Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: C1COCCN1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCOCC3)cc1OCC2
Yield: 44 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and morpholine, the crude product was recrystallised from methanol to give 341 as a white solid (107 mg, 44%). LCMS: RT=3.12 min, [M+H]+382. 1H NMR 400 MHz (DMSO-d) δ: 9.14 (1 H, s), 7.90 (1 H, d, J=0.63 Hz), 7.86 (1 H, s), 6.36 (1 H, s), 5.93-5.92 (1 H, m), 4.57-4.48 (4 H, m), 3.70 (4 H, t, J=4.74 Hz), 3.50 (4 H, t, J=4.74 Hz), 1.49 (6 H, d, J=6.60 Hz)
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.[C@H:21]1([NH:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH2:41])[CH:37]=3)[N:32]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1>>[C@H:21]1([NH:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH:41][C:1]([NH:20][CH:17]4[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]4)=[O:12])[CH:37]=3)[N:32]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CN1CCC(N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CN1CCC(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-methyl-piperidin-4-ylamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=415.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[CH:7]=[C:6]2[C:23]1[N:32](S(C2C=CC(C)=CC=2)(=O)=O)[C:26]2=[N:27][CH:28]=[C:29]([F:31])[CH:30]=[C:25]2[CH:24]=1.[OH-].[K+].ClCCl.CO>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)[CH:7]=[C:6]2[C:23]1[NH:32][C:26]2=[N:27][CH:28]=[C:29]([F:31])[CH:30]=[C:25]2[CH:24]=1
Reactant: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCN(C)CC3)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cc2c(-c3cc4cc(F)cnc4[nH]3)cn(CCN3CCN(C)CC3)c2cc1OC
Yield: 61 %

Procedure:
But using 0.82 g of 2-[5,6-dimethoxy-1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indol-3-yl]-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine dissolved in 100 ml of methanol and 2 g of potassium hydroxide dissolved in 7 ml of water. After flash chromatography on a silica column [eluent: dichloromethane/methanol (70/30 by volume)], 0.37 g of 2-{5,6-dimethoxy-1-[2-(4-methyl-piperazin-1-yl)ethyl]-1H-indol-3-yl}-5-fluoro-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][C:9]#[C:10][CH2:11][OH:12].[CH:13]1([CH3:25])[CH2:18][CH2:17][CH:16]([CH:19]([CH3:21])[CH3:20])[CH:15]([C:22](Cl)=[O:23])[CH2:14]1>O.CCOCC>[OH:12][CH2:11][C:10]#[C:9][CH2:8][NH:7][C:22]([CH:15]1[CH:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:18][CH:13]([CH3:25])[CH2:14]1)=[O:23]
Reactant: NCC#CCO
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1CCC(C(C)C)C(C(=O)NCC#CCO)C1
Reaction time: 2 h

Procedure:
Sodium bicarbonate (2.5 g.) and 4-aminobut-2-yn-1-ol hydrochloride (2.5 g.) were dissolved in water (60 ml.) and a solution of p-menth-3-oyl chloride in ether (100 ml.) added. The mixture was stirred vigorously for two hours and the ether layer separated and dried over MgSO4. Evaporation of the ether gave N-(4-hydroxybut-2-ynyl)-p-menthane -3-carboxamide as a very viscous liquid: b.p. 180°/0.1 mm.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].CO>C1COCC1.O>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccccn2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccn2)cc1F
Temperature: 60 °C

Procedure:
A solution of methyl 2-fluoro-4-(pyridin-2-yl)benzoate (2.50 g, 11.0 mmol) in a mixture of THF (12 mL) and water was treated with lithium hydroxide monohydrate (0.9 g, 4 mmol) in water (12 mL). Methanol (8 mL) was added until a transparent solution formed. This solution was heated at 60° C. overnight, and the organic solvents were removed under vacuum. The residual aqueous solution was acidified with 2 N HCl to pH=2. Solvents were evaporated under reduced pressure to give 2-fluoro-4-(pyridin-2-yl)benzoic acid as a white solid. LC-MS (ESI) m/z: 218 (M+1)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[N:5]2.CN(C)C=O.S(Cl)([Cl:22])=O>ClCCl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([Cl:22])=[O:14])[CH:6]=[N:5]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc2cc(I)ccc2n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc2cc(I)ccc2n1
Temperature: 25 °C

