:22][N:21]=1)=[O:25]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Reaction time: 8 h
Yield: 56 %

Procedure:
DIPEA (76 mg, 0.59 mmol) was added to a stirred solution of 5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid (43 mg, 0.167 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from (o-trifluoromethyl)acetophenone) in DMF (2 mL) followed by HOBt (24 mg, 0.176 mmol) and EDCI.HCl (34 mg, 0.176 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (0.057 mg, 0.167 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. The residue was purified by washing with chloroform to afford 51 mg (56% Yield) of 5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 541, 87.52%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (d, 1H), 8.1 (m, 1H), 7.6 (m, 4H), 7.5 (t, 1H), 7.3 (t, 3H), 6.76 (s, 1H), 4.8 (m, 1H), 4.1 (d, 2H), 3.7 (m, 2H), 3.4 (m, 1H), 3.2 (m, 1H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[C:24]([CH3:29])=[N:25][O:26][C:27]=2[CH3:28])[O:20][N:19]=1>>[CH3:29][C:24]1[C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[N:22]=2)=[C:27]([CH3:28])[O:26][N:25]=1
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: Cc1noc(C)c1-c1nc(Cn2ccc3c(C(F)(F)F)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole: MS (ES) m/z 388 (M+1).
Reaction SMILES: C[C:2]1[CH:7]=C[C:5]([S:8](OC2CCSC2)(=O)=O)=[CH:4][CH:3]=1.[C:17]([O-:20])(=[S:19])[CH3:18].[K+].CC1C=CC(S(OC2CCSCC2)(=O)=O)=CC=1>CN(C)C=O>[CH3:18][C:17]([S:19][CH:3]1[CH2:4][CH2:5][S:8][CH2:7][CH2:2]1)=[O:20]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)OC2CCSC2)cc1
Agent: Cc1ccc(S(=O)(=O)OC2CCSCC2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCSCC1
Yield: 69 %

Procedure:
Similar procedures employed in Preparation J in reacting 3-(p-methylphenylsulfonyloxy)thiolane with potassium thioacetate by reacting 4-(p-methylphenylsulfonyloxy)thiane and 1.5 equivalents of potassium thioacetate at 80° C. in dimethylformamide to obtain 4-methylcarbonylthiothiane in 69% yield after chromatography on silica gel eluted with 10% ethyl acetate/hexane. The NMR spectrum of a deuterochloroform solution of 4-methylcarbonylthiothiane had peaks at 1.62-2.2 (4H, m); 2.32 (3H, s); 2.5-2.8 (4H, m); and 3.52 (1H, tt, J=9, 3 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH3:2]
Reactant: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1OCC
Temperature: 60 °C
Reaction time: 14 h
Yield: 381.2 %

Procedure:
To methyl 7-(3,4-diethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (818 mg) dissolved in THF-methanol (15-7.5 ml) was added a 2 M aqueous solution of potassium carbonate (1.5 ml), and the resulting mixture was stirred at 60° C. for 14 hours. The reaction mixture was treated with 1 N hydrochloric acid to bring the pH to 2. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the precipitated crystals were washed with hexane-ethyl acetate to obtain 7-(3,4-diethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (3.02 g) as white crystals.
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH2:7][OH:8])([O-:3])=[O:2].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>C1C=CC=CC=1>[CH3:9][C:5]([CH2:4][N+:1]([O-:3])=[O:2])=[CH:6][CH2:7][OH:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:2])[O-:19])=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: CC(=CCO)C[N+](=O)[O-]
Solvent: c1ccccc1
Product: O=C([O-])Nc1ccc(Cl)cc1

