Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:21])[CH:12]([N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])[N:11]=1.Br[CH2:34][C:35]1[O:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[CH:39]=1>CN(C)C=O>[O:36]1[C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[CH:39]=[C:35]1[CH2:34][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])=[N:11][CH:12]([N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[C:13]1=[O:21]
Reactant: BrCc1cc2ccccc2o1
Reactant: O=C1Nc2ccccc2C(c2ccccc2F)=NC1N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2F)c2ccccc2N1Cc1cc2ccccc2o1
Reaction time: 1.5 h
Yield: 45.2 %

Procedure:
To a suspension of sodium hydride (0.185 g of a 60% dispersion in mineral oil) in dry N,N-dimethylformamide (5 ml) was added (3RS)-2,3-dihydro-5-(2-fluorophenyl)-3-phtalimido-1H-1,4-benzodiazepin-2-one (1.700 g) under stirring at cooling in an ice-bath. The mixture was stirred under the same condition for 1 hour and then at room temperature for 1.5 hours. To the mixture was added dropwise a solution of 2-bromomethylbenzofuran (1.076 g) in N,N-dimethylformamide (5 ml) under cooling in an ice-bath. After completion of the addition, the mixture was allowed to stand to room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was treated with ethyl acetate and water. The organic layer was washed with water and a brine, and dried over magnesium sulfate. Removal of the solvent gave (3RS)-1-(benzofuran-2-yl)methyl-2,3-dihydro-5-(2-fluorophenyl)-3-phthalimido-1H-1,4-benzodiazepin-2-one (1.018 g) which was used in a following reaction step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])C1C=CC=CC=1OC.[Li+].[OH-:31].Cl>O.C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([C:10](=[O:11])[NH:12][CH:13]3[CH2:14][CH2:15]3)[CH:16]=[CH:17][C:18]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([OH:29])=[O:31]
Reactant: [OH-]
Reactant: COc1ccccc1C(=O)c1cnn(-c2cc(C(=O)NC3CC3)ccc2C)c1N
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)O)c1N
Yield: 88 %

Procedure:
A solution of 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g, see Example 44), LiOH (1.2 g) in water/ethanol (15 ml/20 ml) was heated at 50° C. overnight. The solution was neutralized with dilute HCl (2M), and extracted with ethyl acetate (200 ml×2), dried over Na2SO4. The solvent was evaporated under reduced pressure and ethyl acetate and diethyl ether was added. The resulting solid was filtered to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid. (0.8 g; yield: 88%.).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[C@@H:7]([OH:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[C@H:7]([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CC(=O)N1c2cc(F)ccc2[C@@H](O)C[C@@H]1C
Product: CC(=O)N1c2cc(F)ccc2[C@H](Oc2ccccc2)C[C@@H]1C
Yield: 26.1 %

Procedure:
(Step 4) A compound was produced in the same manner as in Example 2, using 100 mg of trans-1-acetyl-7-fluoro-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline and 84 mg of phenol, and thus 35 mg (26%) of the title compound was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Sulfur trioxide pyridine complex (1.10 g, 7.0 mmol) was added to a solution of 3-[3-(3-cyanophenylsulfonyloxy)-5-methylphenoxy]propanol (1.05 g, 3.0 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.4 mL, 5.6 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (80 mL). The mixture was extracted into dichloromethane (3×60 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (770 mg, 74%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 8.14 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 6.65 (s, 1H), 6.42 (s, 1H), 6.37 (s, 1H), 4.21 (t, J=6.0 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H), 2.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:34](O)=[O:35])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].P(Cl)(Cl)(Cl)=O>CN(C)C1C=CN=CC=1.C(#N)C>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][C:34]([C:31]3([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29][CH2:30]3)=[O:35])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2nonc2-c2noc(=O)n2-c2ccc(F)c(Br)c2)(c2ccccc2)CC1
Temperature: 100 °C

