Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[O:5][C:6]1[C:7]2[C:21]([F:22])=[CH:20][N:19]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)[N:11]=1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C(Cl)Cl>[F:22][C:21]1[C:7]2[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:34](=[O:37])[CH:35]=[CH2:36])[CH:33]=[CH:32][CH:31]=3)=[N:11][C:10]([NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[N:9][C:8]=2[N:19]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[CH:20]=1
Reactant: C=CC(=O)Cl
Reactant: Cn1ccc(Nc2nc(Oc3cccc(N)c3)c3c(F)cn(COCC[Si](C)(C)C)c3n2)n1
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccn(C)n3)nc3c2c(F)cn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.9 %

Procedure:
To a solution of 4-(3-aminophenoxy)-5-fluoro-N-(1-methyl-1H-pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (197 mg, 0.42 mmol) in DCM (20 mL) was added acryloyl chloride (34 μL, 0.42 mmol) and the reaction was stirred at rt for 45 min. Additional acryloyl chloride (34 μL, 0.42 mmol) was added and after another 2 hrs a final charge of acryloyl chloride (34 μL, 0.42 mmol) was added. After 30 min, the reaction was complete and was partitioned between DCM (30 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was separated, dried over Na2SO4 and evaporated to dryness. Purification via flash chromatography eluting with a gradient of 0%-80% EtOAc in heptane afforded the title compound (123 mg, 56 yield) as a solid. 1H NMR (400 MHz, methanol-d4) δ ppm 7.64 (s, 1H) 7.57 (d, J=8.81 Hz, 1H) 7.41 (t, J=8.18 Hz, 1H) 7.27 (d, J=1.76 Hz, 1H) 7.01 (dd, J=8.18, 2.14 Hz, 1H) 6.89 (d, J=2.27 Hz, 1H) 6.30-6.48 (m, 3H) 5.76 (dd, J=9.44, 2.14 Hz, 1H) 5.48 (s, 2H) 3.71 (s, 3H) 3.58 (t, J=8.06 Hz, 2H) 0.90 (t, J=8.06 Hz, 2H) −0.08 (s, 9H). m/z (APCI+) for C25H30FN7O3Si 524.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+]>C(O)C.[Pd]>[F:16][C:11]1[CH:10]=[C:9]([N:4]2[C:3](=[O:17])[CH:2]=[C:7]([OH:8])[CH:6]=[N:5]2)[CH:14]=[C:13]([F:15])[CH:12]=1
Reactant: O=c1c(Br)c(O)cnn1-c1cc(F)cc(F)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1cc(O)cnn1-c1cc(F)cc(F)c1

Procedure:
4-Bromo-2-(3,5-difluorophenyl)-5-hydroxypyridazin-3-one (0.6 g, 1.98 mmoles) was dissolved in ethanol (50 ml) and 1M sodium hydroxide (4 ml) was added. 10% Palladium on carbon (0.15 g) was added and the flask was placed under an atmosphere of hydrogen (balloon) with stirring. The reaction mixture was stirred overnight at room temperature. Filtered off the catalyst using Hyflo and evaporated to dryness. Added 2M hydrochloric acid and extracted into ethyl acetate. Washed with water and dried over anhydrous magnesium sulphate. Filtered and evaporated the filtrate to give a white solid. Triturated with diethyl ether to give the product as a white solid. (0.32 g, 72%)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]2=[O:19])(=[O:12])=[O:11])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.[N:23]1([CH2:32][C:33](O)=[O:34])[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25]>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:33](=[O:34])[CH2:32][N:23]3[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]3=[O:25])[CH2:15][C:14]2=[O:19])(=[O:12])=[O:11])=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: O=C1CNCCN1S(=O)(=O)c1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: Cl
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3c(Cl)cc(Cl)cc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]c1=O
Yield: 88.3 %

