Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CS(O[CH2:18][CH:19]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH3:20])(=O)=O>CN(C)C=O>[CH3:25][S:22]([O:21][CH:19]([CH3:20])[CH2:18][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])(=[O:24])=[O:23]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(COS(C)(=O)=O)OS(C)(=O)=O
Agent: [K]
Solvent: CN(C)C=O
Product: CC(CN1C(=O)c2ccccc2C1=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
5.55 g (30 mmoles) of potassium phthalimide are added in small portions, within 1 hour, to a solution of 7.0 g (30 mmoles) of 1,2-bis(methanesulfonyloxy)-propane in 70 ml of dry dimethyl formamide, heated to 100°-105° C. The mixture is stirred at the same temperature for additional 0.5 hours, thereafter it is cooled and poured onto 350 ml of ice water. The separated crystalline substance is filtered off, washed with water and dried. This crude product, weighing 4.36 g (m.p.: 111°-121° C.) is recrystallized from 25 ml of isopropanol to obtain 3.53 g (41.5%) of N-(β-methanesulfonyloxy-propyl)-phthalimide; m.p.: 129°-132° C.
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]([N:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)[C:2]([C:28]2[CH:29]=[C:30]3[C:22]([CH3:21])=[CH:23][NH:24][C:25]3=[N:26][CH:27]=2)=[N:3]1)([CH3:20])[CH3:19]
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
Reactant: Cc1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1c[nH]c2ncc(-c3nn(C(C)C)cc3-c3ccnc(NC[C@H](C)O)n3)cc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (9) (0.65 g, 1.7 mmol) in toluene (21 mL) and EtOH (7 mL) were added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine 21 (0.7 g, 2.37 mmol in theory) and 2 N aq. Na2CO3 (2.5 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (0.19 g, 0.17 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(1-isopropyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-5) (0.150 mg, 16.2%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[CH:17]=[C:16]([CH2:18][C:19]4[CH:20]=N[CH:22]=[CH:23][CH:24]=4)[C:15](=[O:25])[C:14]4[C:9]3=[C:10]([CH:11]=[CH:12][N:13]=4)[C:4]=2[CH:3]=1.[CH:26](=O)C1C=CC=CC=1>>[CH2:18]([C:16]1[C:15](=[O:25])[C:14]2[C:9]3=[C:10]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=4[N:8]3[CH:17]=1)[CH:11]=[CH:12][N:13]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:26][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Cl)cc3c3ccnc1c32
Product: O=c1c(Cc2ccccc2)cn2c3ccc(Cl)cc3c3ccnc1c32
Yield: 21.6 %

Procedure:
According to Example 1<step 4>, the compound (200 mg) produced in Example 23<step 4> was reacted with benzaldehyde (132 mg) to obtain the title compound (43 mg; 16%).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.C(Cl)CCl.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>ClCCl>[OH:9][C:8]1[CH:10]=[C:2]([CH:3]=[C:4]([OH:5])[C:6]=1[OH:7])[C:1]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:12]
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1ccccc1-c1cc2ccccc2[nH]1)c1cc(O)c(O)c(O)c1

Procedure:
A 25-mL one-necked recovery flask equipped with a stirring bar and a septum was charged with gallic acid (176 mg; 1.03 mmol; 1.00 equiv). A clear, colorless solution was formed on addition of 5 mL of dichloromethane. Solid EDC (197 mg; 1.03 mmol; 1.00 equiv) and 2-(2-aminophenyl)indole (194 mg; 0.932 mmol; 0.904 equiv) were added sequentially as solids. The reaction was worked up after 24 h by extraction with 10 mL of NaHCO3 (satd aq). The organic layer was dried (anhydrous sodium sulfate), filtered and concentrated by rotary evaporation to yield a yellow oily paste. The crude was purified using DCM-MeOH (19:1) to yield a light yellow solid (230 mg; 68%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24](Cl)=[C:23](Cl)[N:22]=[N:21][CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:22]1[CH:23]=[CH:24][C:19]([NH:18][CH2:17][CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[CH:20][N:21]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2cnnc(Cl)c2Cl)CC1
Agent: [Pd]
Solvent: CCO
Product: c1cc(NCC2CCNCC2)cnn1