Procedure:
To a solution of compound 23 (200 mg, 0.67 mmol) in dry dichloromethane (10 mL), under argon and at 0° C., was added dropwise dry N,N-dimethylformamide (100 μL) and thionyl chloride (200 μL, 2.74 mmol). The reaction mixture was stirred at reflux for 3 h. After cooling to room temperature, the solvent was removed under reduced pressure to afford crude 6-iodoquinoxaline-2-carbonyl chloride. This was suspended in dry tetrahydrofuran (10 mL) and were successively added, under argon, p-nitrophenol (93 mg, 0.67 mmol) and dropwise a solution of triethylamine (95 μL, 0.68 mmol) in dry tetrahydrofuran (5 mL). The solution was stirred at 50° C. for 18 h. After cooling to room temperature, dichloromethane (30 mL) was added and the resulting solution was washed with a 5% aqueous sodium carbonate solution (20 mL). The aqueous layer was extracted with dichloromethane (5×15 mL) and the organic layers were combined, dried on magnesium sulfate and evaporated under reduced pressure. The resulting precipitate was triturated with ether (5 mL) and collected by filtration to afford ester 24 (225 mg, 0.53 mmol) as a beige solid. Yield 80%; mp 228-230° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, 2H, J=7 Hz), 8.09 (d, 1H, J=9 Hz), 8.30 (dd, 1H, J=2, 9 Hz), 8.41 (d, 2H, J=7 Hz), 8.72 (d, 1H, J=2 Hz), 9.60 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 4 h
Yield: 90.1 %

Procedure:
To a solution of the 4-fluoro-3-nitrobenzoic acid (0.12 mol, 22.2 g) in 100 mL of anhydrous DCM was added 10 drops of anhydrous DMF. To this solution was added dropwise over 60 min, oxalyl chloride (0.144 mol, 12.6 mL). During the addition, the solid slowly dissolved to give rise to a yellow solution. The mixture was stirred for an additional 4 h and the solvent was stripped down to give a yellow oil. This oil was distilled under vacuum (110° C., 1.5 mm Hg) to give 4-fluoro-3-nitrobenzoyl chloride as a light yellow liquid (22.0 g, 90% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C:6]1([C:14]3[C:9](=NC=CC=3)[N:8](COCC[Si](C)(C)C)[C:7]1=[O:23])[CH2:5]2.Cl.[CH2:29]([NH2:32])[CH2:30]N.[OH-].[Na+].[CH3:35]O>O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][CH:27]=1)[CH2:24][C:6]1([C:14]3[N:32]=[CH:29][CH:30]=[CH:35][C:9]=3[NH:8][C:7]1=[O:23])[CH2:5]2
Reactant: NCCN
Reactant: CO
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc(N)cc3C2)c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2cccnc21
Reaction time: 0.5 h

Procedure:
A solution of (−)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step B (13.7 g, 35.9 mmol) in methanol (300 mL) was saturated with HCl (g). The mixture was resaturated with HCl (g) every 30 min until the starting material was consumed, and then concentrated in vacuo. The residue was dissolved in MeOH (150 mL) and treated with ethylenediamine (2.4 mL, 35.9 mmol) and 10 N sodium hydroxide (7.2 mL, 72 mmol) to adjust the mixture to pH 10. After 30 min, the mixture was diluted with H2O (400 mL) and extracted with CHCl3 (2×1 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was triturated with MeOH (50 mL) to give the title compound. MS: m/z=252 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:37])[C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35]O[CH2:33][CH2:32]5)=[N:27][CH:26]=4)=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:38])[C:4]([O:6][CH3:7])=[O:5].N1CCCC[CH2:41]1>>[CH3:39][CH:2]([CH3:1])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:37])[C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:32][CH2:33][CH2:41][CH2:35][CH2:36]5)=[N:27][CH:26]=4)=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:38])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C1CCNCC1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(N5CCOCC5)nc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(N5CCCCC5)nc4)cc3)cc2C1=O
Yield: 91 %

Procedure:
The compound of example 214 was prepared analogous to compound of example 212 by reaction of compound of example 211 with piperidine.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][S:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncsc1-c1cccc(F)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncsc3-c3cccc(F)c3)n2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]2[C:21](=[O:22])[CH2:20][C:19]3[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:18]=3[CH:17]=[CH:16]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]2[C:21](=[O:22])[CH2:20][C:19]3[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:18]=3[CH2:17][CH2:16]2)[CH2:9]1
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(Cc3ccccc3)C1)C=C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCNC1)CC2

Procedure:
14.3 g (0.0352 mol) of 3-[(N-benzyl-piperidin-3-yl)-methyl]7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one are hydrogenated in 120 ml of glacial acetic acid in the presence of 1.5 g of 10% palladium/charcoal for 4 hours at 50° C. under 5 bar of hydrogen. The catalyst is then removed by suction filtering, the glacial acetic acid is distilled off in vacuo and, after the addition of water, the residue is neutralized with potassium carbonate. The greasy precipitate is extracted with methylene chloride, the organic phase is dried over magnesium sulphate and concentrated by evaporation in vacuo. Yield: 9.3 g (83% of theory), Melting point: 152°-156° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH3:2].[F:13][S:14]([O:17][CH3:18])(=[O:16])=[O:15]>C(Cl)Cl>[F:13][S:14]([O-:17])(=[O:16])=[O:15].[CH2:1]([N+:3]1[CH2:11][C:10]2[C:5]([C:4]=1[O:12][CH3:18])=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:2]
Reactant: COS(=O)(=O)F
Reactant: CCN1Cc2ccccc2C1=O
Solvent: ClCCl
Product: CC[N+]1=C(OC)c2ccccc2C1
Product: O=S(=O)([O-])F
Reaction time: 0.5 h