Procedure:
The title compound (919 mg, 88%) was synthesized by reaction of 1-(4,6-dichloro-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (781 mg, 2.0 mmol) with (thymin-1-yl)-acetic acid (368 mg, 2.0 mmol) as per the procedure of example 64. 1H-NMR (500 MHz; DMSO-d6) δ 11.34 (s, 0.6H), 11.32 (s, 0.4H), 8.42 (d, 0.4H), 8.41 (d, 0.6H), 8.32 (d, 0.4H), 8.30 (d, 0.6H), 7.35 (s, 0.6H), 7.27 (s, 0.4H), 4.69 (s, 1.2H), 4.58 (s, 0.8H), 4.42 (s, 0.8H), 4.27 (s, 1.2H), 4.11 (t, 1.2H), 3.97 (t, 0.8H), 3.93 (t, 1.2H), 3.82 (t, 0.8H), 1.74 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=2[F:19])[N:12]=[C:11]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:10]=1[CH3:27].I[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=2[F:19])[N:12]=[C:11]([N:21]2[CH2:26][CH2:25][N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][CH2:22]2)[C:10]=1[CH3:27]
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Cl
Reactant: Ic1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(N2CCN(c3ccccc3)CC2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinoline 2,2,2-trifluoroacetate (75.0 mg, 0.18 mmol) and iodobenzene (1.0 eq of triethylamine added to account for TFA salt) in toluene to give 4-chloro-5,7-difluoro-3-methyl-2-(4-phenylpiperazin-1-yl)-quinoline. Mass Spectrum (ESI) m/e=374.2 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:11]([N:12]3[CH2:16][CH:15]4[CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH:14]4[CH2:13]3)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]1([N:7]2[C:11]([N:12]3[CH2:13][CH:14]4[CH:15]([CH2:17][NH:18][CH2:19]4)[CH2:16]3)=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3nnnn3-c3ccccc3)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-n2nnnc2N2CC3CNCC3C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl 5-(1-phenyl-1H-tetrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (100 mg) was dissolved in 10% TFA solution in CH2Cl2 (10 mL). The reaction was stirred at room temperature for 24 hours. After removal of solvents, the residue, crude 2-(1-phenyl-1H-tetrazol-5-yl)octahydropyrrolo[3,4-c]pyrrole, was used in the further reactions without purification.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1)=O)C1C=CC=CC=1.[H][H]>CCO.[Pd].[C]>[N:16]1[C:17]2[NH:18][CH2:19][CH2:20][CH2:21][C:22]=2[CH:23]=[CH:24][C:15]=1[CH2:14][CH2:13][CH2:12][NH2:11]
Reactant: [H][H]
Reactant: O=C(NCCCc1ccc2cccnc2n1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NCCCc1ccc2c(n1)NCCC2

Procedure:
A mixture of 1-7 (0.40 g, 1.24 mmol) and 10% Pd/carbon (0.08 g) in EtOH (12 mL) was stirred under a balloon of hydrogen for 20 h. Filtration through a celite pad and then evaporative removal of the filtrate solvent gave 1-8 as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([N:15]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:16][CH:17]=[CH2:18])=[O:14])[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:7]=1.O[N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[O:35]=[C:26]1[C:27]2[C:28](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:30])[N:25]1[O:12][CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([C:13]([N:15]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:16][CH:17]=[CH2:18])=[O:14])[CH:5]=1
Reactant: C=CCN(C(=O)c1cc(Cl)cc(OCCCO)c1)C1CCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCCON2C(=O)c3ccccc3C2=O)c1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 33.3 %