Procedure:
A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (0.15 g, 0.44 mmol), 1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (0.4 g, 1.3 mmol), and 4-dimethylaminopyridine (32 mg, 0.26 mmol) in acetonitrile (2 mL) was treated with phosphoryl chloride (0.13 mL, 1.4 mmol) and heated in the microwave at 100° C. for 10 min. The reaction mixture was concentrated and the residue was diluted with ethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL), dried with sodium sulfate, filtered, and concentrated to a crude residue which was purified by silica gel to give the coupled product, tert-butyl 4-[({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]-4-phenylpiperidine-1-carboxylate. This material was diluted with dichloromethane (5 mL) and treated with 4.0 M HCl in 1,4-dioxane (3 mL) and stirred for 45 min. The reaction mixture was concentrated and the crude residue was purified by preparative LCMS to give the desired product (10 mg, 4%). LCMS for C22H19BrFN6O4 (M+H)+: m/z=529.0, 531.0.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[S:12][C:11]([CH2:13][O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][C:24](OCC)=[O:25])=[CH:17][C:16]=2[F:29])=[C:10]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH:9]=1>>[Cl:7][C:8]1[S:12][C:11]([CH2:13][O:14][C:15]2[C:16]([F:29])=[CH:17][C:18]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:19][C:20]=2[F:21])=[C:10]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[CH:9]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1cc(F)c(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 222 by LAH reduction of ethyl 3-(4-((5-chloro-3-(4-chlorophenyl)thiophen-2-yl)methoxy)-3,5-difluoro phenyl)propanoate to give the desired product as off-white oil. 1H NMR (300 MHz, CD3OD) δ 7.42-7.52 (m, 4H), 7.07 (s, 1H), 6.85 (d, J=9.6 Hz, 2H), 5.11 (s, 2H), 3.58 (t, J=7.8 Hz, 2H), 2.66 (t, J=6.0 Hz, 2H), 1.79-1.86 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][C:41]1=[O:45]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:37][CH2:38][CH2:39][N:40]3[CH2:44][CH2:43][CH2:42][C:41]3=[O:45])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: NCCCN1CCCC1=O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCCN3CCCC3=O)n2)s1
Yield: 80 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.20 g, 0.37 mmol) and 1-(3-aminopropyl)-2-pyrrolidinone (0.52 ml, 3.7 mmol) the title compound was obtained (0.20 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75 (s, 1H), 8.03 (d, J=5.1 Hz, 1H), 7.15-7.64 (m, 7H), 5.81-5.98 (m, 1H), 3.21 (t, J=6.6 Hz, 2H), 3.07-3.16 (m, 2H), 2.21 (t, J=8.0 Hz, 2H), 1.92 (quin, J=7.4 Hz, 2H), 1.66 (br. s., 2H), 1.40 (s, 9H). MS (ES+): 645 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:32][CH:31]5[CH:26]([N:27](C(OC(C)(C)C)=O)[CH2:28][CH2:29][CH2:30]5)[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:32][CH:31]5[CH:26]([NH:27][CH2:28][CH2:29][CH2:30]5)[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCCN(C(=O)OC(C)(C)C)C2C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCCNC2C1
Yield: 140.7 %

Procedure:
To a solution of tert-butyl 6-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (0.60 g) in CH2Cl2 was added a saturated solution of HCl in MeOH. Solid was precipitated out after 2 h reaction. The reaction mixture was filtered, and the residue was dried to give the title compound as a pale yellow solid (0.70 g, 80.00%), HPLC: 96.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.13-1.96 (m, 6H), 2.09-2.43 (m, 2H), 3.29 (m, 2H), 3.68-3.70 (m, 6H), 3.83 (s, 3H), 4.06 (m, 2H), 6.93 (t, J=8.2 Hz, 1H), 7.06 (s, 1H), 7.27 (m, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.87 (d, J=4.2 Hz, 1H), 8.45 (s, 1H) ppm.
Reaction SMILES: [S:1]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7](OC(C)C)=[O:8])([OH:4])(=[O:3])=[O:2].[CH2:17]([CH:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][OH:21])[CH3:18]>C(O)(C)C>[S:1]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:21][CH2:20][CH:19]([CH2:17][CH3:18])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:8])([OH:4])(=[O:3])=[O:2]
Reactant: CC(C)OC(=O)c1ccccc1S(=O)(=O)O
Reactant: CCCCC(CC)CO
Solvent: CC(C)O
Product: CCCCC(CC)COC(=O)c1ccccc1S(=O)(=O)O
Reaction time: 1 h

