Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:12])[CH2:10]Br)[N:8]=1)[CH3:3].C(=O)([O-])O.[K+].Cl.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([NH2:32])[CH3:31])=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20]>CC(C)=O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:32][CH2:10][CH:9]([OH:12])[C:7]2[N:8]=[C:4]([N:2]([CH3:3])[CH3:1])[S:5][CH:6]=2)=[CH2:31])=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Reactant: CN(C)c1nc(C(=O)CBr)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Cc1ccc(C(=O)OC)cc1)NCC(O)c1csc(N(C)C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5 g of 2-(N,N-dimethylamino)-4-bromoacetyl-thiazole in 250 ml of acetone are heated to reflux with 10 g of potassium hydrogen carbonate and 9.5 g of 2-(4-carbomethoxyphenyl)-1-methylethylamine-hydrochloride for 3 hours. After the reaction mixture has been cooled the inorganic products are removed by filtration, and the filtrate is concentrated in a rotary evaporator. The resulting oil residue is taken up in 150 ml of absolute methanol and, at 0°-5° C., 1.75 g of sodium borohydride are added in small portions. The mixture is then stirred at 0°-5° C. for one hour and at room temperature for 24 hours. Then ice-water are added to the reaction mixture, and it is acidified with concentrated hydrochloric acid, made alkaline with ammonia, while cooling in ice, and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using ethyl acetate/methanol =8:2 as eluant.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>O.CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:43]
Reactant: CCOC(=O)CBr
Reactant: CS(=O)(=O)NCCc1ccccc1O
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccccc1CCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.3 %

Procedure:
A mixture of N-[2-(2-hydroxy-phenyl)-ethyl]-methanesulfonamide (4.3 g, 20 mmol), Nal (1.2 g, 8.0 mmol), K2CO3 (6.07 g, 44 mmol), ethyl bromoacetate (3.34 g, 20 mmol), and DMF (70 mL) was stirred at room temperature for 24 h. The reaction was poured into water and the aqueous solution was extracted with CH2Cl2. The organic solution was washed with water (1×) followed by brine (1×). The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (hexanes to 7:3 hexanes:EtOAc) provided the title compound (800 mg). 1H NMR (400 MHz, CDCl3) δ7.18 (m, 2H), 6.93 (t, 1H), 6.71 (d, 1H), 4.97 (m, 1H), 4.65 (s, 2H), 4.24 (q, 2H), 3.42 (m, 2H), 2.94 (t, 2H), 2.75 (s, 3H), 1.27 (t, 3H); MS 319 (M+18).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12](I)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.[Cu](I)I>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([C:26]#[C:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(N)c(I)c1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(N)c(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
[1-(4-Amino-3-iodophenyl)ethyl]carbamic acid tert-butyl ester (500 mg, 1.380 mmol, 1 eq.), dichloro(bistriphenylphosphine) palladium (48.4 mg, 0.069 mmol, 0.05 eq.) and copper iodide 13.1 mg (0.069 mmol, 0.05 eq.) were added in THF. After stirring for 30 min at room temperature, TEA (577.0 μl, 4.140 mmol, 3 eq) and phenylacetylene (197.0 μl, 1.794 mmol, 1.3 eq) were added into the reaction mixture. The reaction mixture was stirred overnight with reflux. A reaction solvent was removed in vacuo. The residue was purified with column chromatography (n-Hx:EA=5:1) to yield title compound (452.7 mg) as a yellow liquid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>C(Cl)Cl>[OH:6][C:7]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cccc(C(=O)OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)OC)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
BBr3 (1.0M in CH2Cl2, 7.53 ml, 7.53 mmol, 2.5 eq) was added dropwise to a stirred solution of dimethyl 2-methoxyisophthalate (0.6785 g, 3.01 mmol, 1 eq) in anhydrous CH2Cl2 (4 ml) at 0° C. under Ar. After 30 min the reaction was warmed to room temperature. After 2 h the reaction was quenched anhydrous MeOH (1 ml) and stirred overnight. The solvent was removed in vacuo and the residue dissolved in EtOAc. The organic layer was washed with saturated aqueous NaHCO3 (×2), water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.4045 g (1.92 mmol, 64% yield) of dimethyl 2-hydroxyisophthalate.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]([C@H:14]2[O:20][C@H:19]([CH2:21][OH:22])[C@H:17]([OH:18])[C@@H:15]2[OH:16])[C:12]2[CH:23]=[C:24]([Cl:28])[C:25]([Cl:27])=[CH:26][C:11]=2[N:10]=1)C1C=CC=CC=1.CI>>[Cl:27][C:25]1[C:24]([Cl:28])=[CH:23][C:12]2[N:13]([C@@H:14]3[O:20][C@@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[C:9]([S:8][CH3:1])=[N:10][C:11]=2[CH:26]=1
Reactant: OC[C@H]1O[C@H](n2c(SCc3ccccc3)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Solvent: CI
Product: CSc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@@H](CO)[C@@H](O)[C@H]1O