Procedure:
A mixture of alcohol 17 (8.8 g, 26 mmol), tetrahydrofuran (100 mL), N-hydroxyphthalimide (3.8 g, 23 mmol) and triphenylphosphine (5.2 g, 20 mmol) was stirred at 0° C. for 5 min. To the mixture was added DEAD (3.4 mL, 20 mmol) dropwise. The reaction mixture was then allowed to warm to ambient temperature and stirred for 12 h prior to concentration in vacuo. The residue was purified by chromatography to provide phthalimide 18 (3.7 g) contaminated with Mitsunobu by-products. This material was used directly in subsequent experiments. 1H NMR (300 MHz, CDCl3) δ 7.78-7.85 (m, 2H), 7.73-7.77 (m, 2H), 6.94 (t, 2H), 6.38 (d, 1H), 5.95 (bs, 1H), 5.18 (d, 2H), 4.40 (t, 2H), 3.8-4.4 (m, 4H), 2.20-2.28 (m, 2H), 1.4-1.9 (m, 1H). Mass spectrum (CI) calcd. for C26H27N2O5Cl: 483 (M+H). Found: 483.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:23][NH2:24]>CCO>[NH:23]([C:16]([C:15]1[CH:20]=[CH:21][C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][CH:14]=1)=[O:17])[NH2:24]
Reactant: NN
Reactant: COC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a suspension of methyl 4-[(3-phenylpropanoyl)amino]benzoate (1.40 g, 4.94 mmol) in EtOH (16 mL) was added hydrazine hydrate (3.6 mL). After stirring for 16 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with water (4×5 mL) and drying under vacuo at 60° C. for 2 hrs gave 1.08 g of the title compound (77%) as a white solid in 99.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Na].[C:2](OCC)(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Na+].C(O[C:20](=[O:27])[CH:21]=[C:22]([NH2:26])[CH:23]1[CH2:25][CH2:24]1)C>C(O)C.O>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[C:20]([OH:27])=[CH:21][C:22]([CH:23]2[CH2:24][CH2:25]2)=[N:26][C:2]=1[OH:9])[CH3:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)C=C(N)C1CC1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(O)cc(C2CC2)nc1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Sodium metal (8.1 g, 119 mmol) was cut into small pieces and added portionwise to stirred ethanol (120 mL) at room temperature under a nitrogen atmosphere. The mixture was then stirred at 60° C. under N2 overnight to ensure complete dissolution of the metal. Diethyl malonate (18.1 ml, 119 mmol) was added to the sodium ethoxide solution at 60° C. and the mixture was stirred at 60° C. under N2 for 1 h. A solution 3-Amino-3-cyclopropyl-acrylic acid ethyl ester (10.3 g, 40 mmol) in ethanol (10 mL) was added dropwise at 60° C. and the mixture was heated at reflux under N2 for 5 days to give an orange suspension. The mixture was allowed to cool to room temperature and the resulting solid collected by filtration. The filtrate was concentrated in vacuo to give more solid. The combined solids were dissolved in water (150 mL) and the solution washed with EtOAc (150 mL). The aqueous was acidified to pH2 using concentrated HCl causing a white solid to precipitate. The solid was collected by filtration, washed with cold water and then Et2O, and then dried in vacuo at 40° C. overnight to give the title product (5.32 g) as a fine white solid. The filtrate was concentrated in vacuo to half its volume causing more product to precipitate. This second crop of solid was collected by filtration, washed with water and Et2O and dried in vacuo at 40° C. to give a further 0.35 g of the title compound as a pale beige solid.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[C:18]2[N:19]([CH3:24])[N:20]=[CH:21][C:22]=2[Br:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(N(C)C)=O.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>CS(C)=O>[CH:35]([O:34][C:32](=[O:33])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:12]([C:18]2[N:19]([CH3:24])[N:20]=[CH:21][C:22]=2[Br:23])[CH:13]=1)([CH3:37])[CH3:36]
Reactant: CC(C)OC(=O)Cl
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCCCC1
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: CC(C)OC(=O)Nc1ccc(OCCN2CCCCCC2)c(-c2c(Br)cnn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 4-(2-azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (0.06 g, 0.1539 mmol) 2.0 mL of DMA was added isopropyl chloroformate (0.021 g, 0.1687 mmol), and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted to 5.0 mL with DMSO and purified by RP-HPLC. The proper fractions were collected and evaporated to ¼ volume and the aqueous was neutralized with 1N NaOH to a pH 9.0. Next, the product was extracted with ethyl acetate (2×, 30 mL). The pooled organic layer was dried with sodium sulfate, filtered and evaporated to dryness to afford [4-(2-Azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-carbamic acid isopropyl ester as a colorless solid in 69% yield. LCMS m/z (%)=478 (M+H 79Br, 100), 480 (M+H 81Br, 98). 1H NMR (400 MHz, DMSO-d6) δ: 8.79 (bs, 1H), 8.69 (bs, 1H), 7.59 (s, 1H), 7.34 (d, J=2.62 Hz, 1H), 7.21-7.31 (m, 1H), 7.14 (d, J=9.04 Hz, 1H), 4.02-4.12 (m, 1H), 3.92-4.12 (m, 2H), 3.67 (s, 3H), 2.69-2.78 (m, 2H), 2.53-2.59 (m, 2H), 1.4-1.58 (bs, 8H), 1.26 (d, J=6.82 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2cc(F)cc(F)c2)sc1C(=O)NCc1ccccc1
Yield: 48 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3,5-difluorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 48% yield; m.p. 84-86° C.; 1H NMR (CDCl3, 300 MHz) δ 7.44-7.24 (m, 7H), 7.01 (tt, J=2.2, 8.4 Hz, 1H), 6.05 (s, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.41 (s, 3H); MS (ES+) m/z 388.1 (M+1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[F:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cccc(F)c4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3cccc(F)c3F)c2O1

