Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:40].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:20]=3)=[O:40])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)CC(c1cccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(c1cccc(CS(=O)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 87.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)thio)methyl)phenyl)propanoate (158 mg) in methanol (0.95 mL) was added a solution of sodium periodate (66 mg) in water (50 μL), and the mixture was stirred at room temperature for 7 hr. To the reaction mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (143 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8](=[O:19])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH:14]([CH3:18])[CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([C:29]([C:31]2[CH:41]=[C:40]([CH3:42])[C:34]3[N:35]([CH3:39])[C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:24]=1>CN(C=O)C>[CH3:39][N:35]1[C:34]2[C:40]([CH3:42])=[CH:41][C:31]([C:29]([C:25]3[N:26]=[CH:27][N:28]=[C:23]([N:15]4[CH2:16][CH2:17][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[CH:20][C:6]=6[NH:7][C:8]5=[O:19])[CH2:13][CH:14]4[CH3:18])[CH:24]=3)=[O:30])=[CH:32][C:33]=2[O:37][C:36]1=[O:38]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNC(C)C1)C(=O)N2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)C(C)C1)C(=O)N2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
60 mg (0.21 mmol) 7-methoxy-3-(2-methyl-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 60 mg (0.20 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.040 mL (0.29 mmol) TEA were combined in 1 mL DMF and stirred for three days at RT. Then 7-methoxy-3-(2-methyl-piperidin-4-yl)-1,3,4,5-tetrahydrobenzo[d][1,3]diazepin-2-one was added again and the mixture was stirred for 3 h at 80° C. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and the solvent was evaporated down by half. The aqueous residue was extracted with DCM, the combined organic phases were dried on sodium sulphate, filtered and the filtrate was evaporated down.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:12]2[O:13][CH2:14][CH2:15][CH3:16])=[C:4](N)[N:3]=1.NC1N=C2C(N=CN2[C@@H]2O[C@H](CO)[C@@H](OCCC)[C@H]2[OH:36])=C(N)N=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>P([O-])([O-])([O-])=O.CS(C)=O>[CH2:14]([O:13][C@@H:12]1[C@H:17]([OH:18])[C@@H:19]([CH2:21][OH:22])[O:20][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:36])[C:5]=2[N:6]=[CH:7]1)[CH2:15][CH3:16]
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Reactant: CCCO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)nc(N)nc32)O[C@@H]1CO
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
A mixture of 2,6-Diamino-9-(2'-O-propyl-β-D-ribofuranosyl) purine and 2,6-Diamino-9-(3'-O-propyl-β-D-ribofuranosyl) purine (4.6 gm) and adenosine deaminase (200 mg, Sigma Chemicals Type II) were stirred at room temperature overnight in 0.1M tris buffer (150 ml, pH 7.4), DMSO (100 ml) and 0.1M sodium phosphate buffer (10 ml). A further aliquot of adenosine deaminase (140 mg) in 0.1M phosphate buffer (30 ml) and DMSO (20 ml) was added and the reaction stirred an addition 24 hrs. The solvent was evaporated in vacuo and the residue flash chromatographed on silica gel utilizing 5→20% MeOH/CH2Cl2. Product-containing fractions were evaporated in vacuo and the residue crystallized from H2O to yield 2.6 gm of product. m.p. dec>270° C. 1H NMR (DMSO-d6) δ 0.75 (t, 3, CH3), 1.42 (tq, 2, CH2), 3.3-3.6 (m, 4, H-5', O--CH2), 3,85 (m, 1), 4.2 (m, 1), 4.23 (m, 1), 5.10 (t, 1, 5'-OH), 5.13 (d, 1, 3'-OH) 5.75 (d, 1, H-1') 6.45 (br s, 2, NH2), 7.95 (s, 1, H-8) and 10.67 (br s, 1, NH). Anal. Calcd. for C13H19N5O5 : C, 47.99; H, 5.89; N, 21.53. Found: C, 47.90, H, 5.85; N, 21.44.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([C:18](=[O:30])[N:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[CH3:8].ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH:11]([C:18](=[O:30])[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:39])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCCCCN(CCCCC)C(=O)C(CCC(=O)OC)CSc1ccc(C)c(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCN(CCCCC)C(=O)C(CCC(=O)OC)CS(=O)c1ccc(C)c(C)c1
Temperature: -78 °C
Yield: 21 %