Procedure:
Into a one-liter, four-necked round bottom flask equipped with a thermometer, distillation head, and glass stirrer with TEFLON paddle were charged 82.5 grams of 2-propyl o-sulfobenzoate solution in isopropanol and 100 grams of 2-ethylhexanol. The solution was vacuum distilled to a pot temperature of 105° C. and subsequently the vacuum was turned off and the reaction mixture held at 105° C. for one hour. The resultant 2-ethylhexyl o-sulfobenzoate was a brown liquid with an acid value of 102.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.FC(F)(F)C(O)=O.[F:26][C:27]([F:42])([F:41])[C:28]([N:30]1[CH2:35][C:34]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[O:33][CH2:32][CH2:31]1)=[O:29]>C(#N)C>[F:42][C:27]([F:26])([F:41])[C:28]([N:30]1[CH2:35][C:34]2([CH2:40][CH2:39][N:38]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][OH:11])[CH:4]=3)[CH2:37][CH2:36]2)[O:33][CH2:32][CH2:31]1)=[O:29]
Reactant: OCCc1cccc(CBr)c1
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCOC2(CCN(Cc3cccc(CCO)c3)CC2)C1)C(F)(F)F
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 2-(3-(bromomethyl)phenyl)ethanol (example 6, step a) (0.223 g) dissolved in acetonitrile (1 mL) was added dropwise to a stirred solution of triethylamine (0.318 mL) and 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate (example 12, step d) (0.38 g) in acetonitrile (2 mL) at 20° C., over a period of 2 minutes. The resulting mixture was stirred at 20° C. for 3 hours. The solvent was evaporated off and residue partitioned between dichloromethane and water, the aqueous layer was re-extracted twice with DCM and the combined organics were dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with 6% methanol and 1% triethylamine in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.260 g.
Reaction SMILES: CN([S+](N(C)C)N(C)C)C.C[Si-](F)(F)(C)C.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18].[O:26]1[CH2:30][CH2:29][CH:28]=[C:27]1[O:31][Si](C)(C)C.BrBr>C(#N)C.C1COCC1>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH:28]2[CH2:29][CH2:30][O:26][C:27]2=[O:31])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: C[Si](C)(C)OC1=CCCO1
Reactant: O=[N+]([O-])c1ccccc1
Agent: BrBr
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si-](C)(C)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C1OCCC1c1ccc([N+](=O)[O-])cc1
Reaction time: 20 h
Yield: 31.9 %

