Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:20]=[O:21].Cl>O1CCCC1.CCCCCC>[O:10]1[C:4]2[CH:3]=[C:2]([CH:20]=[O:21])[CH:12]=[CH:11][C:5]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)OCCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)OCCCC2
Temperature: 25 °C
Yield: 105.8 %

Procedure:
To a solution of 2.01 g (8.8 mmol) of 8-bromo-2,3,4,5-tetrahydro-1-benzoxepine in 54 mL of anhydrous tetrahydrofuran and 13.5 mL of hexane under nitrogen cooled in a dry ice/acetone bath was added dropwise 4.1 mL (10.2 mmol, 1.15 equiv) of 2.5M n-butyllithium in tetrahydrofuran, keeping the internal temperature <−65° C. The mixture was stirred with cooling for 45 minutes. A solution of 1.03 mL (13.3 mmol, 1.5 equiv) dimethylformamide in 9 mL of anhydrous tetrahydrofuran was added dropwise over 5 minutes. The mixture was stirred overnight while warming to ambient temperature. The reaction mixture was poured into 81 mL of 2N HCl, and the layers were separated. The aqueous layer was extracted with 3×85 mL of ether. The combined organic layer was washed with 75 mL each of water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1.64 g of a yellow oil. Purification by flash chromatography (5-40% ethyl acetate in hexanes) gave the product as a colorless oil. MS (m+1)=177.2; 1H NMR (400 MHz, CDCl3) 9.92 (s, 1H), 7.49 (m, 2H), 7.29 (d, 1H, J 7.5 Hz), 4.03 (m, 2H), 2.89 (m, 2H), 2.00 (m, 2H), 1.76 (m, 2H).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:34]2[N:33]=[C:32](N)[N:31]=[C:23]([NH:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]=2[N:21]=[CH:20]1)(=O)C.[F:36][B-](F)(F)F.[H+].N([O-])=O.[Na+]>C1COCC1>[F:36][C:32]1[N:31]=[C:23]([NH:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:22]2[N:21]=[CH:20][N:19]([C:34]=2[N:33]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(F)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
The above 2',3',5'-tri-O-acetyl-N-(1-piperidinyl)adenosine (1.33 g, 2.7 mmol) was dissolved in THF (50 ml) and the temperature of the solution was held between -10° C. and -20° C. Fluoroboric acid (48%, 100 ml) was added followed by an aqueous solution of sodium nitrite (0.75 g/ml, 1.5 ml). Addition of three identical amounts of sodium nitrite was continued at 0.3 hour intervals, after which TLC investigation (on a neutralised sample) indicated that the starting material was consumed [rf 0.47 (SiO2, ethyl acetate/methanol (90/10))]. The pH of the reaction mixture was adjusted to ca. 6 with 50% sodium hydroxide solution with cooling to below 0° C. and the now red reaction mixture was diluted with water (250 ml). The solution was extracted with chloroform (2×100 ml) and the combined extracts were dried (MgSO4). The residue on evaporation (containing 2',3',5'-tri-O-acetyl-2-fluoro-N-(1-piperidinyl)adenosine was treated with methanolic ammonia (150 ml) (previously saturated at -10° C.) and stirred at room temperature for 72 hours. The reaction mixture was evaporated and the resultant residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (0-10%) to provide the title compound (0.093 g) as a white solid, after washing with ethyl acetate. M.p. 197°-199° C.; 1H NMR (400 MHz, Me2SO-d6) δ3.57, 3.65 (2H, ABX, H-5'a and H-5'b), 3.92 (1H, q, H-4'), 4.12 (1H, m, H-3'), 4.50 (1H, q, H-2'), 5.80 (1H, d, H-1'), 8.35 (1H, s, H-8). HPLC retention time 10.12 (gradient elution, 5-25% acetonitrile/0.1M pH 3.3 ammonium sulphate buffer: 214 nm detector): 100% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)=[C:12]([CH:16]=2)[C:13]([OH:15])=[O:14])[CH:5]=[N:6][CH:7]=1.[CH2:23](Cl)[CH2:24]Cl.C1C=CC2N(O)N=NC=2C=1.ClC1C=C(CN)C=CC=1OC.CN1CCOCC1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)=[C:12]([CH:16]=2)[C:13]([O:15][CH2:23][CH3:24])=[O:14])[CH:5]=[N:6][CH:7]=1
Reactant: Cc1cncc(-c2ccc(-c3cnccn3)c(C(=O)O)c2)c1
Reactant: ClCCCl