Procedure:
Into a solution of methyl 5-(3,4-dimethylphenylthio)-4-(N,N-dipentylcarbamoyl)pentanoate (0.55 g) in dry dichloromethane (10 ml) were added portions of m-chloroperbenzoic acid (70%, 0.31 g) with stirring at -78° C. After stirring at -78° C. for 3 hours, sodium sulfite was added. The reaction mixture was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica by eluting with benzene/ethyl acetate (2:1) to give 0.12 g of methyl 5-(3,4-dimethylphenylsulfinyl)-4-(N,N-dipentylcarbamoyl)pentanoate (diastereomer A) in a early fraction and 0.36 g of diastereomer B in a later fraction.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][CH:31]([N:34]([C:36]([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=2)=[O:37])[CH3:35])[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:44][C:41]3[CH:42]=[CH:43][C:38]([C:36](=[O:37])[N:34]([CH3:35])[CH:31]4[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]4)=[CH:39][N:40]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CN(C(=O)c1ccc(N)nc1)C1CCN(C(=O)OC(C)(C)C)CC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N(C)C4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 16.2 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (170 mg, 0.58 mmol) and 4-[(6-amino-pyridine-3-carbonyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (292 mg, 0.87 mmol), followed by deprotection using General Procedure A to give 7-cyclopentyl-2-[5-(methyl-piperidin-4-yl-carbamoyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (46 mg, 16%). MS (ESI) m/z 491.3 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[H-].[Na+].[CH3:14]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2C)c1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 5-methoxyindole (200 mg, 1.36 mmol) in 1.5 mL of dry N,N-dimethylformamide was added sodium hydride (55%, 66 mg, 1.5 mmol) at 0° C. After the reaction mixture was stirred at the same temperature for 30 min, methyl iodide (0.10 mL, 1.6 mmol) was added with additional stirring at room temperature overnight. After the reaction mixture was quenched with water (5 mL) at 0° C., the solution was extracted with diethyl ether (20 mL) twice. The combined extracts were washed with brine (5 mL), and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain 5-methoxy-1-methylindole (182 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[Mg]Br.FC1C=C(F)C=CC=1Br.[Mg].[C:21]([O:24][CH2:25][C:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])=[O:27])(=[O:23])[CH3:22].Cl>C1COCC1>[C:30]([O:29][CH2:28][C:26]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:27])[CH2:25][O:24][C:21](=[O:23])[CH3:22])(=[O:32])[CH3:31]
Reactant: CC(=O)OCC(=O)COC(C)=O
Reactant: Fc1ccc([Mg]Br)c(F)c1
Agent: Cl
Agent: Fc1ccc(Br)c(F)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Temperature: -30 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, 850 ml of THF solution of 2,4-difluorophenylmagnesium bromide prepared from 202.6 g (1.05 mol) of 2,4-difluorobromobenzene and 26.7 g (1.1 mol) of magnesium turnings was added dropwise at -30° C. to 1.7 l of THF solution of 174 g (1.00 mol) of 1,3-diacetoxyacetone which was previously cooled to -30° C. After the resulting liquid was stirred at -60° C. for 2 hours, a temperature thereof was gradually raised to room temperature. Then, to the reaction mixture was added 1 l of 1.2N aqueous solution of hydrochloric acid at 5° C. or below, and an aqueous layer was extracted twice with 1 l of ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give 302 g of crude oil. The obtained oil was purified by means of column chromatography on silica gel (hexane: ethyl acetate=1:1) to give 125 g of the desired compound. The compound was recrystallized from toluene/hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:19])[C@@H:12]([CH2:17][OH:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)N(C)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 97 %

Procedure:
A solution of 2C (8.5 g, 28 mmol) in DMF (30 mL) was added with an. K2CO3 (1.5 mol eq, 5.99 g) and, after few minutes, iodomethane (1.2 mol eq, 3.21 mL) was added and the mixture heated at 50° C. for 12 h. The solvent was removed under reduced pressure, water was added to the residue (150 mL) and the aqueous phase extracted with EtOAc (3×60 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 3C as a pale yellow oil (8.6 g, 97% yield). 1HNMR (DMSO, 200 MHz) δ 2.88 (s, 3H), 3.52 (s, 3H), 3.66 (m, 2H), 4.02 (q, 1H, J=6), 4.602 (t, 1H, J=6.1), 5.11 (t, 1H), 7.64 (d, 2H), 7.76 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25].C1(NC2CCCCC2)CCCCC1>C(#N)C.CCOCC.[Cu]I>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Brc1ccc2ccccc2n1
Reactant: C#CCCCCOCCCCCCBr
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Solvent: CCOCC
Product: BrCCCCCCOCCCCC#Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.9 %