Procedure:
A mixture of 4-[(5,6-dichloro-pyridazin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 65, 2.00 g, 5.06 mmol), Pd/C (10%, 0.20 g) in absolute ethanol (15 mL) was vigorously stirred under 1 atm H2 provided by a H2 balloon for 7 h. Filtered and concentrated, the reaction gave 4-[(Pyridazin-4-ylamino)-methyl]-piperidine. M.S. (M+1): 193.25
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1N
Product: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J2) (170 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (308 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.[C:13]1([C@H:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:21][C@@H:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:20])[CH:6]=[N:5]2
Reactant: Clc1cnc2cc(Br)ccc2n1
Reactant: C[C@@H](N)c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H](Nc1cnc2cc(Br)ccc2n1)c1ccccc1
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 6-Bromo-2-chloro-quinoxaline (0.45 g, 1 eq, 1.85 mmol) in DMSO (6 mL), was added (R)-1-phenylethanamine (0.67 g, 3 eq, 5.55 mmol) at room temperature. The mixture was stirred overnight. After completion of the reaction (confirmed by TLC), cold water (40 mL) was added to the reaction mixture and this was stirred for 1 hour at room temperature. The precipitate was filtered off, washed with water (10 mL) and then dried under vacuum to afford the title compound (0.48 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C@H:7]2[CH2:12][C@@H:11]([C:13](=[O:20])[CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[NH2:30]O.Cl>CO.CO.O.O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:20][NH:30][C:15](=[O:16])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(Cl)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
A solution of cis-methyl 2-(4-chlorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.45 g, 3.80 mmol) in MeOH (10 mL) was added to a solution of sodium hydroxide (3.16 mL, 3.80 mmol) in MeOH/H2O (2.981 mL/0.179 mL) at −30° C. After 10 min a solution of hydroxylamine hydrochloride (0.528 g, 7.59 mmol) and sodium hydroxide (0.304 g, 7.59 mmol) in MeOH (10 mL) and H2O (10 mL) was added. Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (6.33 mL, 37.97 mmol) at 80° C. and heated at 80° C. for 1 hour. Concentration of the organic solvent and extraction with diethyl ether (×3), drying over Na2SO4 and evaporation gave a yellow foam. Purification using prepLC (2 injections, pH=3, large column 20-80% MeCN over 30 min) yielded cis-methyl 2-(4-chlorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (557 mg, 41%). 1H NMR (400 MHz, cdcl3) δ 1.83-2.00 (m, 3H), 2.02-2.12 (m, 1H), 2.59 (dd, 1H), 2.77 (dd, 1H), 2.97-3.02 (m, 1H), 3.08-3.20 (m, 1H), 3.62 (s, 3H), 4.00 (dd, 1H), 4.21-4.29 (m, 1H), 5.73 (s, 1H), 7.04 (d, 2H), 7.21-7.25 (m, 2H). MS m/z 351, 353 (M+H)+
Reaction SMILES: [N:1]([CH:4]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[O:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[O:15])=[CH:12][CH:11]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH:4]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[O:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[O:15])=[CH:12][CH:11]=1
Reactant: CCOC(CCCNC(=O)c1ccc(COc2cccc(C(N=[N+]=[N-])c3ccccc3)c2)cc1)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(CCCNC(=O)c1ccc(COc2cccc(C(N)c3ccccc3)c2)cc1)OCC
Temperature: 60 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a solution of 4-((3-(azido(phenyl)methyl)phenoxy)methyl)-N-(4,4-diethoxybutyl)benzamide (0.51 g, 1.03 mmol) in tetrahydrofuran (10 mL), was added polymer supported triphenylphosphine (3 mmol/g, 0.38 g, 1.13 mmol) and water (0.2 mL). The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered, the filter-cake washed with dichloromethane and concentrated under reduced pressure to give the title compound (0.41 g, 83%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>CS(C)=O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a sealed tube were added 5-bromo-2-nitropyridine 125-1 (5.1 g, 25.2 mmol), tert-butyl piperazine-1-carboxylate 125-2 (4.7 g, 25.2 mmol), DIEA (12 mL, 75 mmol) and DMSO (20 mL). The reaction was heated to 120° C. and stirred for 16 hours. The reaction was cooled down to room temperature. Triethylamine was removed by rotary evaporation. The residue was triturated in 15 mL ethyl acetate. The solid was collected by filtration and washed with small amount of ethyl acetate to give tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 125-3 as light yellow solid. MS m/z 309.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[Br:10]N1C(=O)CCC1=O>CN(C=O)C>[Br:10][C:6]1[CH:7]=[C:2]([F:1])[C:3]([OH:9])=[C:4]([F:8])[CH:5]=1
Reactant: Oc1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Oc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
To a solution of 2,6-Difluorophenol (10.0 g, 76.86 mmoles) in DMF (60 mll), N-bromosuccinimide (13.68 g, 76.86 mmoles) was added at 0° C. and stirred at RT for 20 h. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as light yellow liquid (15.1 g, 93% yield). 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 10.49(s,1H), 7.35 (d, J=6.2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:11])[N:10]=[C:2]([Cl:1])[CH:3]=1)[CH3:18]
Reactant: CCO
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Cl)nc(Cl)c1
Reaction time: 6 h