Procedure:
The procedure is the same as that described for compound 11b, except that methyl iodide (0.06 mL, 1.0 mmole) was used instead of benzylbromide. The TLC (co-spots solvent system 1) and proton spectrum were identical to that obtained for compound 12a. Yield: 142 mg (39%) as white crystals. Mp: 204-206° C. Anal. (C13H14O4N2Cl2S) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([CH:14]2C(=O)OC(C)(C)OC2=O)=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O1CCOCC1>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:13])[CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)C2C(=O)OC(C)(C)OC2=O)C1
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(2,2-dimethyl-4,6-dioxo-[1,3]dioxane-5-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.05 mmol) in a mixture of actic acid (0.5 mL), water 0.25 mL and dioxane (3 mL) was stirred under microwaves at 100° C. for 30 minutes. After concentration to dryness, the residue was coeveoparted with dichloromethane (2×100 mL). The title product was obtained as a colorless gum (600 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:23][C:17]1[CH:16]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(Br)cc1F
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(c3cnccc3C)C2=O)cc1F
Yield: 86.2 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with 4-bromo-2-fluoro-1-methoxy-benzene (191 mg, 0.932 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (29.4 mg, 0.2542 mmol) and potassium phosphate (449 mg, 2.11 mmol) to afford 220 mg of the product (86% yield).
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:24][OH:25])[OH:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1>>[C:1]([O:20][CH2:21][CH:22]([CH2:24][OH:25])[OH:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:26]([O-:31])(=[O:32])[CH2:27][CH2:28][C:29]([O-:19])=[O:30]
Reactant: O=C1CCC(=O)O1
Agent: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCC(O)CO
Product: O=C([O-])CCC(=O)[O-]
Temperature: 140 °C
Reaction time: 3 h

