Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5](=[N:7][OH:8])[NH2:6].Cl.[C:14](Cl)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.N>>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: NC(=NO)c1ccc(F)c(F)c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: N
Product: Fc1ccc(-c2noc(-c3cccnc3)n2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 1 using 3,4-difluoro-N′-hydroxybenzimidamide (Tyger Scientific) and nicotinoyl chloride hydrochloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.74 (dd, J=7.5, 4.4 Hz, 1 H), 8.60 (dt, J=7.8, 2.1 Hz, 1 H), 8.93 (dd, J=4.8, 1.6 Hz, 1 H), 9.38 (dd, J=2.2, 1.0 Hz, 1 H), 9.44-9.48 (m, 3 H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:18])[C:5](=[O:17])[NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:1][CH2:2][CH2:3][N:4]([CH3:18])[C:5]([NH:6][C:7]1[CH:16]=[CH:15][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1)=[O:17]
Reactant: COC(=O)c1ccc(NC(=O)N(C)CCO)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(CCO)C(=O)Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.8 %

Procedure:
To a cooled (−78° C.) solution of methyl 4-(3-(2-hydroxyethyl)-3-methylureido)benzoate (2.02 g, 8.00 mmol) in THF (80 mL) was added a solution of lithium aluminium hydride (2.0 M solution in THF, 6.0 mL, 12.0 mmol). After 20 minutes the coolant was removed and the reaction mixture stirred at RT for 18 h. The reaction mixture was quenched with water (0.46 mL), 2 M aqueous sodium hydroxide (0.46 mL) and water (3×0.46 mL). The mixture was diluted with ethyl acetate and magnesium sulfate added. The mixture stirred for 1 hour and then filtered. The filtrate was evaporated at reduced pressure and the residue was purified by flash column chromatography eluting with 0 to 100% ethyl acetate/iso-hexane to afford the title compound (1.09 g, 60%).
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7]([O-:9])=O>S(Cl)(Cl)=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:12](=[O:13])[O:14][C:7](=[O:9])[C:6]2=[CH:10][CH:11]=1
Reactant: O=C([O-])c1ccc(Cl)cc1C(=O)O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: O=C1OC(=O)c2cc(Cl)ccc21
Yield: 64.3 %

Procedure:
The mixture of commercial 4-chlorophthalic acid monosodium salt (40 g) and thionyl chloride (50 ml) was stirred under reflux for 2 h. From the resulting viscous mass all volatiles were removed at the water aspirator. The residue was heated with benzene (150 ml) and the still hot slurry was filtered by suction. The filter cake was washed twice with benzene (50 ml) and the filtrate was concentrated in vacuo to give a yellowish solid. The crude was recrystallised from n-hexane/benzene 3:1 (filtration of the boiling solution needed) to yield 4-chlorophthalic anhydride (21.1 g) as colourless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.Br[C:12]1[CH:13]=[CH:14][C:15]([F:19])=[C:16]([CH3:18])[CH:17]=1>>[F:19][C:15]1[CH:14]=[CH:13][C:12]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]2)=[CH:17][C:16]=1[CH3:18]
Reactant: COC(=O)C1CCNCC1
Reactant: Cc1cc(Br)ccc1F
Product: COC(=O)C1CCN(c2ccc(F)c(C)c2)CC1

Procedure:
starting with 10.6 g (74.0 mmol) of methyl piperidine-4-carboxylate and 4.67 g (24.7 mmol) of 5-bromo-2-fluorotoluene, the general procedure [E] gives 2.74 g (40% of theory) of product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:22]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cccnc3)ccn2c1=O
Yield: 88 %