Agent: COc1ccc(CN)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cc(-c2cncc(C)c2)ccc1-c1cnccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of the carboxylic acid (3-4, 0.062 g, 0.186 mmol, 1 equiv), EDC (0.053 g, 0.279 mmol, 1.5 equiv), and HOBt (0.045 g, 0.297 mmol, 1.6 equiv) in DMF (1 mL), 1-(3-chloro-4-methoxyphenyl)methanamine (0.045 g, 0.260 mmol, 1.4 equiv) was added followed by N-methylmorpholine (0.102 mL, 0.929 mmol, 5 equiv) and the reaction was stirred overnight at room temperature The reaction mixture was filtered and put on a reverse phase preparative HPLC system running acetonitrile/water with a TFA buffer (5 to 75% CH3CN in water). The cleanest fractions were pooled, concentrated and freebased to afford the product (3-5) as a white solid. Data for H-1: HRMS [M+H] C25H21ClN4O2 calc'd 445.1426. found 445.1439.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12].[CH3:17][C:18]([CH3:20])=O>>[CH3:12][C:11]1([CH3:13])[N:14]([CH:18]([CH3:20])[CH3:17])[C:15](=[O:16])[N:6]2[C:2]([N:3]([C:15]([NH:14][CH:11]([CH3:13])[CH3:12])=[O:16])[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)=[N:1]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CC(C)=O
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)N1C2=NC(C)(C)N(C(C)C)C(=O)N2c2ccccc21

Procedure:
The title compound was prepared from 2-aminobenzimidazole, acetone and isopropyl isocyanate employing the method of the first paragraph of Example 1. The product was purified by column chromatography on silica, eluting with chloroform to give a white solid, mp 80°-89° C. The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][C:15]1[CH:16]=[C:17]([C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[CH:18]=[CH2:19].Cl>CN(C=O)C>[CH3:14][C:15]1[CH:16]=[C:17]([CH2:18][CH2:19][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1
Reactant: C=Cc1cc(C)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1cc(C)ccc1[N+](=O)[O-])C(=O)OCC
Temperature: 60 °C
Yield: 28.4 %

Procedure:
To a suspension of 60% sodium hydride (1.36 g, 34 mmol) in DMF (35 mL) was added diethyl malonate (7.00 g, 43.7 mmol). The mixture was heated at 60° C. for 1.5 h, allowed to cool at room temperature and 3-methyl-6-nitrostyrene (4.80 g, 29.4 mmol) in DMF (10 mL) was added dropwise. The mixture was again heated at 4°~50° C. for 4 h, poured into 0.1N hydrochloric acid, and extracted with a 1:1 toluene/ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 10:1 hexane/ethyl acetate to give 2.70 g of the title compound (28%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[N:24]=[CH:25][C:26]4[CH:31]=[CH:30][NH:29][C:27]=4[N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2[CH2:17]C2)[CH2:12][CH2:11][CH2:10][CH2:9]1.[H][H]>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:31]4[CH:26]=[CH:25][NH:24][C:30]=4[N:29]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH2:15][CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: [H][H]
Reactant: c1cc2cnc(-c3cnn(C(CC4CC4)C4CCCC4)c3)nc2[nH]1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoro-acetate salt (prepared in Example 729) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a catalytic amount of 5% Pd—C was added. The mixture was stirred under 1 atmosphere of hydrogen via an affixed balloon. After 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford the product (14 mg, 69%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:2]=1.[CH:17]1([Bi](C2CC2)C2CC2)[CH2:19][CH2:18]1.N1C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Cu+2].ClCCl>[CH:17]1([N:12]2[C:13]3[C:9](=[CH:8][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:15][CH:14]=3)[CH2:10][C:11]2=[O:16])[CH2:19][CH2:18]1
Reactant: O=C1Cc2cc(-c3cccnc3)ccc2N1
Reactant: C1CC1[Bi](C1CC1)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2cc(-c3cccnc3)ccc2N1C1CC1
Temperature: 75 °C

Procedure:
To 5-pyridin-3-yl-1,3-dihydro-indol-2-one (CAS#220904-98-3, 63 mg, 0.3 mmol) was added freshly prepared tricyclopropyl-bismuthine [(J. Am. Chem. Soc., 2007, 129, 44-45), CAS#925430-09-7, 250 mg, 0.75 mmol], Cu(OAc)2 (82 mg, 0.45 mmol) and dichloromethane (3 ml). The reaction mixture was degassed by sparging with argon for 5 min. Then pyridine (0.073 ml, 0.9 mmol) was added and the reaction was heated at 75° C. for 1.5 hr. The reaction mixture was cooled to room temperature and then directly loaded on to a silica gel flash chromatography column. The 1-cyclopropyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one was eluted via a gradient of ethyl acetate-heptane (0 to 100%); HRMS: (ESI) m/z 251.1173 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.88-1.01 (m, 2H), 1.07-1.19 (m, 2H), 2.60-2.76 (m, 1H), 3.60 (s, 2H), 7.22-7.31 (m, 1H), 7.49 (s, 1H), 7.55 (d. J=8.5 Hz, 1H), 7.81 (br. s., 1H), 8.36 (d, J=7.7 Hz, 1H), 8.63 (br. s., 1H), 8.92 (br. s., 1H.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:8]=[C:7]2[CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.[H-].[Na+].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[S:37]([Cl:40])(=[O:39])=[O:38]>C1COCC1>[ClH:40].[CH3:1][C:2]1[CH:3]=[C:4]([O:26][S:37]([C:31]2[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:30]=2[F:29])(=[O:39])=[O:38])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:8]=[C:7]2[CH:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: Cc1cc(O)cc2c(C3CCN(C)CC3)cn(CCc3ccccc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OS(=O)(=O)c2c(F)cccc2F)cc2c(C3CCN(C)CC3)cn(CCc3ccccc3)c12
Product: Cl
Yield: 44.1 %

Procedure:
By a method similar to Example 56, using 7-methyl-3-(1-methylpiperdin-4-yl)-1-phenethyl-1H-indol-5-ol (0.55 mmol, 0.190 g) in THF (1.4 mL), sodium hydride (0.65 mmol, 0.026 g, 60% dispersion in mineral oil), and 2,6-diflurobenzenesulfonyl chloride (0.60 mmol, 0.128 g) afforded 0.136 g (44%) of the title compound: MS (ion spray): m/z=511 (M+1); 1H NMR (DMSOd6): 7.97-7.87 (m, 1H), 7.45-7.38 (m, 2H), 7.29-7.17 (m, 2H), 7.13 (d, 2H), 6.63 (d, J=1.10 Hz, 1H), 4.53 (t, J=7.50 Hz, 2H), 3.47-3.39 (m, 2H), 3.11-2.95 (m, 4H), 2.87-2.69 (m, 4H), 2.60 (s, 3H), 1.94-1.71 (mm, 4H); Calculated for C28H28F2N2O3S-1.9 H2O: C, 61.73; H, 5.88; N, 5.14. Found: C, 61.43; H, 5.51; N, 4.93.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=1.CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[N:1]1([C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=2)[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC(=O)c1cncc(N)c1
Reactant: COC1CCC(OC)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cncc(-n2cccc2)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of methyl 5-amino-3-pyridinecarboxylate (1.7 g) and 2.5-dimethoxytetrahydrofuran (2.2 g) in acetic acid (5 ml) was refluxed for 30 minutes. After being cooled to room temperature, the reaction mixture was poured into a mixture of ethyl acetate (50 ml) and water (50 ml) under stirring, and adjusted to pH 8.5 with 10% potassium carbonate aqueous solution. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from diethyl ether-n-hexane to afford methyl 5-(pyrrol-1-yl)-3-pyridinecarboxylate (1.29 g).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]3[CH:24]4[CH:20]3[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23]4)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>>[CH:24]12[CH:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[CH:20]1[CH2:21][NH:22][CH2:23]2
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC1C2CNCC21)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
tert-Butyl 6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.9 g, 1.0 eq.) was dissolved in DCM (20 mL) TFA (1.38 mL, 4 eq) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was cooled to 0° C. and neutralized by saturated NaHCO3. The solid precipitated out was collected by filtration to afford 1.0 g of (9H-fluoren-9-yl)methyl 3-azabicyclo[3.1.0]hexan-6-ylcarbamate (69% yield).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:37][C:38]([Cl:42])=[C:39]([NH2:41])[CH:40]=1)(=[O:35])=[O:34])([CH3:31])[CH3:30]>>[Cl:42][C:38]1[S:37][C:36]([S:33](=[O:35])(=[O:34])[NH:32][C:29]([CH3:31])([CH3:30])[CH2:28][OH:27])=[CH:40][C:39]=1[NH:41][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II. Light yellow solid. MS (ISP) 640.1 [ (M+H)+]; mp 223° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([O:34]C)=O)[CH:28]=[CH:29][CH:30]=1.[NH2:36][C:37]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:38]=1[C:39](OC)=[O:40]>C1COCC1.CO>[Cl:47][C:45]1[CH:46]=[C:37]2[C:38]([C:39]([OH:40])=[C:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)[CH:26]=3)[C:32](=[O:34])[NH:36]2)=[CH:43][CH:44]=1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: COC(=O)Cc1cccc(Oc2ccccn2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1cccc(Oc2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