Procedure:
2-ethyl-1-(3H)-isoindolone (1.6 g) was dissolved in dry methylene chloride, and methyl fluorosulfonate (1.2 g) was was added. The reaction mixture was stirred for 30 minutes and then evaporated to dryness. The resuling oil was triturated with acetonitrile and ether. The solid intermediate compound was collected by filtration and used for preparing dyes without further purification.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11](=[O:14])([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=C>CC(C)=O.C(OCC)C>[CH2:11]([O:14][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:3](=[O:4])[CH3:2])[CH:17]=[CH2:18]
Reactant: O=C(CO)c1ccccc1
Reactant: C=CCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C(C)=O
Yield: 50 %

Procedure:
To a stirring suspension of 2-hydroxyacetophenone 72 (5 ml, 42 mmol) and potassium carbonate (6.516 g, 47 mmol, 1.1 equ) in acetone (30 ml) was added allyl bromide (4 ml, 46 mmol, 1.1 equ). The reaction was heated to reflux for 20 hours. The reaction was then concentrated in vacuo, taken up in water and extracted into ethyl acetate (2×). The organic layer was then dried (MgSO4) and concentrated in vacuo to give an yellow oil. This was taken up in diethyl ether, washed with 1M potassium hydroxide then dried (MgSO4) and concentrated in vacuo to give 1-(2-allyloxy-phenyl)-ethanone (3.70 g, 51%) as a pale yellow oil.
Reaction SMILES: C[C@@H](CCC)CCCO[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=O)=[CH:9][CH:8]=1.[CH3:19][C@@H:20]([CH2:36][CH2:37][CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1>>[CH2:11]([C:10]1[CH:9]=[CH:8][C:7]([O:32][C:31](=[O:33])[C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]([CH3:19])[CH2:36][CH2:37][CH3:38])=[CH:35][CH:34]=2)=[CH:15][CH:14]=1)[CH2:14][CH2:15][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCC[C@H](C)CCCCCOc1ccc(C(=O)O)cc1
Reactant: CCC[C@H](C)CCCOc1ccc(C(=O)O)cc1
Product: CCCCCCCCc1ccc(OC(=O)c2ccc(OCCCCC[C@@H](C)CCC)cc2)cc1

Procedure:
The procedure of Example 8 was followed except that the (S)-4-(4'-methylheptyloxy)benzoic acid was replaced by (S)-4-(6'-methylnonyloxy)benzoic acid to thereby give the title compound.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[NH2:8][CH2:9][C:10]1[C:18]2[S:17](=[O:20])(=[O:19])[N:16]=[C:15]([C:21]3[C:22](=[O:37])[N:23]([NH:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)[C:24]4[C:29]([C:30]=3[OH:31])=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:14][C:13]=2[S:12][CH:11]=1.C[S:39](Cl)(=[O:41])=[O:40]>CN(C)C=O>[CH:34]1([CH2:33][NH:32][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]([OH:31])=[C:21]([C:15]3[NH:14][C:13]4[S:12][CH:11]=[C:10]([CH2:9][NH:8][S:39]([CH2:6][CH3:7])(=[O:41])=[O:40])[C:18]=4[S:17](=[O:19])(=[O:20])[N:16]=3)[C:22]2=[O:37])[CH2:35][CH2:36]1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
To the suspension of the triethylamine salt of the product of Example 353E (85.26 mg, 0.16 mmol) in N,N-dimethylformamide (1.6 mL) was added triethylamine (48 μL, 0.34 mmol) and then methanesulfonyl chloride (13.3 μL, 0.17 mmol) at room temperature. The solution was stirred at room temperature for 20 minutes and concentrated in vacuo. The residue purified by reverse phase chromatography, eluting with 20% to 95% acetonitrile/0.1% triflouroacetic acid in water to give the title compound (39.86 mg, 49%). MS (ESI+) m/z 524 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 0.15 (m, 2 H) 0.42 (m, 2 H) 1.01 (m, 1 H) 2.84 (d, J=7.35 Hz, 2 H) 2.99 (s, 3 H) 4.29 (d, J=6.25 Hz, 2 H) 6.37 (br s, 1 H) 7.41 (m, 2 H) 7.75 (t, J=6.25 Hz, 1 H) 7.87 (m, 1 H) 8.08 (d, J=8.09 Hz, 1 H) 8.16 (m, 1 H) 14.46 (m, 1 H).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[CH:5][CH:4]=1.[K+].Cl[CH2:14][CH2:15][CH2:16]Cl.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O-:25])=[O:24])=[CH:21][CH:20]=1.[Na+]>CS(C)=O.CN1CCCC1=O.CN(C)C=O>[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:14][CH2:15][CH2:16][O:25][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([NH2:18])=[CH:20][CH:21]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(=O)[O-])cc1
Reactant: ClCCCCl
Agent: [K+]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: Nc1ccc(C(=O)OCCCOC(=O)c2ccc(N)cc2)cc1
Yield: 91.5 %