Procedure:
Methyl 8-(pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and pyridin-3-yl-boronic acid (63 mg, 0.51 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (100 mg, 87%). ESI-MS m/z: 335 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH:24]1[C:28]2[CH2:29][CH2:30][CH2:31][C:27]=2[C:26]([NH2:32])=[N:25]1>O1CCCC1.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH:32][C:26]3[C:27]4[CH2:31][CH2:30][CH2:29][C:28]=4[NH:24][N:25]=3)=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1n[nH]c2c1CCC2
Reactant: O=C(O)Cc1ccc(-c2cccc(F)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2cccc(F)c2)cc1)Nc1n[nH]c2c1CCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
230 mg of 2-(3′-fluoro-biphenyl-4-yl)-acetic acid is dissolved in 5 ml of tetrahydrofuran, mixed with 0.11 ml of oxalyl chloride and one drop of dimethylformamide, and stirred for 2 hours at room temperature. 62 mg of 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine is added to this solution. The mixture is stirred for 12 hours at room temperature and then concentrated by evaporation. The residue is extracted with ethyl acetate. The extract is washed with sodium bicarbonate solution and water, dried on magnesium sulfate and concentrated by evaporation. The brown residue is dissolved in 5 ml of methanol and mixed with 0.1 ml of a 30% sodium methylate solution. It is stirred for 4 hours at room temperature and then concentrated by evaporation. The residue is extracted with ethyl acetate. The extract is washed with sodium bicarbonate solution and sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. A yellow, resinous oil is obtained that is purified by HPLC. 2-(3′-Fluoro-biphenyl-4-yl)-N-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-acetamide with a melting point of 180-181° C. is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[C:22]([CH:37]2[CH2:39][CH2:38]2)=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:20][C:21]2[C:22]([CH:37]3[CH2:39][CH2:38]3)=[N:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=3)=[N:25][CH:26]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)CCc1ccc(O)c2ccccc12
Product: CCOC(=O)CCc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c2ccccc12

Procedure:
A] In analogy to the procedures described in example 5C] and 5D], 3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester [Helvetica Chimica Acta (2001), 84(8), 2198-2211] was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 9E]) to give 3-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-naphthalen-1-yl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[CH2:3][CH2:2]1.[ClH:24]>C(OCC)(=O)C>[ClH:24].[CH:1]1([CH2:4][O:5][C:6]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:7][NH:8][CH2:9]2)[CH2:2][CH2:3]1
Reactant: Cc1ccccc1C1(OCC2CC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1C1(OCC2CC2)CNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
2.8 g (9.0 mmol) of tert-butyl 3-cyclopropylmethoxy-3-o-tolylazetidine-1-carboxylate are placed in 40 ml of a 3M solution of hydrogen chloride in ethyl acetate and are stirred at room temperature for 1 hour 30 minutes. The reaction medium is concentrated under a stream of nitrogen and then taken up in a 50/50 heptane/ethyl acetate mixture and concentrated under vacuum. 2.2 g (96%) of 3-cyclopropylmethoxy-3-o-tolylazetidine hydrochloride are obtained in the form of a beige-coloured solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23](F)[C:20]=1[C:21]#[N:22]>>[NH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=3)[CH2:9][CH2:10]2)[C:20]=1[C:21]#[N:22]
Reactant: COc1ccc(CN2CCC(CO)CC2)cc1
Reactant: N#Cc1c(N)cccc1F
Product: COc1ccc(CN2CCC(COc3cccc(N)c3C#N)CC2)cc1

Procedure:
Prepared as in Example 22b from (1-(4-methoxybenzyl)piperidin-4-yl)methanol (Example 125c) and 2-amino-6-fluorobenzonitrile as an orange solid (19%). MS 352 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][C:12]2=[O:15])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][CH:12]2[OH:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)C(O)CCC2
Temperature: 5 °C