Procedure:
2,6-Dichloroisonicotinic acid (4.0 g) (prepared according to M. M Robinson, J.Amer.Chem.Soc. 80,5481,1958) was dissolved in ethanol (20 ml) and concentrated sulphuric acid (1 ml). After 6 hours at 80°, the solution was cooled, concentrated in vacuo and the residue worked up in the usual manner to give ethyl-2,6-dichloroisonicotinate (3.7 g). NMR 1H: 7.84(2H,s), 4.48(2H,q), 1.48(3H,t).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:10][C:11]1[C:16]([F:17])=[C:15]([CH:18]=O)[CH:14]=[CH:13][N:12]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[Cl:10][C:11]1[C:16]([F:17])=[C:15]([CH2:18][N:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[CH:14]=[CH:13][N:12]=1
Reactant: O=Cc1ccnc(Cl)c1F
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(Cc2ccnc(Cl)c2F)CC1

Procedure:
1-Acetylpiperazine (0.164 g 1.28 mmol)was dissolved in 5 mL DCE and the resulting solution was added to 2-chloro-3-fluoro-pyridine-4-carbaldehyde (14-2, 0.170 g, 1.07 mmol). NaBH(OAc)3 (0.248 g, 1.17 mmol) was added followed by the addition of 0.100 mL of HOAc. After 45 min the reaction was quenched with sat NaHCOC3 (aq). The mixture was extracted 3× with DCM, and the organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (10 g column, DCM (for 4 min) gradient to 95:5 DCM/MeOH (over 8 min)), desired comes off shortly after 95:5 is attained (13 min) affording good separation from close peak preceeding desired. Afforded pure titled compound. 1H NMR (CDCl3) δ8.18 (d, 1H, J=4.9 Hz), 7.38 (t, 1H, J=4.6 Hz), 3.66 (m, 4H), 3.50 -3.48 (m, 2H), 2.50-2.46 (m, 4H), 2.09 (s, 3H).
Reaction SMILES: [CH2:1]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[CH2:26](O)[CH3:27]>>[CH2:1]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([C:22]([O:24][CH2:26][CH3:27])=[O:23])=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCO
Reactant: CCCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Agent: Cl
Product: CCCCCCCCCCCCc1cc2cc(C(=O)OCC)ccc2[nH]1

Procedure:
A solution of 2-(n-dodecyl)indole-5-carboxylic acid (13.8 g) in ethanol (80 ml) containing a solution of hydrogen chloride gas in ethanol (100 ml of strength 39% w/v) was refluxed for 6 hours. The solid which separated on cooling was collected and was recrystallised from ethanol to give ethyl 2-(n-dodecyl)indole-5-carboxylate (11.2 g), in the form of a buff powder, m.p. 77°-79° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CS(C)=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][N:8]1[CH2:7][C:6]2[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]1=2)[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)Oc1ccccc1NC2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CN1Cc2ccc(OC)cc2Oc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 1-4 (2.04 g, 8.97 mmol) in DMSO (10 mL) was cooled to 0° C. and treated with sodium hydride (450 mg of 60% in oil, 11.2 mmol). The reaction mixture was warmed to room temperature for 15 min, followed by addition of ethyl bromoacetate (1.67 g, 10.0 mmol) and warming to 50° C. overnight. The solvent was removed in vacuo and the residue diluted with water and extracted with three portions of dichloromethane. The combined organic extracts were washed with brine and dried (Na2SO4). The solvent was removed in vacuo. Preparative centrifugal chromatography (SiO2, 6 mm, 50% EtOAc, 50% hexane) afforded 1-5.
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Si:11]([O:28][CH2:29][CH2:30][C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>S(Cl)(Cl)=O.C(Cl)Cl>[Si:11]([O:28][CH2:29][CH2:30][C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[NH:33][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[F:1])([C:24]([CH3:27])([CH3:25])[CH3:26])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](OCCc1ccccc1N)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccnc1F
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)[Si](OCCc1ccccc1NC(=O)c1cccnc1F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A mixture of 2-fluoronicotinic acid (Aldrich, 0.42 g, 2.9 mmol) in thionyl chloride (15 mL) was refluxed for two hours before being concentrated in vacuo to a residue which was used without further purification. The residue was dissolved in anhydrous DCM (5 mL) then added dropwise to a 0° C. solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)aniline (1.10 g, 2.9 mmol) and TEA (0.43 mL, 3.1 mmol) in anhydrous DCM (15 mL). The reaction was then stirred at ambient temperature for 16 hours before being quenched with water then stirred for an additional thirty minutes. The layers were separated and the aqueous layer extracted with DCM. The combined organic layers were washed sequentially with water, saturated aqueous NaHCO3, and brine before being dried over anhydrous MgSO4, and then concentrated in vacuo. The resultant residue was purified by silica gel flash chromatography, eluting with 4:1 hexane/EtOAc, to afford the desired compound as a white solid (1.1 g, 72%). 1H NMR (DMSO-d6) δ 9.93 (s, 1H), 8.41 (d, 1H, J=4.4 Hz), 8.22 (t, 1H, J=7.6 Hz), 7.27-7.60 (m, 15H), 3.84 (t, 2H, J=6.7 Hz), 2.98 (t, 2H, J=6.7 Hz), 0.92 (s, 9H); HRMS(ESI+), 499.2217 (M+H)+ calc, 499.2230 (M+H)+ found.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH:13]=1)([O-])=O>O.C(O)C>[NH2:9][C:12]1[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH:13]=1
Reactant: COc1ccc2c(=O)c([N+](=O)[O-])coc2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(=O)c(N)coc2c1
Reaction time: 0.25 h