Potassium bis(trimethylsilyl)amide in toluene (0.5M, 10.8 ml, 5.4mmol) was added dropwise to a solution of methyl [3-(2-pyridyloxy)phenyl]acetate (0.52 g, 2.14 mmol) and methyl 2-amino-4-chlorobenzoate (0.43 g, 2.32 mmol) in dry THF (30 ml). The reaction mixture was stirred at room temperature for 3 1hours then methanol (10 ml) was added. The solution was concentrated in vacuo, the residue was dissolved in 0.5M sodium hydroxide (25 ml) and washed with diethyl ether (2×25 ml). The aqueous phase was acidified with 5M hydrochloric acid. The resultant precipitate was collected and recrystallised from dimethylformamide/water to afford the title compound as a pale cream solid (0.463 g, 59%). A further recrystallisation from propan-2-ol gave analytically pure material; m.p. 269°-271° C. (from propan-2-ol) (Found: C, 65.92;H, 3.71;N, 7.59. C20H13ClN2O3 requires C, 65.85;H, 3.71;N, 7.68%); δH (360 MHz, DMSO-d6) 7.03-7.14 (4H, m, ArH), 7.23 (1H, dt, J 2, 8.5 Hz, ArH), 7.32 (1H, d, J 2 Hz, ArH), 7.43 (1H, t, J 8 Hz, 5'-H), 7.85 (1H, m, ArH), 7.94 (1H, d, J 8.7 Hz, 5-H), 8.18 (1H, dd, J 5, 2 Hz, 6"-H), 10.46 (1H, br s, OH), 11.55 (1H, br s, NH); m/z 364 (M+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:34])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[N:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[CH:22]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([CH3:15])=[CH:10][C:9]2[NH:16][C:17](=[O:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[N:31][CH:30]=[C:29]([CH3:33])[N:28]=4)[CH:22]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(Cl)cc3NC(=O)OC(C)(C)C)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(-c2cccc(C3=Nc4cc(Cl)c(C)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-{3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M119) (0.39 g, 0.79 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (260 mg, 88%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:6]([CH3:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:17][S:18]([O-:21])(=[S:20])=[O:19].[K+]>C(O)C>[CH3:17][S:18]([S:20][CH2:2][CH2:3][O:4][C:5]1[C:6]([CH3:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:21])=[O:19]
Reactant: CCOC(=O)c1cccc(OCCBr)c1C
Reactant: CS(=O)([O-])=S
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cccc(OCCSS(C)(=O)=O)c1C

Procedure:
2 g (7 mmol) of ethyl 3-(2-bromoethoxy)-2-methylbenzoate and 1.1 g (7.3 mmol) of potassium thiomethanesulfonate are dissolved in 10 ml of abs. ethanol. The reaction mixture is refluxed for 20 hours. The solvent is then distilled off and the residue is taken up in methylene chloride and washed with water. The organic phase is dried over sodium sulfate and the solvent is removed. The useful product is purified by column chromatography.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][CH:20]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH2:26])=[O:27])=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C(N)=O)cc3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCNC3)cc1
Reaction time: 24 h
Yield: 71.1 %

Procedure:
Combine 6-(4-carbamoyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4.0 g, 10.83 mmol), CH2Cl2 (100 mL), and TFA (25 mL) at room temperature. Stir for 24 hours, followed by the addition of 1.0 M K2CO3 (aq), and extract the product out of the aqueous layer with several washings of ethyl acetate/THF. Concentrate the organic phase under reduced pressure and add to 2, 10 g SCX Columns pre-treated with 5% AcOH/MeOH. After several washings of the SCX Columns with MeOH, elute with 1.0 N NH3-MeOH solution to afford 2.08 g, 7.7 mmol (71% yield) of the title compound as a white foam: 1H NMR (500 MHz, DMSO-d6); 2.9-3.1 (2H, m), 3.10-3.25 (1H, m), 3.3-3.5 (2H, m), 4.1-4.3 (2H, m), 7.0-7.2 (3H, m), 7.2-7.4 (1H, m), 7.4-7.6 (1H, m), 8.0-8.1 (1H, m), 8.2-8.4 (1H, m), 8.5-8.65 (1H, m), 9.2-9.4 (2H, m); MS m/z 269 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][OH:16].[CH3:17][S:18](Cl)(=[O:20])=[O:19].CNC1C=CC=C(NC)N=1.CCN(CC)CC>[Cl-].[Na+].O.O.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][O:16][S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: COc1ccccc1C1CCCCC1CO