Procedure:
In a mixture of 150 ml of methanol and 50 ml of tetrahydrofuran, 24.1 g of 7-methoxycarbonyl-3,4-dihydro-(2H)-1-naphthalenone was dissolved and 5 g of sodium borohydride was added by portions with ice cooling. The mixture was stirred at 5° C. for an hour and successively the solvent was distilled off under reduced pressure. The concentrated residue was adjusted to pH 2 by adding a 2N aqueous hydrochloric acid solution and extracted with chloroform. The chloroform layer was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude intermediate 7-methoxycarbonyl-1,2,3,4-tetrahydro-1-naphthol. The crude intermediate was dissolved in 150 ml of benzene, 5 g of Amberlyst 15 was added, a Dean-Stark Trap was mounted, and the mixture was refluxed by heating for 2 hours. After cooling, the reaction mixture was filtered and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography using a mixture, ethyl acetate: n-hexane=1:10, as a developer. 7-methoxycarbonyl-3,4-dihydronaphthalene thus obtained was 19.2 g.
Reaction SMILES: C(O[C:6](=[O:15])[NH:7][CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])(C)(C)C.FC(F)(F)C(O)=O.COC([C:27]1[C:28]([OH:51])=[C:29]2[C:34](=[CH:35][N:36]=1)[N:33]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32](=[O:44])[C:31]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[CH:30]2)=O>C(Cl)Cl>[CH3:14][S:11]([NH:10][CH2:9][CH2:8][NH:7][C:6]([C:27]1[C:28]([OH:51])=[C:29]2[C:34](=[CH:35][N:36]=1)[N:33]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32](=[O:44])[C:31]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[CH:30]2)=[O:15])(=[O:12])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
(2-Methanesulfonylamino-ethyl)-carbamic acid tert-butyl ester (94 mg, 0.38 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed by evaporation, and the residue was taken up in EtOH (3 mL). NaOMe was added with vigorous stirring until pH was about 8. The resulting mixture was transferred to a microwave vial containing 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (38 mg, 0.098 mmol), and the mixture was heated at 140° C. for 6 h in a microwave reactor. The solvent was evaporated, and the residue was partitioned between EtOAc and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 16 mg of the title compound. MS: (+) m/z 493.32 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[CH:4][C:3]=1[CH3:10].C([N:19]=[C:20]=[S:21])(=O)C1C=CC=CC=1.[OH-].[Na+]>CC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:20]([NH2:19])=[S:21])=[CH:4][C:3]=1[CH3:10]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1cc(N)cc(C)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1cc(NC(N)=S)cc(C)c1Br
Temperature: 50 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
A solution of 4-bromo-3,5-dimethyl-phenylamine (200 mg) and benzoyl isothiocyanate (0.14 ml) in acetone (2 ml) was heated under reflux for 30 minutes. After cooling the reaction solution, a 1 N aqueous sodium hydroxide solution (2.19 ml) was added and the mixture was stirred at 50° C. for 12 hours. The mixture was extracted with dichloromethane, and the organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was triturated with hexane to give (4-bromo-3,5-dimethyl-phenyl)-thiourea (146 mg, 57%).
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][N:20]=[C:14]2[CH2:13]1)=[O:11])=O)C.[ClH:31]>CO>[ClH:31].[ClH:31].[NH2:7][C@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][N:20]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1ccc(F)c(F)c1
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1ccc(F)c(F)c1

Procedure:
The title compound was prepared from 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(3,4-difluorophenyl)butanoyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (72 mg, 0.171 mmol, from Step C), in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Concentration gave 66 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CD3OD) δ 2.96-3.13 (m, 4H), 3.93 (m, 1H), 4.13 (m, 2H), 4.26-4.38 (m, 2H), 4.26-4.38 (m, 2H), 4.90-5.04 (m, 2H), 7.19-7.36 (m, 3H), 7.58 (m, 1H). ESI-MS 321 (M+1).
Reaction SMILES: [F:1][C:2]([F:33])([C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[CH2:34]=O.Cl>C(O)=O>[F:1][C:2]([F:33])([C:23]([F:31])([F:32])[C:24]([F:29])([F:30])[C:25]([F:26])([F:27])[F:28])[CH2:3][CH2:4][CH2:5][N:6]([CH2:7][CH2:8][CH2:9][C:10]([F:21])([F:22])[C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH3:34]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCNCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CN(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 90 °C
Yield: 88 %

Procedure:
A solution of bis(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)amine (3.0 g) and formic acid (90%, 1.5 g) was cooled in an ice-water bath and 8 ml of formaldehyde (37% weight) was added. The solution was slowly heated to 90° C. and maintained overnight. (Foaming and gas evolution at 60-75° C.) Concentrated hydrochloric acid (1 ml) was added and 7 ml of solution were removed by distillation. The remaining solution was cooled and treated with KOH (aq. 10%) to pH 11. The mixture was extracted with methylene chloride (3×50 ml). The combined methylene chloride extracts were washed with water (2×50 ml), dried over sodium sulfate, and concentrated on vacuum to give a residue. Distillation of the residue at reduced pressure gave 2.7 g of bis(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)methylamine, yield 88%. 19F NMR (CDCl3) -81.7 (m, 6F), -115.1 (m, 4F), -125.1 (m, 4F), -126.6 (m, 4F) ppm. 1H NMR (CDCl3) 2.40 (t, J=6 Hz, 4H), 2.19 (s, 3H), 2.16 (m, 4H), 1.76 (m, 4H) ppm. 13C NMR (CDCl3) 18.4, 28.7 (t, J=23 Hz), 41.3, 56.5, 108-123 (m) ppm. MS (m/e) 532 (M+ -F, 7.5%), 382 (1.0%), 304 (100%), 195 (0.6%), 169 (0.8%), 119 (2.5%), 69 (9.4%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[N-:13]=[N+]=[N-].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC#N.O>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH2:13])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1CCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: NCCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(2-Bromoethyl)-2-nitrobenzene (6.96 g, 30.5 mmol) in CH3CN was added a solution of NaN3 (6 g, 91.6 mmol) in water (20 ml) and the reaction mixture was refluxed for 20 hours. The solution was cooled and extracted with DCM (3×). The organics were combined, washed with brine, dried (MgSO4) and evaporated to dryness. The residue was taken up in toluene (160 ml) and to this was added PPh3 (8 g, 30.5 mmol) and the reaction mixture was stirred at RT for 16 hours. The solvent was evaporated to dryness and the residue was treated with acetic acid (30 ml) and 48% HBr in acetic acid (30 ml) at 100° C. for 1 h. The reaction mixture was cooled, concentrated and extracted with DCM. The aqueous was brought to pH˜10 with NaOH (aq.) and extracted with EtOAc (3×). The organics were combined, washed with brine, dried (MgSO4) and evaporated to dryness (4.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]([NH:14]C(OC(C)(C)C)=O)[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:22])[C@@H:4]([NH2:14])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](CCOc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CCOc1ccccc1
Reaction time: 16 h