Procedure:
29.97 gm (84.6 mmoles) of glyceryl monolinoleate were added to a dry 100 ml, single neck, round bottom flask. A football stir bar was added and a nitrogen inlet adapter was attached. The reaction flask was placed into a room temperature oil bath and a nitrogen blanket was applied. The oil bath temperature was raised to 140° C. Once at 140° C., 8.47 gm (84.6 mmoles) succinic anhydride were added and the temperature was raised to 200° C. Heat tape was wrapped around the outside of the top of the flask and adapter to keep the succinic anhydride from subliming. The reaction was continued for 3 hours at 200° C. The flask was removed from the oil bath and allowed to cool to room temperature. The polymer was a pale yellow, viscous liquid.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[Si:1]([O:18][CH:19]1[CH2:20][CH2:21][CH:22]([CH:25]=[O:26])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC1CCC(CO)CC1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)[Si](OC1CCC(C=O)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of (4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl)methanol (7.38 g) and triethylamine (8.37 mL) in DMSO (50 mL) was added sulfur trioxide pyridine complex (9.56 g). The reaction mixture was stirred at room temperature for 3 hr and extracted with diethyl ether and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (5.83 g).
Reaction SMILES: C[S:2][C:3](=S)[NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[CH3:16][OH:17]>>[CH3:16][O:17][C:3](=[S:2])[NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CO
Reactant: CSC(=S)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=S)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
14.1 g of N-(4-chlorophenylsulfonyl)-dithiocarbamic acid-S-methyl ester (0.05 mol) are refluxed in 100 ml of methanol, and after about 5 hours the formation of mercaptan has finished. The solvent is distilled off in a rotary evaporator, and the residue is recrystallised from methanol; yield 116 g (87% of theory), m.p. 129°-130° C.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:1][C:2]#[CH:3])[CH2:8][CH2:7]1
Reactant: C#CCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
Propargyl bromide (23.8 g, 200 mmol) was added dropwise to a mixture of 1-methyl-piperazine (20 g, 200 mmol) and cesium carbonate (65 g, 200 mmol) in 350 mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The inorganic salts were then filtered off, and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were then evaporated to give 7.5 g of 1-methyl-4-prop-2-ynyl-piperazine: mass spectrum (m/e): M+H 139.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:27]([C:30]1[C:38]2[N:37]=[C:36]([NH:39][CH2:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1)([O-:29])=[O:28].O>CN(C)C=O.C(O)(=O)C.ClCCl>[C:1]1([CH2:11][N:44]2[CH2:45][CH2:46][CH:41]([CH2:40][NH:39][C:36]3[NH:35][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([N+:27]([O-:29])=[O:28])[C:38]=4[N:37]=3)[CH2:42][CH2:43]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccc2[nH]c(NCC3CCNCC3)nc12
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 1-naphthoaldehyde (3 mmol) and sodium triacetoxyborohydride (3 mmol) to a solution of (4-nitro-1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine (450 mg, 1 mmol) in dimethylformamide-acetic acid (10:1) (7 mL), the mixture was stirred at room temperature overnight. Water and dichloromethane were added, and extraction was performed with dichloromethane. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/triethylamine=100/0→98/2) to obtain (1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(4-nitro-1H-benzimidazol-2-yl)-amine. The compound was identified by LC-MS.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][C:9]=1[F:16].[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O>O1CCOCC1>[Cl:7][C:8]1[C:9]([F:16])=[CH:10][C:11]2[NH:14][C:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][C:20]=3[C:12]=2[CH:13]=1
Reactant: NNc1ccc(Cl)c(F)c1
Reactant: CN1CCCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3cc(F)c(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid is added to a solution of 4-chloro-3-fluorophenyl hydrazine hydrochloride (1 equiv.) in dioxane, and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 3 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to give a mixture or regioisomeric products. For this Example, silica gel chromatography separates the title compound from the other regioisomer (Compound 4) obtained in Example 10.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[N:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([CH2:27][NH:28][CH2:29][CH2:30][CH3:31])[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1C=CC=C1>CO.[Pt]>[CH2:1]([O:8][C:9](=[O:38])[N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH2:27][NH:28][CH2:29][CH2:30][CH3:31])[CH:19]=2)[CH:12]=1)[CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCc1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Product: CCCNCc1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1N

Procedure:
A mixture of cyclohexyl-[3-(4-nitro-3-propylaminomethyl-phenoxy)-phenyl]-carbamic acid benzyl ester (0.00181 mol) in methanol (50 mL) was hydrogenated with 5% Pt/C (0.5 g) as a catalyst in the presence of thiophene solution (1 mL). After uptake of H2 (3 equiv), the catalyst was filtered off and the filtrate was evaporated to yield the title compound as a residue which was used in subsequent reactions without further purification.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]([C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:29]=1[NH2:30])([CH3:27])[CH3:26]>C(O)C>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=[N:30][C:29]2[C:31]([CH:35]([CH3:36])[CH3:37])=[CH:32][CH:33]=[CH:34][C:28]=2[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CCO
Product: CC(C)c1cccc(C(C)C)c1N=Cc1cccc(-c2c(CNC(C)(C)C)ccc3ccccc23)n1