Procedure:
The title compound was prepared (0.068 g, 60%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.148 g, 0.329 mmol) and methylamine (0.102 g, 3.29 mmol). mp 177-179° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH2:19][CH3:20])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2ncccc2c1
Yield: 81 %

Procedure:
To a solution of quinoline-6-carboxylic acid (2.8 g, 16 mmol) in ethanol (100 mL) was added concentrated sulfuric acid (2 mL). The reaction was heated to reflux overnight. The solvent was evaporated to give a brown residue that was taken up in ethyl acetate (150 mL). The mixture was washed with water (2×30 mL), saturated aqueous sodium bicarbonate (2×30 mL), and brine (2×30 mL). The organic layer was dried over sodium sulphate, filtered, and concentrated to an oil. Purification by flash column chromatography gave the title compound (2.0 g, 81%) as a brown solid.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:8]=[CH:9][C:10]([NH:12][C:13]1[C:14](=[CH:18][CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:15]([OH:17])=[O:16])=[O:11]>>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:8]=[CH:9][C:10]([NH:12][C:13]1[C:14](=[CH:18][CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:15]([O-:17])=[O:16])=[O:11].[Na+:2]
Reactant: COc1ccc(C=CC(=O)Nc2cc(Cl)ccc2C(=O)O)cc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C=CC(=O)Nc2cc(Cl)ccc2C(=O)[O-])cc1OC
Yield: 83.8 %

Procedure:
In 300 ml of an aqueous alcoholic solution (ethanol 1:water 1) containing 0.4 g of sodium hydroxide is added 3.6 g of N-(3,4-dimethoxycinnamoyl)-4-chloroanthranilic acid and the mixture is warmed to be completely dissolved. The solution is concentrated under a reduced pressure, the residue is dissolved in 200 ml of warmed ethanol and to this solution is added 900 ml of ether. The precipitated crystals are collected by filtration and dried under reduced pressure to obtain 3.2 g of sodium N-(3,4-dimethoxycinnamoyl)-4-chloroanthranilate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([O:27]C)[C:21]=3[O:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:27])[C:21]=3[O:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc2c1Oc1ccccc1C21CCN(Cc2ccccc2)CC1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cccc2c1Oc1ccccc1C21CCN(Cc2ccccc2)CC1

Procedure:
1'-Benzyl-4-methoxyxanthene-9-spiro-4'-piperidine is demethylated using 45% w/v hydrobromic acid in glacial acetic acid as described in Example 4 to give 1'-benzyl-4-hydroxyxanthene-9-spiro-4'-piperidine converted to its hydrochloride, m.p. 164° C. on recrystallisation from ethanol-ether.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=Cc1cn(S(=O)(=O)c2ccc(F)cc2)c2ccccc12