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-4-phenoxy-butyric acid methyl ester (1.15 g) in dichloromethane (3 ml) was added under an argon atmosphere trifluoroacetic acid (4.2 ml). The mixture was stirred for 16 h. The mixture was concentrated. The residue was treated with sodium bicarbonate solution until the pH was basic and extracted with dichloromethane twice. The combined organic layers were dried (MgSO4) and evaporated. The product was used without purification for the next step, yellow oil. MS (ISP): 210.3 ([M+H]+)).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=O)=[O:2].[NH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:14][CH2:13][NH:12][C:8]([C:7]2[CH:6]=[C:5]([CH3:11])[NH:4][C:3]=2[CH:1]=[O:2])=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCCN1CCCC1
Reactant: Cc1cc(C(=O)O)c(C=O)[nH]1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Yield: 75.9 %

Procedure:
2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (3.0 g, 19.6 mmol) reacted with 1-(2-aminoethyl)pyrrolidine (2.73 mL, 21.5 mmol) to give 3.71 g (76%) of 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide.
Reaction SMILES: O.[ClH:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([OH:11])=[O:10].[CH3:12]O>S(Cl)(Cl)=O>[ClH:2].[Cl:2][C:6]1[CH:7]=[CH:8][N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1
Reactant: O=C(O)c1ccccn1
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Yield: 85 %

Procedure:
H2O (18 mL) was added dropwise to a stirred suspension of picolinic acid hydrochloride, compound 1 (157.9 g, 1.0 mol) in thionyl chloride (400 mL). The resulting mixture was heated under reflux for 4 days giving a clear orange solution. After cooling to ambient temperature, the solution was concentrated to a syrup and the residue coevaporated with toluene (2×500 mL). The residue was dissolved in toluene (1 L) and cooled to 0-5° C. Methanol (44.0 g, 1.0 mol) was added dropwise to the ice cold reaction mixture giving a heavy white precipitate. This precipitate was collected by filtration, washed with toluene (3×100 mL) and dried at 40° C. for 24 hr to give 176.5 g (85%) of compound 2 as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1C(O)=O.[OH-].[Na+].[Na]>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][CH:3]=1
Reactant: Nc1c(C(=O)O)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
1-Amino-4-hydroxyanthraquinone-2-carboxylic acid (31.1 grams, 0.11 mole) was dissolved in 2000 ml. of water and 50 ml. of 10 M sodium hydroxide solution. The mixture was heated on a steam bath to 90°-100° C., and 40 g (0.23 mole) sodium hydro ulfite was added. Heating was continued with stirring for 2 hours, after which the mixture was cooled to room temperature. The resulting solid was collected by filtration and washed with water until the filtrate was neutral. The solid was dried at 80° C. to give 26.2 g (75% yield) of 1-amino-4-hydroxyanthraquinone. The Thin Layer Chromatogram of the crude product showed the presence of a small amount of impurity.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (270 mg, 70%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2].[K+].[Br-]>>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccccc21
Agent: [Br-]
Agent: [K+]
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2ccccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-2-benzoyl-1-(ethoxycarbonyl)indole (step 1). 1H-NMR (CDCl3) δ: 9.78 (1H, br s), 8.24 (1H, d, J=8 Hz), 8.22 (1H, br s), 7.82 (2H, d, J=8 Hz), 7.64-7.52 (3H, m), 7.42-7.25 (2H, m), 7.16 (1H, t, J=8 Hz), 2.26 (3H, s) IR (KBr) ν: 3360, 1670, 1620, 1540, 730 cm−1