Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([N:10]=[S@:11]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31]([NH:35][C:36]([C:38]2[N:42]([CH3:43])[N:41]=[C:40]([CH3:44])[CH:39]=2)=[O:37])[CH:32]=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(C)=O.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.[Cu]I>[CH3:43][N:42]1[C:38]([C:36]([NH:35][C:31]2[CH:30]=[C:29]([C:27]#[C:28][C:2]3[CH:3]=[C:4]([C:8]([N:10]=[S@:11]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=3)[CH:34]=[CH:33][CH:32]=2)=[O:37])=[CH:39][C:40]([CH3:44])=[N:41]1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Reactant: COC(=O)CCCC[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)CCCC[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To the flame-dried 100 mL round bottom flask containing (S)-Methyl 5-{N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl}pentanoate (609 mg, 1.39 mmol), N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (0.50 g), triethylamine (0.77 mL), bis(triphenylphosphine)palladium(II) dichloride (97.3 mg), and triphenylphosphine (9.1 mg) under nitrogen/hydrogen (1:1) atmosphere at room temperature was added copper(I) iodide (52.8 mg). The resulting reaction mixture was heated and stirred at 60° C. for 1 hour. It was then diluted with EtOAc, washed sequentially with saturated aqueous NaHCO3 (2×), brine (1×), and finally dried with anhydrous sodium sulfate. The solution was decanted and concentrated with silica gel. Chromatography (EtOAc-Hex from 1:2 to 3:2) yielded the title compound as white foam in amount of (712 mg, 86%).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[C:8]([C:19]2[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=2[F:27])=[N:7][CH:6]=1)=[O:4].CO>O>[OH:4][CH2:3][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[C:8]([C:19]2[C:20]([F:27])=[CH:21][C:22]([F:26])=[CH:23][C:24]=2[F:25])=[N:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(C=O)cnc(-c3c(F)cc(F)cc3F)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2c(CO)cnc(-c3c(F)cc(F)cc3F)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
Sodium borohydride (17 mg) was added to a mixture of methyl 4-formyl-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (150 mg) and methanol (10 mL) under ice-cooling, followed by stirring at room temperature for 10 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, dried, and then concentrated under reduced pressure to obtain methyl 4-(hydroxymethyl)-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (140 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:11][CH2:12][CH2:13]O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.CCN(S(F)(F)[F:35])CC>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:11][CH2:12][CH2:13][F:35])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(CCCO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCC(CCCF)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(1-(3-(4-chlorophenyl)-6-hydroxyhexan-3-yl)-1H-indol-4-yl)methanesulfonamide (21 mg, 0.05 mmol), as described in Example 45 Step A, in dichloromethane (2 mL) was added DAST (16 mg, 0.1 mmol) at −78° C. The mixture was gradually warmed to room temperature and stirred for 3 h, then quenched with methanol (0.5 mL). The crude product was purified by PREP-TLC eluting with PE/EA (2/1, v/v) to obtain the title compound as colorless oil. LC/MS m/z=444.7[M+Na]+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:12]1[N:17]=[C:16]([CH2:18][CH2:19][CH3:20])[C:15]([O:21][C:22]2[C:27](I)=[CH:26][N:25]=[C:24]([C:29](OC)=[O:30])[CH:23]=2)=[CH:14][CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:33][C:2]([F:1])([F:34])[C:3]([C:12]1[N:17]=[C:16]([CH2:18][CH2:19][CH3:20])[C:15]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH2:29][OH:30])[CH:23]=2)=[CH:14][CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1nc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cc(C(=O)OC)ncc1I
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a solution of methyl 4-(6-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylpyridin-3-yloxy)-5-iodopicolinate (500 mg, 0.823 mmol) in tetrahydrofuran (8.2 mL), lithium aluminum hydride (63 mg, 1.65 mmol) was added under ice-cold conditions, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, the resultant mixture was added with water under ice-cold conditions, and stirred at room temperature for 30 minutes. Then, the reaction solution was filtered using celite and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/acetone), and (4-(6-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylpyridin-3-yloxy) pyridin-2-yl)methanol (141 mg, yield 38%) was obtained as a yellow oil.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[N:17]=3)=[CH:12][CH:11]=2)C(=O)C2=CC=CC=C12.O.NN>>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[N:17]=2)=[CH:12][CH:11]=1
Reactant: COc1cc(Nc2nccc(-c3ccc(OCCCN4C(=O)c5ccccc5C4=O)cc3)n2)cc(OC)c1OC
Agent: NN
Solvent: O
Product: COc1cc(Nc2nccc(-c3ccc(OCCCN)cc3)n2)cc(OC)c1OC
Yield: 28.4 %