Procedure:
To 0.1 Mol of 4-nitro-3-methyl-2-butenol was added 0.1 Mol of melted p-chlorophenylisocyanate. The reaction mixture was allowed to stand at room temperature for several hours, before it was dissolved in hot benzene. After crystallizing overnight a solid by-product was filtered off and the benzene was evaporated. The residue was purified by dissolving in a hot hexane-benzene mixture, decanting, while hot, from an insoluble oil, followed by crystallization in a ice bath. The product was obtained as orange crystals, m.p. 79°-81°.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[CH:4]=[C:5]([C:10]2[O:11][C:12]([CH3:33])=[C:13]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C@H:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:22][CH2:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].[Li+].[OH-].O>C(O)C.C1COCC1>[CH3:34][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([C:10]2[O:11][C:12]([CH3:33])=[C:13]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C@H:23]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(C)c(N(C)C)c4)oc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc(CCOc3ccc4c(c3)CC[C@H]4CC(=O)O)c(C)o2)cc1N(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a solution of ethyl [(1S)-5-(2-{2-[3-(dimethylamino)-4-methylphenyl]-5-methyl-1,3-oxazol-4-yl}ethoxy)-2,3-dihydro-1H-inden-1-yl]acetate (175.0 mg, 0.38 mmol) in ethanol (1 mL) and THF (1 mL) was added LiOH (159 mg) followed by addition of 1 mL water. The reaction mixture was then stirred at rt for 4 h. The reaction mixture was then acidified to pH 5-6 and the solvent was removed by reduced pressure. The residue was redissolved in methanol, filtered through a plug of C8-Silica plug before preparative HPLC purification using 10 to 70% acetonitrile in water to afford desired product 156 mg (95% yield). 1H NMR (300 MHz/CD2Cl2) δ 7.96 (s, 1H), 7.80 (d, 1H), 7.35 (d, 1H), 7.06 (d, 1H), 6.77 (s, 1H), 6.67 (d, 1H), 4.21 (t, 2H), 3.47 (qr, 1H), 3.11 (s, 6 H), 2.97 (t, 2H), 2.75-2.90 (m, 2H), 2.70 (dd, 1H), 2.54 (s, 3H), 2.29-2.46 (m, 5H), 1.65-1.78 (m, 1H). EI-LCMS(rel abundance), m/z 435.4 (MH+, 100%). HPLC RT: 3.52 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:16]([OH:26])=[C:17]([CH3:25])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:16]([O:26][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:17]([CH3:25])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCCBr
Reactant: Cc1cc2cccnc2c(N2CCCN(C(=O)OC(C)(C)C)CC2)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(7-Hydroxy-6-methyl-quinolin-8-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.3 g, 3.8 mmol) and methyl 4-bromobutyrate (680 mg, 3.8 mmol) were dissolved in DMF (7.5 mL). To this solution was added Cs2CO3 (3.7 g, 11.3 mmol) and reaction was stirred at room temperature for 18 h. The reaction was diluted with CH2Cl2 and washed with H2O (4×50 mL), then brine. The organic was then dried over MgSO4, filtered, and concentrated to give the crude product.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[F:31])=[O:19])=[CH:13][C:12]=3[O:32]CC3C=CC=CC=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.O.[OH-].[Na+].Cl>Br.C(O)(=O)C.C(O)(=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:22]=4[F:31])=[O:19])=[CH:13][C:12]=3[OH:32])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2scc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3OCc3ccccc3)c12
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncnc2scc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3O)c12
Temperature: 25 °C
Yield: 19.2 %

Procedure:
A solution of Example 351B (99 mg, 0.18 mmol) in 30% HBr/acetic acid (1 mL) and acetic acid (2 mL) was stirred at 70° C. for 3 hours, cooled to room temperature, poured into water, basified with 2N NaOH, adjusted to pH to 7-8 with 1N HCl, and extracted with methanol/dichloromethane. The extract was concentrated and the residue was purified by silica gel chromatography with 5% methanol/dichloromethane to provide 16 mg (19% yield) of the desired product. MS(ESI(+)) m/e 464.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 6.94 (dd, J=8.5, 2.0 Hz, 1H); 7.15 (d, J=8.1 Hz, 1H); 7.31 (s, 1H); 7.38-7.43 (m, 2H; 7.48-7.55 (m, 1H); 8.30 (s, 1H); 8.64 (dd, J=7.5, 2.4 Hz, 1H); 8.91 (d, J=2.7 Hz, 1H); 9.29 (s, 1H); 9.87 (s, 1H)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=3[CH3:24])=[CH:11][CH:12]=2)[C@H:7]([NH:25]C(OC(C)C)=O)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl.CCOC(C)=O.CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=3[CH3:24])=[CH:11][CH:12]=2)[C@H:7]([NH2:25])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)c(C)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Methyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-3-methylbenzoate (for a preparation see Intermediate 97) (320 mg, 0.730 mmol) was added to a cold (ice bath) suspension of aluminium chloride (370 mg, 2.77 mmol) in dichloromethane (DCM) (4 mL). The reaction was stirred at approximately 0° C. for 30 min, then treated with a solution of methanol (0.320 mL) and triethylamine (1.230 mL, 8.82 mmol). The resulting mixture was stirred further at approximately 0° C. for 20 min then was diluted with EtOAc (25 mL) and a saturated NaHCO3 aqueous solution (25 mL). The reaction mixture was then filtered through celite and the insoluble residues were washed with EtOAc (15 mL) and a saturated NaHCO3 aqueous solution (15 ml). The filtered aluminum residues were suspended in MeOH and sonicated. The resulting suspension was filtered and the filtrate was concentrated in vacuo to give a white solid. This solid was loaded onto a 20 G SCX cartridge and eluted with MeOH then with 2M NH3 in MeOH. The ammonia fractions were combined and concentrated in vacuo to give methyl 4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-3-methylbenzoate (145 mg, 56%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=1
Reactant: CCOC(=O)c1cnc(C)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(CBr)s1
Reaction time: 1 h
Yield: 41.7 %