Reactant: CS(=O)(=O)Cl
Agent: CNc1cccc(NC)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1C1CCCCC1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
Combine [2-(2-methoxy-phenyl)-cyclohexyl]-methanol (0.725 g, 3.29 mmol), methanesulfonyl chloride (0.415 g, 3.62 mmol), 2,6-dimethylaminopyridine (80.0 mg, 0.66 mmol), Et3N (1.0 mL, 7.24 mmol), and dichloromethane (30.0 mL) at 0° C. After 20 min stir at room temperature under nitrogen. Reaction stirred for 18 hours then add water and brine. Separate layers and dry over anhydrous sodium sulfate. Concentrate and flash chromatography using 5 to 30% ethyl acetate/hexanes to yield the titled compound (0.810 g, 83%). TLC Rf=0.25 in 30% ethyl acetate/hexanes. 1H NMR (CDCl3): 7.2 (m, 1H), 7.1 (m, 1H), 6.9 (m, 2H), 4.3 (t, 1H, J=10.0 Hz), 3.9 (m, 4H), 3.3 (m, 1H), 2.8 (s, 3H), 2.6 (m, 1H), 1.8 (m, 6H), 1.5 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]([NH:16][C@H:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20](=[O:27])[CH2:19][CH2:18]4)[C:13]([N+:28]([O-])=O)=[CH:12][N:11]=3)[C:6]=2[CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O.C(Cl)Cl>[NH2:28][C:13]1[C:14]([NH:16][C@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[CH2:19][CH2:18]2)=[N:15][C:10]([N:7]2[C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[N:11][CH:12]=1
Reactant: O=C1CC[C@@H](Nc2nc(-n3cnc4ccc(F)cc43)ncc2[N+](=O)[O-])c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Nc1cnc(-n2cnc3ccc(F)cc32)nc1N[C@@H]1CCC(=O)c2ccccc21
Reaction time: 1.5 h

Procedure:
To the solution of (4R)-4-(2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-5-nitropyrimidin-4-ylamino)-3,4-dihydronaphthalen-1(2H)-one (80 mg) in THF (10 mL) was added Na2S2O4 (480 mg) and NaHCO3 (240 mg) in H2O (10 mL), and stirring continued at room temperature for 1.5 h. The reaction mixture was diluted with CH2Cl2, washed with saturated brine, dried over MgSO4, and concentrated in vacuo. The crude (32 mg) was subjected to the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N:4]([C:7]1[CH:22]=[CH:21][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:19][N:18]=[CH:17][C:16]=3[CH:20]=2)=[CH:9][CH:8]=1)=[C:5]=[O:6]>C(OCC)C>[CH3:1][N:2]([CH3:3])[C:5]([NH:4][C:7]1[CH:22]=[CH:21][C:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:19][N:18]=[CH:17][C:16]=3[CH:20]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C=Nc1ccc(Oc2ccc3sncc3c2)cc1
Reactant: CNC
Solvent: CCOCC
Product: CN(C)C(=O)Nc1ccc(Oc2ccc3sncc3c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
5 parts of gaseous dimethylamine were passed into a solution of 26.8 parts of 5-(4'-isocyanatophenoxy)-benzisothiazole in 300 parts of diethyl ether, the reaction mixture was stirred for 12 hours at from 20 to 30° C., and the resulting precipitate was isolated. 27.6 parts (88% of theory) of 5-(4'-dimethylaminocarbonylaminophenoxy)-benzisothiazole of melting point 156° C. were obtained.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>>[CH3:11][N:12]([C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH2:13][CH2:14][OH:15]
Reactant: CNCCO
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Product: CN(CCO)c1c([N+](=O)[O-])cnn1C
Yield: 81 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 2-(methylamino)ethanol gave 2-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)ethanol as a yellow oil (0.2 g, 81%). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 3.79 (s, 3H), 3.72 (q, J=5.4 Hz, 2H), 3.33 (t, J=5.4 Hz, 2H), 2.93 (s, 3H), 1.91 (t, J=5.4 Hz, 1H)