Procedure:
Sodium dithionite (140 g, 0.804 mole) was added to a suspension of 3-nitro-7-methoxy-4H-1-benzopyran-4-one (50 g, 0.261 mole) in water (330 ml) and absolute ethanol (110 ml). The reaction mixture was stirred for 15 min., concentrated at reduced pressure and filtered. The solids were washed with water and recrystallized from ethyl acetate to give light brown crystals, 159°-162°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29]O[CH2:27][CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([NH:20][CH3:21])=[O:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[O:30]1[C:34]2(CCC(=O)CC2)[O:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29][C:34]4([O:33][CH2:32][CH2:31][O:30]4)[CH2:27][CH2:26][C:11]=3[N:12]([C:14]([NH:16][C@@H:17]([C:22]([CH3:23])([CH3:25])[CH3:24])[C:18]([NH:20][CH3:21])=[O:19])=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCC1(C2)OCCO1)C(C)(C)C

Procedure:
Compound 63 was prepared according to the procedure described for the synthesis of compound 28 by replacing tetrahydro-4H-pyran-4-one with 1,4-dioxaspiro[4.5]decan-8-one in the synthesis of intermediate 16. LCMS (+ESI) m/z=463.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH:2]=1.Br[C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:38])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:26][CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C(C)=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:37][N:34]1[CH2:33][CH2:32][N:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:23]([NH:22][C:17]3[CH:16]=[CH:15][C:20]([CH3:21])=[C:19]([NH:13][C:9]4[N:8]=[C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH:12]=[CH:11][N:10]=4)[CH:18]=3)=[O:38])=[CH:25][CH:26]=2)[CH2:36][CH2:35]1
Reactant: Nc1nccc(-c2cccnc2)n1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 4-(3-pyridyl)-2-pyrimidine-amine (172.2 mg, 1.0 mmol), N-(3-bromo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide (402.4 mg, 1.0 mmol) and sodium tert.-butylate (144.2 mg, 1.5 mmol) is added a mixture of rac-BINAP (31.2 mg, 0.050 mmol) and Pd2(dba)3*CHCl3 (13 mg, 0.013 mmol) under argon. After addition of 3 ml of xylene the suspension is sonicated for 10 minutes then stirred for 5 hours under reflux. After cooling to room temperature, water (10 ml) is added to the dark brown oil and the product extracted 4 times with methylene chloride (10 ml each). The combined organic extracts are dried over MgSO4 and concentrated in vacuo. The brown oil is purified by flash-chromatography (SiO2, methanol). The product, a pale yellow solid is dissolved in methylene chloride, filtered and concentrated in vacuo. Yield: 484.3 mg of the title compound, 72% of theory, (99.9% area by HPLC). The product contains typically roughly 10% of isomers which can be eliminated by preparative reversed phase chromatography.