Procedure:
A mixture of 4.80 g (15.0 mmol) of 6-{2-[(tert-butylamino)methyl]-1-naphthyl}pyridine-2-carbaldehyde and 2.70 g (15.0 mmol) of 2,6-diisopropylaniline in 50 ml of dry ethanol was refluxed overnight. The resulting mixture was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane-methanol-triethylamine=100:10:1, vol.). Yield 5.50 g (76%) of orange oil which crystallized at room temperature. Anal. calc. for C33H39N3: C, 82.97; H, 8.23; N, 8.80. Found: C, 83.10; H, 8.41; N, 8.68. 1H NMR (CDCl3): 8.41 (m, 1H, 3-H in Py), 8.38 (s, 1H, CH═N), 8.00 (m, 1H, 4-H in Py), 7.91 (d, J=8.6 Hz, 4-H in naphthyl), 7.88 (m, 1H, 8-H in naphthyl), 7.66 (d, J=8.6 Hz, 3-H in naphthyl), 7.56 (m, 1H, 5-H in Py), 7.37-7.47 (m, 3H, 5,6,7-H in naphthyl), 7.10-7.18 (m, 3H, 3,4,5-H in Ph), 3.60 (m, 2H, CH2N), 3.02 (sept, J=6.8 Hz, 2H, CHMe2), 1.18 (d, J=6.8 Hz, 6H, CHMeMe′), 1.19 (d, J=6.8 Hz, 6H, CHMeMe′), 0.95 (s, 9H, tBu).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27]CC)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:33]1N=C(C2CC2)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC>>[CH:30]1([C:11]2[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])=[N:13][C:14]([CH2:15][CH3:16])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH2:33][CH2:31]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1Br
Product: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-[(5-bromo-3-cyclopropyl-6-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.94-1.02, 1.14-1.19, 1.26-1.30, 1.68-1.86, 2.06, 2.28-2.49, 3.08-3.32, 4.06-4.18, 4.83-4.87, 5.49, 5.62-5.66, 7.27-7.50; MS (ESI+) for C24H23Cl2N3O m/z 440(MH)+.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:17][CH3:18].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[O:30]>>[Si:8]([O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([C:23]2([OH:30])[C:22]3[C:26](=[CH:27][CH:28]=[C:20]([Cl:19])[CH:21]=3)[NH:25][C:24]2=[O:29])=[C:3]([O:17][CH3:18])[CH:4]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 21.6 %

Procedure:
With 6.99 g of the compound obtained in Step 237-2 and 3.21 g of 5-chloroisatin as starting materials, 1.66 g of the title compound (colorless solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:37]([NH:36][C:32]5[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=5)=[O:38])=[CH:5][CH:6]=4)[C:19]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NCc2ccc(Nc3n[nH]c4ncnc(Nc5cccc(Cl)c5)c34)cc2)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of 115 mg (0.3 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3chloro-phenylamino)-1H-pyrazolo-[3,4-d]pyrimidine hydrate (see Step 77.5), 0.041 ml (0.318 mmol) of 3-methoxy-phenyl isocyanate and 4 ml of THF is stirred at 20° C. for 15 hours and then concentrated by evaporation in vacuo. After recrystallization of the residue from ethyl acetate/hexane, 4-(3-chloro-phenylamino)-3-{4-[(3-methoxy-phenyl-amino)-carbonylamino-methyl]-phenylamino}-1H-pyrazolo-[3,4-d]pyrimidine is obtained in the form of the monohydrate; m.p. 157-160° C.; ESI-MS: (M−H)−=513.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl-].[N:21]1([CH:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CCN(CC)CC>CC#N>[N:21]1([CH:27]2[CH2:28][CH2:29][CH:30]([NH:33][C:2]3[C:3]4[C:10]5[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:14][C:9]=5[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:31][CH2:32]2)[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: NC1CCC(N2CCOCC2)CC1
Reactant: CCOC(=O)c1ccc2sc3ncnc(Cl)c3c2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c2c1
Yield: 66.8 %

Procedure:
A solution of ethyl 4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate (500 mg, 1.7 mmol, 1.00 equiv), 4-(morpholin-4-yl)cyclohexan-1-amine chloride (1.1 g, 4.25 mmol, 2.5 equiv) and potassium carbonate (2.3 g, 17 mmol, 10.17 equiv) in CH3CN (100 mL) was Et3N (2 mL) at room temperature under nitrogen. The resulting solution was heated to reflux overnight. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to give the desired ethyl 3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaene-12-carboxylate (500 mg, 66%) as a yellow solid. LCMS: (ES, m/z) 441 [M+H]+. 1H-NMR (300 MHz, CD3OD): δ 1.44-1.53 (4H, m), 1.57-1.65 (3H, m), 2.24-2.29 (2H, m), 2.25-2.33 (3H, m), 2.56-2.67 (4H, m), 3.45-3.75 (4H, m), 4.31-4.43 (1H, m), 4.45-4.50 (2H, m), 8.07-8.16 (2H, m), 8.49 (1H, s), 8.78 (1H, s).