Procedure:
A mixture of 2-bromoquinoline (3.00 g), 6-[(6-bromohexyl)oxy]-1-hexyne (3.77 g), BTPC (90 mg), copper (I) iodide (11 mg), and dicyclohexylamine (2.79 g) in acetonitrile (35 ml) was stirred at room temperature under nitrogen for 20 h. The mixture was diluted with ether (90 ml), filtered and the filtrate evaporated in vacuo to give a brown oil. Purification by FCC eluting with hexane:ether (4:1→2:1) gave the title compound as a brown oil (4.25 g), t.l.c. (hexane:ether 2:1) Rf 0.22.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.BrN1C(=[O:18])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>ClC1C=CC=CC=1.O>[OH:18][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nccnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1
Product: OCc1ccc2nccnc2c1
Temperature: 85 °C

Procedure:
In a 100 ml flask, 6-methyl-quinoxaline (1.25 g, 8.68 mmol) was dissolved with N-bromosuccinimide (2.32, 13.0 mmol) and benzoyl peroxide (0.15 g, 0.62 mml) in 31 g of chlorobenzene. The mixture was heated up to 85° C. to give a pale yellow solution that turned reddish with time. The solution was maintained at 85° C. for two hours and it was then cooled to −10° C. and filtered. The solution was vacuum dried to give an orange solid residue. The orange solid was then mixed with an alkaline solution prepared by dissolving 2.6 g of sodium hydroxide pellets in 50 ml of water. The mixture was gently heated to 85-95° C. to give a solution of 6-hydroxymethyl-quinoxaline that was mixed with the catalyst (5% Pt/C, 0.2 g) and maintained at that temperature with air sparging. The reaction was monitored by GCMS showing the consumption of 6-hydroxymethyl-quinoxaline and the formation of 6-quinoxalinecarboxaldehyde. After 10 hours, both compounds were completely consumed indicating the end of the reaction. The aqueous solution was cooled to room temperature and filtered. The yellow solution obtained was neutralized with 3.18 g of 96% sulfuric acid dissolved in 5 ml of water. A yellow precipitated was formed during the addition of acid. The yellow solid was filtered and air dried to give 0.67 g of dry product (45% yield). The lower yield in this experiment is attributed to a loss of bromomethyl-quinoxaline that was not recovered with from the succinimides precipitate by washings with pentane as explained in Examples 1 and 2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[C:12]([CH3:18])[C:11]=1[CH3:19])=[O:8].[CH2:20](Cl)[C:21](=[CH2:23])[CH3:22]>CN(C)C=O>[CH:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:22][C:21]([CH3:23])=[CH2:20])=[C:12]([CH3:18])[C:11]=1[CH3:19])=[O:8]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(C)c(NC=O)c(C)c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
Potassium carbonate (74.0 g, 0.54 mol) was added to a solution of 4-formylamino-2,3,5-trimethylphenol (85.5 g, 0.48 mol) and methallyl chloride (45.3 g, 0.5 mol) in dimethylformamide (300 ml) and the mixture was stirred at 80° C. for 3 hours under an argon atmosphere. The reaction mixture was poured into ice-cold water. Crystals precipitated were filtered, washed with water and dried. The crude crystals obtained were recrystallized from isopropyl ether to obtain the desired compound (80.0 g, yield: 71.6%), m.p. 144°-145° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([NH2:17])=[CH:9][CH:8]=3)[CH2:5]1)([CH3:3])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:17][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]2[CH2:16][CH2:15][CH:13]3[CH2:14][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]2)=[N:20][CH:21]=1
Reactant: CC(C)N1CC2CCC(C1)c1cc(N)ccc12
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(C)C)C2)ncc1Cl