Procedure:
N-Bromosuccinimide (0.91 g, 5.1 mmol) was added to a solution of ethyl 2-methyl-thiazole-5-carboxylate (0.8 g, 4.7 mmol) in carbon tetrachloride. The resultant reaction mixture was stirred for one hour whilist being illuminated by a photoflood lamp. After removing the solvent from the reaction mixture the resultant material was partitioned between ethyl acetate and water. The organic phase was then separated off, dried (MgSO4) and the evaporated. Chromatography on silica, eluting with 30% ethyl acetate in hexane, gave ethyl 2-(bromomethyl)-1,3-thiazole-5-carboxylate (490 mgs), NMR: δH (300 MHz, DMSO-d6, 1.20–1.38 (3 H,t); 4.20–4.37 (2 H,q); 5.05 (2 H, s); 8.55 (1 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[C:11](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11](/[CH:16]=[CH:17]/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(-c2ccc(Cl)cc2)noc1/C=C/c1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: OCc1c(-c2ccc(Cl)cc2)noc1/C=C/c1ccccc1
Yield: 78.8 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-5-([E]-styryl)-isoxazole-4-carboxylic acid (6.0 g, 18.4 mmol) and triethylamine (2.58 mL, 18.4 mmol) in THF (150 mL) was added at room temperature a solution of ethyl chloroformate (1.8 mL, 18.4 mmol) in THF (17.4 mL). After 1 h triethylamine hydrochloride salt was filtered off, and washed with a small amount of THF. The solution was then added to a solution of sodium borohydride (1.82 g, 46.1 mmol) in water (18 mL). After stirring overnight at room temperature sodium hydroxide solution (1 N) was added. Extraction with tert-butylmethylether and purification by chromatography (silica, dichloromethane) afforded the title compound (4.52 g, 79%) as a white solid. MS: m/e=369.9 [M+CH3COO]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[NH:11][CH2:10][C:9]=2[CH3:19])=[CH:4][CH:3]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[Cl:36][CH2:37][C:38](Cl)=[O:39]>O1CCCC1>[Cl:36][CH2:37][C:38]([N:11]1[CH2:10][C:9]([CH3:19])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]2[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]12)=[O:39]
Reactant: O=C(Cl)CCl
Reactant: CC1=C(c2ccc(Cl)cc2)n2ncc(C#N)c2NC1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: C1CCOC1
Product: CC1=C(c2ccc(Cl)cc2)n2ncc(C#N)c2N(C(=O)CCl)C1

Procedure:
A 10 g portion of 7-(4-chlorphenyl)-4,5-dihydro-6-methylpyrazol[1,5-a]pyrimidine-3-carbonitrile and 9 g of [1,8-bis(dimethylamino)naphthalene, N,N,N',N'-tetramethyl-1,8-naphthalenediamine] in 300 ml of dry tetrahydrofuran under nitrogen was mixed and 6 ml of chloroacetyl chloride in 70 ml of dry tetrahydrofuran was added over 15 minutes with stirring. The mixture was stirred at reflux for 5.5 hours, then at room temperature overnight and then filtered. The filtrate was concentrated to an oil. This oil was triturated with ether, the solid collected and dried, giving 10 g of the desired intermediate, mp 138°-140° C.