Procedure:
Japanese Kokai 58059949 A2 discloses the preparation of 1,3-propanediol-bis(p-aminobenzoate) by heating Cl(CH2)3R (R=Cl, Br) with sodium or potassium p-aminobenzoate in an aprotic dipolar solvent, e.g., dimethyl formamide, dimethyl sulfoxide, or N-methylpyrrolidone. Thus, 0.15 mol of Cl(CH2)3Cl was heated with 0.3 mol sodium p-aminobenzoate in dimethyl sulfoxide at 100° for three hours to give 91.5 percent 1,3-propanediol bis(p-aminobenzoate) of 97.4 percent purity as opposed to a 3 percent yield with ethylene glycol as solvent. Cl(CH2)nCl(n=2, 4, 5, 8), instead of Cl(CH2)3Cl, gave the corresponding alkylene bis(p-aminobenzoates) in much lower yield.
Reaction SMILES: [F:1][C:2]([F:21])=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6](NC(OC(C)(C)C)=O)[CH2:5][CH2:4]1.Cl>ClCCl.O1CCOCC1>[F:21][C:2]([F:1])=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)NN1CCC(=C(F)F)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC(F)=C1CCNc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 104.1 %

Procedure:
0.11 g of tert-butyl 4-difluoromethylene-3,4-dihydro-2H-quinoline-1-carbamate in 10 ml of dichloromethane is introduced into a round-bottomed flask equipped with a magnetic stirrer. 6 ml of a 4N solution of hydrochloric acid in dioxane are added. After stirring at ambient temperature for 6 h, the reaction medium is concentrated under vacuum. 0.07 g of 4-difluoromethylene-1,2,3,4-tetrahydroquinoline is obtained.
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[O:52])[CH2:10][CH2:11][S:12][CH2:13][CH:14]([O:34][C:35](=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:15][O:16][C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:35]([O:34][CH:14]([CH2:15][O:16][C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:13][S:12][CH2:11][CH2:10][C:9]([OH:52])=[O:8])(=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)OCc1ccc(OC)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid p-methoxybenzyl ester as obtained in Reference Example 3 (1.17 g), a solution of anisole (0.33 ml) in trifiuoroacetic acid (3.3 ml) was added at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was washed with hexane to yield the title compound (643 mg, yield 65%) as a powder.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]([C:24]2[C:28]3[CH:29]=[N:30][CH:31]=[C:32]([F:33])[C:27]=3[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=2)=[O:23])[CH:19]=[N:20][CH:21]=1>>[F:33][C:32]1[C:27]2[N:26]([CH:34]([CH3:37])[CH2:35][OH:36])[CH:25]=[C:24]([C:22]([C:18]3[CH:17]=[C:16]([NH:15][C:8](=[O:10])[CH2:7][N:6]4[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]4)[CH:21]=[N:20][CH:19]=3)=[O:23])[C:28]=2[CH:29]=[N:30][CH:31]=1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)Nc1cncc(C(=O)c2cn(C(C)CO)c3c(F)cncc23)c1

Procedure:
Prepared according to Method M (Example 206) using [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26). The residue was purified using preparative TLC eluting with 5% MeOH in EtOAc.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[Br:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[N:28]2)=[CH:23][CH:22]=1.O>CN(C=O)C>[Br:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[N:28]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.6 %

Procedure:
Triethylamine (8.9 mL, 64 mmol) and tert-butyl N-(3-aminopropyl)carbamate (30.95 g, 177.6 mmol) were added to a solution of 7-bromo-4-chloro-3-nitroquinoline (42.55 g, 148.0 mmol, U.S. patent application publication no. US 2004/0147543, Example 1, Parts A through D) in DMF (500 mL), and the reaction was stirred for four days at ambient temperature. The reaction mixture was poured into water (2 L), and a precipitate formed. The precipitate was isolated by filtration and dried in a vacuum oven overnight at 65° C. to provide 56.4 g of tert-butyl 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propylcarbamate.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[C:30]([OH:35])(=[O:34])[CH:31]([CH3:33])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH:31]([C:30]([OH:35])=[O:34])[CH3:33])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and allowed to cool, whereupon the product separates as off-white crystals.