Procedure:
2-[5-Chloro-2-(10-isopropyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide was prepared from 10-isopropyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide in an analogous manner to Example 273. Product isolated as a clear thin film (21 mg, 33%). LCMS (m/e) 527 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.13 (s, 1H), 8.48 (d, 1H, J=8.3 Hz), 7.99 (s, 1H), 7.94 (dd, 1H, J=1.5 and 8.0 Hz), 7.58-7.51 (m, 1H), 7.26-7.19 (m, 3H), 7.08 (s, 1H), 6.98 (dd, 1H, J=3.4 and 5.3 Hz), 5.21 (bs, 1H), 3.00-2.90 (m, 1H), 2.89-2.77 (m, 4H), 2.62 (d, 3H, J=2.7 Hz), 2.31 (d, 2H, J=1.0 Hz), 2.16 (d, 2H, J=8.1 Hz), 1.55 (d, 2H, J=8.2 Hz), 0.94 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]1([C:21]2[CH:22]=[CH:23][C:24]([CH3:29])=[C:25]([CH:28]=2)[CH2:26]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(#N)C>[CH3:1][O:2][C:3]1[N:4]([CH2:26][C:25]2[CH:28]=[C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:22]=[CH:23][C:24]=2[CH3:29])[C:5](=[O:8])[NH:6][N:7]=1
Reactant: Cc1ccc(-c2ccccc2)cc1CBr
Reactant: COc1n[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1n[nH]c(=O)n1Cc1cc(-c2ccccc2)ccc1C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
To a solution of 626 mg (5.44 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one (said compound is a known compound described in J. Chem. Soc. Perkin I, 2645 (1973) and this was produced according to the method described in this literature. In this literature, said compound is named as 3-methoxy-1,2,4-triazol-5(4H)-one) in 7 ml of dry acetonitrile was added 0.79 g (5.71 mmol) of potassium carbonate. To the mixture was added dropwise a solution of 1.42 g (5.44 mmol) of 5-phenyl-2-methylbenzylbromide in 20 ml of dry acetonitrile at 55° C. After the mixture was stirred at the same temperature for additional 5 hours, water was added to the reaction mixture and it was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated. To the resultant solid residue (1.51 g) was added tert-butyl methyl ether and the solid was washed and ice-cooled. The solid was collected by filtration and dried to obtain 0.72 g (2.44 mmol) of 5-methoxy-4-(2-methyl-5-phenylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([Si](C(C)C)(C(C)C)C(C)C)[CH:23]=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1
Reactant: COc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Cc1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To [6-Methoxy-5-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)-amine (31, 0.0340 g, 0.0598 mmol) was added tetrahydrofuran (5 mL) followed by tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 66 μL, 0.0658 mmol). The reaction was allowed to stir at room temperature for 2 hours, then poured into 1:1 water:saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and the volatiles were removed by rotary evaporation. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane followed by 1% methanol in dichloromethane and finally 3% methanol in dichloromethane. This provided 20 mg of the desired compound as a white solid (P-0012, 0.048 mmol, 81%). MS (ESI) [M+H+]+=413.2.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH2:28][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CN1CCNCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN(C)CC3)c2c1

Procedure:
The title compound was prepared as a solid by the method of Example 59 step iv) using product of Example 59 step iii) and 1-methylpiperazine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([CH2:19][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][NH:6][C:7]3=[O:12])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NCCc2c(O)cccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: O=C1NCCc2c(OCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a mixture of 2.4 g (14.7 mmol) of 3,4-dihydro-5-hydroxy-1(2H)-isoquinolinone and 2.5 g of cesium carbonate in 30 ml of ethanol was added 2.5 g (15.0 mmol) of benzyl bromide. The mixture was stirred for 18 hours at room temperature. Then an additional 2.5 g of cesium carbonate and 2.5 g of benzyl bromide was added and the mixture was heated under reflux conditions for four hours. The reaction was partitioned between water and ether, the ether layer was filtered (to remove solid), dried (MgSO4), and concentrated. The residue was dissolved in hexane, filtered, concentrated, and the residue was crystallized from ethanol to give 3.01 g (81%) of the desired product; mp 171°-173°.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[N:24]=[N:25][C:26](Cl)=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1.O>[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[N:24]=[N:25][C:26]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)nnc2CC1
Reactant: OB(O)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3ccccc3)nnc2CC1
Temperature: 90 °C
Yield: 149.9 %

Procedure:
5 g phenylboronic acid in 30 mL dioxane was added to 3.2 g 3-chloro-5,6,8,9-tetrahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester and 388 mg (1,1′-bis(diphenyl-phosphinoferrocene)palladium(II)dichloride in 50 mL dioxane under argon. The reaction was stirred at 90° C. over night. The mixture was cooled to RT diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydroxide and brine. The solvent was removed and the precipitate was purified by column chromatographie to yield 5.5 g of the desired product. (M+H)+=325