Procedure:
The same procedures used in Example 17 were repeated except for using 870 mg of indole-3-carbaldehyde and 4-fluorobenzenesulfonyl chloride instead of the benzenesulfonyl chloride used in Example 17 to give 1.73 g of 1-(4-fluorobenzenesulfonyl)indole-3-carbaldehyde as brown crystals. The yield thereof was found to be 95%.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH:8]1C=CC=CC=1.CO.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH2:25][CH:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)[CH3:27]>CC(O)=O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH2:25][CH:26]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:8])=[O:33])=[CH:35][CH:36]=1)[CH3:27]
Reactant: COc1ccc(Br)c(CC(C)c2ccc(C(=O)O)cc2)c1
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(C(C)Cc2cc(OC)ccc2Br)cc1

Procedure:
(Trimethylsilyl)diazomethane (2.0M hexanes, 4.8 mL) was added dropwise to a benzene/MeOH solution (7/3, 50 mL) containing the intermediate from Step A (2.8 g, 8.0 mmol). After 20 minutes AcOH was added dropwise to quench the excess reagent. The solution was concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.98 (d, J=8.2 Hz, 2H); 7.43 (d, J=8.2 Hz, 1H); 7.29 (d, J=8.2 Hz, 2H); 6.63 (dd, J=3.0, 8.7 Hz, 1H); 6.50 (d, J=3.0 Hz, 1H); 3.93 (s, 3H); 3.68 (s, 3H); 3.26-3.19 (m, 1H); 2.96 (d, J=7.0 Hz, 2H); 1.34 (d, J=6.9 Hz, 3H). LCMS1 4.14 min. (M-31)=331
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([C:23](O)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)C1CCCC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCCC4)cc23)CC1

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.0 mg (0.10 mMol) cyclopentanecarboxylic acid, 16.4 mg (100+%) of the title compound were recovered.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(N(CCCC)CCCC)CCC.C(O)C.[CH3:29][C:30]1[C:35]2[C:36]([NH2:41])=[N:37][C:38]([NH2:40])=[N:39][C:34]=2[CH:33]=[CH:32][C:31]=1[CH2:42][NH:43][C:44]1[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=1.FC(F)(F)C([O-])=O>CC(O)C>[CH3:29][C:30]1[C:35]2[C:36]([NH2:41])=[N:37][C:38]([NH2:40])=[N:39][C:34]=2[CH:33]=[CH:32][C:31]=1[CH2:42][NH:43][C:44]1[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=1.[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OC
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(C)O
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
This part of the preparation was carried out, as far as possible, under a nitrogen atmosphere. Equivalent quantities of ascorbic acid (0.463 g) and tributylamine (0.487 g) were heated in 20 ml of 200 proof ethanol at 60° C. to give a clear solution. This was cooled to room temperature and a half-equivalent of trimetrexate trifluoroacetate (0.635 g; assumed unsolvated) added and the mixture heated to near reflux to give a clear yellow solution. To the hot solution was added 50 ml of 2-propanol. A light-colored flocculent solid was immediately precipitated. The mixture was heated at 50° C. for 3 minutes, and then allowed to stand in air for about 1.5 hours. The solid was collected, washed with 2:1 2-propanol/ethanol at room temperature, and immediately transferred to a desiccator and dried (diaphragm pump vacuum) over P2O5 to give 0.425 g of the salt as a very pale yellow-green powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])/[CH:5]=[CH:6]/[C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:16])[CH2:9][CH2:8]1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:16])[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)/C=C/[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of 3.8 g (11.2 mmol) trans-3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-(E)-acrylic acid ethyl ester and 400 mg of palladium (10% on carbon) in 40 ml of methanol was stirred for 20 hours at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration and the solvent evaporated under reduced pressure to give 3.67 g of crude trans-3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-propionic acid ethyl ester as colorless viscous oil, MS: 359 (MNH4+).