Procedure:
A solution of 2.75 g (10 mmol) of TASF in 3 mL of acetonitrile and 3 mL of THF was added to a solution of 1.02 mL (10 mmol) of nitrobenzene and 1.93 mL (10.50 mmol) of [(oxacyclopent-2-ene-2-yl)oxy]trimethylsilane (OCS) in 12 mL of anhydrous THF at -78° C. over 10 min. The last traces of TASF from the dropping funnel were washed down with additional 5 mL of THF. The mixture was stirred for 20 hrs. at -78° C. Then, 0.460 mL (8.98 mmol) of bromine was added from a dropping funnel. The mixture was stirred at -78° C. for 15 min, and then the cold bath was removed. Stirring was continued for 1 hr. Thirty mL of freshly prepared saturated sodium bisulfite was added, and the product was extracted into four 60 mL portions of ether. Combined ether extracts were washed with saturated potassium hydrogen phosphate and sodium chloride. Concentration and chromatography on silica yielded two products identified as the ortho and para addition products. The ortho-adduct yielded 0.660 g (32%) of product which had a melting point of 112°-117° C. (dec). The para-adduct yielded 0.282 g (14%) of product which had a melting point of 76° to 78° C. Both the o- and p- products were analyzed by ultraviolet absorption, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry.
Reaction SMILES: N1(CCN2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)CCCCCC1.Cl.Cl.NC1C=C[C:39]([C@H:42]([N:44]([CH3:51])[CH:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[CH3:43])=CC=1>>[CH3:51][N:44]([CH:45]1[CH2:46][CH2:47][O:48][CH2:49][CH2:50]1)[C@@H:42]([C:43]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[C:25]([O:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][CH:22]=3)=[O:18])=[CH:14][CH:15]=1)[CH3:39]
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Reactant: C[C@H](c1ccc(N)cc1)N(C)C1CCOCC1
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)Nc3ccc([C@@H](C)N(C)C4CCOCC4)cc3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and amine 72.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[C:5]([CH3:15])=[CH:4][C:3]=1[OH:16].OS(O)(=O)=O.[CH3:22]O>>[CH3:22][O:13][C:12](=[O:14])[CH2:11][C:7]1[C:6]2[C:5]([CH3:15])=[CH:4][C:3]([OH:16])=[C:2]([F:1])[C:10]=2[S:9][CH:8]=1
Reactant: Cc1cc(O)c(F)c2scc(CC(=O)O)c12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1csc2c(F)c(O)cc(C)c12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of (7-fluoro-6-hydroxy-4-methyl-1-benzothiophen-3-yl)acetic acid (267 mg) and MeOH (8.0 mL) was added conc. H2SO4 (0.100 mL). The mixture was stirred at 80° C. for 1 h. The mixture was concentrated. The mixture was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (255.5 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:41])=[C:19]([C:21]4[NH:25][C:24]([C:26]5([CH3:39])[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35](C)(C)C)=[O:33])[CH2:28][CH2:27]5)=[N:23][C:22]=4[CH3:40])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(C2CN(C(C3C=CC(C)=C(C4N=C(C5CCN(C(OC(C)(C)C)=O)CC5)NC=4C)C=3)=O)C2)=CC=1)#N>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:41])=[C:19]([C:21]4[NH:25][C:24]([C:26]5([CH3:39])[CH2:31][CH2:30][N:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]5)=[N:23][C:22]=4[CH3:40])[CH:20]=3)=[O:14])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(C)CCN(C(=O)OC(C)(C)C)CC2)nc1C
Agent: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Product: COC(=O)N1CCC(C)(c2nc(C)c(-c3cc(C(=O)N4CC(c5ccc(C#N)cc5)C4)ccc3C)[nH]2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 184, except tert-butyl 4-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate (compound 185.3) was used in place of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl) piperidine-1-carboxylate (compound 182.3). m/z (ES+) 512 M+H+.
Reaction SMILES: C(OC([N:8]([C:18]1[C:19]2[N:20]([N:29]=[CH:30][N:31]=2)[C:21]([C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)=[CH:22][N:23]=1)[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])=O)(C)(C)C.[CH2:32]([NH2:34])[CH3:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.CO.CCO.C(N(CC)CC)C>[CH2:32]([NH:34][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([NH:8][C:18]2[C:19]3[N:20]([N:29]=[CH:30][N:31]=3)[C:21]([C:24]3[CH:28]=[N:27][NH:26][CH:25]=3)=[CH:22][N:23]=2)[CH:10]=1)[CH3:33]
Reactant: CC(C)(C)OC(=O)N(c1cccc(C(=O)O)c1)c1ncc(-c2cn[nH]c2)n2ncnc12
Reactant: CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cccc(Nc2ncc(-c3cn[nH]c3)n3ncnc23)c1
Reaction time: 8 h
Yield: 20.1 %