Procedure:
The compound was prepared in a manner analogous to the preparation of the compound of Example 48 from the compound of Example 50 (830 mg, 1 .54 mmol) and hydrazine monohydrate (0.23 ml, 4.62 mmol) to give the title compound (63 mg) as a white solid m.p. 161-162°. MS m/z 411 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:24])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)(=[O:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[CH2:31]([N:9]([S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])[C:10]1[CH:11]=[CH:12][C:13]([CH3:24])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)[CH3:32]
Reactant: CCOC(=O)c1cc2c(C)ccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C)ccc(N(CC)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a mixture of ethyl 7-[(2-thienylsulfonyl)amino]-4-methyl-1H-indole-2-carboxylate (2.89 g), potassium carbonate (1.2 g) and N,N-dimethylformamide (25 ml) was added dropwise a solution of ethyl iodide (0.67 ml) in N,N-dimethylformamide (2 ml) under ice-cooling. The mixture was stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained yellow oil was crystallized from ethyl acetate-hexane, and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (2.16 g, yield 70%) as colorless prism crystals. melting point 148-149° C.
Reaction SMILES: [Na].[C:2]1([O:9][CH3:10])[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11]1([CH:17](Cl)[CH:18]=[CH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[CH3:10][O:9][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:18]=[CH2:19]
Reactant: C=CC(Cl)c1ccccc1
Reactant: COc1ccccc1O
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(Oc1ccccc1OC)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 5 g of guaiacol sodium salt in 60 ml of dimethylformamide, 1-phenylallyl-chloride (5.22 g) (J.C.S. 1959, p. 2720) was added under a nitrogen atmosphere. The whole was stirred for 4 hours at room temperature and for two hours at 50° C., poured into water and extracted with ethyl ether. After standard working up, followed by chromatographic separation, 3-(2-methoxy-phenoxy)-3-phenyl-propylene (8.1 g; 98%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29]([OH:31])=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([OH:31])=[O:30])=[CH:4][CH:3]=1
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: O=C(O)CBr
Product: COc1ccccc1C1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11](=O)[CH2:12][CH2:13][CH2:14][Cl:15])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].O>C([SiH](CC)CC)C.FC(F)(F)C(O)=O>[C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(C(=O)CCCCl)s1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCc1ccc(CCCCCl)s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 70.5 %

Procedure:
A mixture of 2-acetylaminomethyl-5-(4-chlorobutyryl)thiophene (15 g) in triethylsilane (21.6 ml) and trifluoroacetic acid (70 ml) was stirred at room temperature for 10 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 10 g of 2-acetylaminomethyl-5-(4-chlorobutyl)thiophene.
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]([NH2:13])=[C:6]([F:14])[C:5]=1F.[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>C(OCC)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Reactant: Cc1ccccc1N
Solvent: CCOCC
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1C
Temperature: 25 °C
Reaction time: 36 h
Yield: 68 %

Procedure:
4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (12.0 g, 51.7 mmol) is suspended in xylenes (60 mL) and ortho-toluidine is added (55.2 mL, 518 mmol). The reaction mixture is heated to reflux with stirring under a nitrogen atmosphere. After 36 hours, the reaction mixture is cooled to room temperature, diluted with diethyl ether and washed with 10% aqueous HCl solution. The aqueous washing are extracted with diethyl ether. The combined organic extracts are concentrated under reduced pressure. The residue is dissolved in methylene chloride and filtered through silica gel in a fritted funnel, rising with methylene chloride. Three fractions are recovered. The first (2 liter) is nearly clean by HPLC. The second (1 liter) and third (1 liter) fraction are only partially pure. The first fraction is concentrated under reduced pressure and triturated with diethyl ether to give 11.2 g (68%) of clean desired product as a bright yellow solid: MS APCI (−) m/z 318 (M−1) detected.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([CH3:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([CH3:26])[C:3]=1[OH:27].O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31]>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([CH3:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([CH3:26])[C:3]=1[O:27][C@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Cc1cc(-c2c3ccccc3c(C)c3sc4ccccc4c23)cc(C)c1O
Product: Cc1cc(-c2c3ccccc3c(C)c3sc4ccccc4c23)cc(C)c1O[C@H](Cc1ccccc1)C(=O)O

Procedure:
Prepared from of 2,6-dimethyl-4-(6-methyl-benzo[b]naphtho [2,3-d]thiophen-11-yl)-phenol (Example 25) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: NMR (DMSO-d6); δ13.0 (broad band, 1 H), 8.18 (d, J=8 Hz, 1 H), 7.91(d, J=8 Hz, 1 H), 7.61 - 7.53 (m, 2 H), 7.43 (ddd, J=8, 7, 1 Hz, 1 H), 7.45 - 7.28(m, 5 H), 7.25 - 7.21 m, 1 H), 7.01 (ddd, J=8, 7, 1 Hz, 1 H), 6.95 (d, J=5 Hz, 2 H), 6.53 (d, J=8Hz, 1 H), 4.75 (t, J=7 Hz, 1 H), 3.32 - 3.24 (m, 2 H), 2.87 (s, 3 H), 2.56 (s, 3 H), 2.18 (s, 3 H): MS(EI): [M+] 516; Anal. Calc. for C34H28O3S: C, 79.04, H, 5.46, N, 0.00. Found: C, 79.13, H, 5.41, N, 0.11.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:12]2[O:11][C:3]3[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=3[N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(C(=O)O)c1O
Product: O=C(O)c1cccc2nc(-c3ccccc3)oc12
Yield: 86 %

Procedure:
2-Phenylbenzoxazole-7-carboxylic acid was prepared from 3-aminosalicyclic acid and benzoyl chloride using a procedure identical to that described in Step A of Example 1. This material was obtained in 86% yield as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.30 (dd, J=7.2, 2.1 Hz, 2H), 7.98 (dd, J=12.9, 7.8 Hz, 2H), 7.60 (m, 3H), 7.48 (t, J=7.8 Hz, 1H); MS (APCI) m/z 240 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10].[Br:14]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.[Hg]>[Br:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(=O)c1ccccc1C
Agent: [Hg]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=O)c1ccccc1CBr
Yield: 49.3 %

Procedure:
5.34 g (30 millimoles) of methyl 2-methylphenylglyoxylate and 5.34 g (30 millimoles) of N-bromosuccinimide in 1,000 ml of tetrachloromethane are exposed to a 300 W mercury vapor lamp for one hour. Thereafter, the organic phase is washed once with water and three times with sodium bicarbonate solution, dried over sodium sulfate/sodium carbonate and evaporated down, and the crude product is then chromatographed over silica gel using 1:9 methyl tert-butyl ether/n-hexane. 3.8 g (49%) of the abovementioned compound are obtained as a yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH2:19]([N:21]([CH2:35][CH3:36])[C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])[CH3:20].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:24]([C:23]3[CH:27]=[C:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:29]=[CH:30][C:22]=3[N:21]([CH2:35][CH3:36])[CH2:19][CH3:20])=[O:25])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride (Example 1.20b) and 2-diethylamino-5-methanesulfonyl-benzoic acid (Example 2.5) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid. MS (m/e): 501.4 (M+H+; 100%)
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].CC(C)([O-])C.[K+].Cl[C:18]([O:20][CH3:21])=[O:19].O>O1CCCC1>[Br:10][C:4]1[N:3]([C:18]([O:20][CH3:21])=[O:19])[C:2]([Br:1])=[C:6]([C:7]#[N:8])[C:5]=1[Br:9]
Reactant: COC(=O)Cl
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)n1c(Br)c(Br)c(C#N)c1Br
Reaction time: 0.33 h

Procedure:
A solution of 2,4,5-tribromopyrrole-3-carbonitrile (3.0 g, 0.091 mol) in tetrahydrofuran is treated portionwise with potassium t-butoxide (1.33 g, 0.012 mol) at room temperature, stirred for 20 minutes, treated dropwise with a solution of methyl chloroformate (1.29 g, 0.014 mol) in tetrahydrofuran, stirred for 21/2 days, poured into water and extracted with ether. The combined ether extracts are washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown solid residue. The residue is recrystallized from ethyl acetate/hexanes to afford the title compound as a tan solid, 1.4 g (39.5%) mp 119.5° to 122.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:34][CH:35]([CH3:38])[CH2:36][OH:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:34][CH:35]([CH3:38])[CH2:36][OH:37])=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Reactant: CC(N)CO
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-2-amino-1-propanol employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.16 (1H, d, J=8 Hz), 8.54 (1H, s), 7.15 (2H, dd, J=8.5, 5.3 Hz), 7.04 (1H, s), 7.02 (2H, t, J=8.5 Hz), 4.90 (1H, d, J=17 Hz), 4.83 (1H, d, J=17 Hz), 4.27 (1H, m), 4.11 (2H, s), 3.76 (1H, m), 3.66 (1H, m), 3.50-3.44 (4H, m), 2.24 (1H, br), 2.05 (2H, m, J=7 Hz), 1.89 (2H, m, J=7 Hz), 1.29 (3H, d, J=7 Hz); HRMS calcd for C25H27FN4O5+H+: 483.2044. Found: 483.2047.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].N12CCCNC1CCCC=C2.[CH2:20]([CH:32]([O:36][S:37]([OH:40])(=[O:39])=[O:38])[C:33](=[O:35])[CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH2:20]([CH:32]([O:36][S:37]([OH:40])(=[O:39])=[O:38])[C:33]([OH:35])([CH3:34])[P:1]([O:5][CH2:6][CH3:7])(=[O:8])[O:2][CH2:3][CH3:4])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCOP([O-])OCC
Reactant: CCCCCCCCCCCCC(OS(=O)(=O)O)C(C)=O
Agent: C1=CN2CCCNC2CCC1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(OS(=O)(=O)O)C(C)(O)P(=O)(OCC)OCC