Procedure:
3-{tert-Butoxycarbonyl-[5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-amino}benzoic acid (42 mg, 0.10 mmol), ethylamine (12 M aq., 42 μL, 0.50 mmol), and triethylamine (28 μL, 0.20 mmol) are stirred in DMF (0.30 mL) and PyBOP (57 mg, 0.11 mmol) is added. Stirring is continued overnight. The reaction mixture is partitioned between EtOAc (7 mL) and NaHCO3 (sat. aq., 7 mL) and the layers are separated. The combined organic layers are washed with brine (2×5 mL) and dried over Na2SO4. Evaporation of the solvent affords an oil which is dissolved in MeOH (0.3 mL) containing HCl (12 M aq., 0.15 mL) and stirred overnight. Triethylamine (0.25 mL) and EtOH (2 mL) are added and the solvents removed under reduced pressure. The residue is purified by preparative HPLC to afford the title compound as a white solid (7 mg). 1H NMR (DMSO-d6, 400 MHz): δ=13.29 ppm (s, 0.8H); 10.01 (s, 0.9H); 8.77 (s, 1.0H); 8.65 (s, 1.0H); 8.52 (s, 1.1H); 8.41-8.37 (m, 2.1H); 8.25 (s, 1.0H); 8.08 (d, 1.0H); 7.47 (d, 1.0H); 7.41 (t, 1.1H); 7.04-7.03 (m, 0.5H); 3.32 (s, 29.2H (water)); 1.14 (t, 3.5H). LCMS: Rt=0.95 min (100%), m/z (ESI) 349 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].C[Si](Cl)(C)C.O>ClCCl>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCNCC
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: ClCCl
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)N(CC)CC)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
6.5 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.02 mol) is dissolved in 60 mL of dichloromethane. 1.46 g of diethylamine (0.02 mol, 1 eq) is added and the reaction mixture is cooled to 0° C. 0.43 g TMSCl (0.004 mol, 0.2 eq) is added in 5 min. The reaction mixture is heated to room temperature and stirred for 5 hours. 50 mL of water is added to the mixture, it is stirred for 15 min and the phases are separated. The organic phase is washed with 30 mL of water then it is concentrated. The residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 5.58 g of the title compound (VId) (77%) as a yellowish solid.
Reaction SMILES: [SH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.C([N:14](CC)CC)C.NOS(O)(=O)=O>ClCCl.O>[CH3:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([S:1][NH2:14])=[N:3][CH:4]=1
Reactant: CCN(CC)CC
Reactant: Cc1cnc(S)c([N+](=O)[O-])c1
Agent: NOS(=O)(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1cnc(SN)c([N+](=O)[O-])c1

Procedure:
A solution of 12 g of 2-mercapto-5-methyl-3- nitropyridine and 28.6 g of triethylamine in 180 cm3 of dichloromethane is treated dropwise with 12 g of hydroxylamine-O-sulfonic acid dissolved in the minimum amount of water. At the end of the reaction, the solvent is removed under partial vacuum and the residue is taken up in 20 cm3 of water. The precipitate obtained is collected on a filter, washed with water and dried. It is recrystallized from a dichloromethane/petroleum jelly mixture.
Reaction SMILES: C(O)C.[Na].[CH2:5]([OH:17])[C@H:6]([OH:16])[C@@H:7](O)[C@H:8]([OH:14])[C:9]([C:11]([OH:13])=[O:12])=[O:10].Cl>CC(C)=O>[O:12]=[C:11]1[O:13][C@H:7]([C@H:6]([CH2:5][OH:17])[OH:16])[C:8]([OH:14])=[C:9]1[OH:10]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: CCO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
JP-A 58-177986 describes a process which comprises the addition of ethanol and acetone to the sodium salt of 2-keto-L-gulonic acid, neutralization with hydrochloric acid, the removal of the precipitated sodium chloride by filtration and then the maintenance of the reaction mixture at temperatures in the range from 25° C. to 75° C., by means of which L-ascorbic acid is obtained.