Procedure:
11.3 g (81.9 mmol) of diethyl phosphite and 2 ml of 1,8-diazabicyclo[5.4.0]undecene (DBU) are initially introduced into 200 ml of anhydrous tetrahydrofuran, a solution of 15.0 g (81.9 mmol) of dodecylsulfoxyacetone in 50 ml of tetrahydrofuran is added dropwise, and the mixture is subsequently refluxed for 8 hours. When the solution has cooled, it is washed twice using saturated sodium chloride solution and dried over sodium sulfate, and the solvent is distilled off, finally at 0.5 mbar and 60° C. bath temperature.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Cl)=[CH:5][N:4]=1)#[N:2].[CH2:11]([NH2:14])[CH2:12][NH2:13]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:13][CH2:12][CH2:11][NH2:14])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ccc(CCl)cn1
Reactant: NCCN
Solvent: CC#N
Product: N#Cc1ccc(CNCCN)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
A solution of 2-cyano-5-pyridylmethyl chloride (4.6 g) in acetonitrile (20 ml) was added dropwise to a solution of ethylenediamine (9 g) in acetonitrile (50 ml) at 5° to 10° C. After the addition, the mixture was stirred at room temperature for 3 hours. Acetonitrile and the excess of ethylenediamine were distilled off under reduced pressure from the reaction mixture. Dichloromethane was added to the residue, and a portion of it soluble in dichloromethane was separated. Dichloromethane was distilled off under reduced pressure. Volatile materials were removed at 50° C. and 1 mmHg to give N-(2-cyano-5-pyridylmethyl)ethylenediamine (4.5 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]2[S:16][CH2:15][CH2:14][C:9]3([S:13][CH2:12][CH2:11][S:10]3)[C:6]=2[C:7]=1[CH3:8].C([Li])CCC.[C:23](=[O:25])=[O:24]>O1CCCC1.CCCCCC>[CH3:8][C:7]1[C:6]2[C:9]3([CH2:14][CH2:15][S:16][C:5]=2[C:4]([CH3:17])=[CH:3][C:2]=1[C:23]([OH:25])=[O:24])[S:13][CH2:12][CH2:11][S:10]3
Reactant: Cc1cc(Br)c(C)c2c1SCCC21SCCS1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)c(C)c2c1SCCC21SCCS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound of Step A (2.7 g, 7.7 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere cooled to -78° C. was added n-butyllithium (Aldrich, 4.6 mL, 11.5 mmol of a 2.5 M solution in hexane) dropwise while maintaining the temperature below -60° C. After stirring for 2 h, excess carbon dioxide (dry ice) was added. The resulting mixture was allowed to warm to room temperature and was left at room temperature overnight. To this reaction mixture was added hexanes (30 mL), and the mixture was filtered. The solid was added to a mixture of water:methylene chloride (20 mL:20 mL), cooled to about 0° C., and acidified to pH 1 with concentrated hydrochloric acid. The organic layer was separated, and aqueous layer was extracted with diethyl ether (3×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to about 10 mL. A white solid precipitated and this solid was isolated by filtration to afford the title compound of Step B (1.62 g) as a solid melting at 236-238° C. 1H NMR (Me2SO-d6): δ2.17 (s,3H), 2.68 (m,2H), 2.81 (s,3H), 3.11 (m,2H), 3.50-3.70 (4H), 7.33 (s,1H), 12.78 (s,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:14]([OH:16])[CH3:15].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12](=[NH:13])[O:16][CH2:14][CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCO
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Agent: Cl
Product: CCOC(=N)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 24 h

Procedure:
Through a cooled solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (5.0 g, 26.1 mmol, Aldrich) and ethanol (2.3 mL, 39.1 mmol) was bubbled HCl gas at 0° C. for 30 minutes. After standing at 4° C. for 24 hours, the reaction mixture was concentrated and triturated with diethyl ether. The precipitate was collected and dried to obtain the titled compound. MS (ESI+) m/z 238 (M+H)1.