Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([CH2:11][CH:12]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13](=[CH2:19])[CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[CH2:43][NH:42][CH2:41][CH2:40]2>O>[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[CH2:43][N:42]([CH2:11][CH:12]([C:13]([CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[CH2:19])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:41][CH2:40]2
Reactant: C=C(C[Si](C)(C)C)C(CC(C)C)CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C[Si](C)(C)C)C(CC(C)C)CN1CCc2cc(OC)c(OC)cc2C1
Temperature: 80 °C
Reaction time: 30 h
Yield: 70.1 %

Procedure:
(3-(tosylmethyl)-5-methyl-2-methylenehexyl)trimethylsilane (Formula 4; 72.0 mg, 0.195 mmol) and Na2CO3 (41.4 mg, 0.391 mmol) were added to DMF (2 mL). Then, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Formula 3; 75.4 mg, 0.391 mmol) was added thereto, and the mixture was heated up to 80° C. and stirred for 30 hr. Distilled water was put into the reaction solution to complete the reaction, and then the temperature was increased to normal temperature. An organic layer was extracted, the organic layer collected was washed with distilled water and a brine solution, and the remaining solvent was distilled under reduced pressure. Anhydrous magnesium sulfate was used to dry the organic layer, filtration under reduced pressure and evaporation under reduced pressure were performed, and then column chromatography was used to obtain 53.3 mg (yield 75%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[S:17]([N:27]1[C:35]2[C:30](=[C:31]([CH2:36][NH2:37])[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:37][CH2:36][C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:30]=4[CH:29]=[CH:28][N:27]5[S:17]([C:20]4[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=4)(=[O:19])=[O:18])[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN)cccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CNc4nccc(Nc5cc(C6CC6)[nH]n5)n4)cccc32)cc1
Temperature: 120 °C
Yield: 47.9 %

Procedure:
A tube was charged with 53 (415 mg, 1.38 mmol), 46 (486 mg, 2.07 mmol), DIPEA (1.0 ml) and IPA (3 mL), degassed, sealed and heated at 120° C. overnight. The mixture was concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (3.3 to 5% MeOH) to afford 330 mg (48%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-tosyl-1H-indol-4-yl)methyl)pyrimidine-2,4-diamine (50) as yellow solid: MS (ESI) m/z=500.3 [M+1]+.
Reaction SMILES: BrC(Br)=C[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[CH2:19]([Li])[CH2:20]CC.CCCCCC.[C:30](=[O:32])=[O:31].O>O1CCCC1>[Si:11]([O:10][C:5]1[CH:4]=[CH:9][C:8]([CH2:19][CH2:20][C:30]([OH:32])=[O:31])=[CH:7][CH:6]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13]
Reactant: O=C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1C=C(Br)Br
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(=O)O)cc1
Reaction time: 1 h

Procedure:
1,1-dibromo-2-(tert-butyldimethylsilyloxyphenyl)ethylene (190.9 mg, 0.487 mmol) prepared in 2) was dissolved in tetrahydrofuran (2.9 ml) in nitrogen atmosphere, and a 1.58 mol/l n-butyllithium/hexane solution (832 μl, 1.31 mmol) was dropwise added at −78° C. After stirring for one hour, crushed dry ice was added to return the solution to 0° C. After stirring for 10 minutes, water was added, and the solution was concentrated under reduced pressure. The residue was diluted with diethyl ether and extracted with water. The obtained aqueous layer was acidified (pH=4) with a saturated potassium hydrogen sulfate aqueous solution and extracted with ethyl acetate. The obtained organic layer was washed with a saturated salt solution, dried over anhydrous sodium sulfate, subjected to filtration and concentrated under reduced pressure to give 3-(4-tert-butyldimethylsilyloxyphenyl)propionic acid (134.6 mg, quant.) as crude crystals.
Reaction SMILES: [H-].[Na+].CCCCCC.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18](=[O:20])[CH:17]([CH2:21][CH3:22])[CH:16]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH2:15][C:14]=2[CH:31]=1.[CH3:32][N:33]([CH2:35][CH2:36]Cl)[CH3:34]>CN(C)C=O>[ClH:9].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:36][CH2:35][N:33]([CH3:34])[CH3:32])[C:18](=[O:20])[C@@H:17]([CH2:21][CH3:22])[C@@H:16]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH2:15][C:14]=2[CH:31]=1
Reactant: CCC1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC[C@@H]1C(=O)N(CCN(C)C)c2ccc(Cl)cc2C[C@@H]1c1ccc(OC)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of prewashed (hexane) sodium hydride (~50% in mineral oil) (0.064 g; 1.34 mmole; 1.2 eq.) in dry dimethylformamide (10 ml) was added 7-chloro-3-ethyl-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (370 mg; 1.12 mmole). After stirring the mixture at 25° C. for 1 hour, 3.2 ml (5.6 mmole) of 1.7N N,N-dimethyl-2-chloroethylamine (in toluene) was added, and the solution was heated at 80° C. for 24 hours. The reaction was quenched with 1N hydrochloric acid, made basic with 50% sodium hydroxide solution, extracted with ethyl acetate (two times) and dried (magnesium sulfate). After solvent removal, 0.49 g of a brown oil remained. This crude product was flash chromatographed (silica gel/3:1-hexane:ethyl acetate, followed by 2:1-hexane: ethyl acetate, followed by 1:1-hexane: ethyl acetate, followed by ethyl acetate). Those fractions which contained the cis amine product were dissolved into ether. The salt was precipitated out by the dropwise addition of hydrogen chloride saturated ether solution. The resultant white solid was collected by suction-filtration, yielding 200 mg. The lower Rf trans isomer of the title compound was likewise obtained (10 mg) as well as a cis-trans mixture (50 mg), and unreacted starting material (40 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[CH:26]([N:24]([CH3:25])[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:17])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C1(NC(=O)c2ccncc2N(C)C(C)C)Cc2ccccc2C1
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N(C)c1cnccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 96 h
Yield: 88 %

Procedure:
2-{[3-(Isopropyl-methyl-amino)-pyridine-4′-carbonyl]-amino}-indan-2-carboxylic acid ethyl ester 357, 270 mg, 0.71 mmol) is charged with 1,4-dioxane (3 mL) and MeOH (3 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH monohydrate (75 mg, 1.94 mmol). After 4 days, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 3 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.22 g, 88%).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([N:19]([CH3:33])[C:20](=[O:32])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17]C)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br>CC(O)=O.CCOC(C)=O>[C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([N:19]([CH3:33])[C:20](=[O:32])[C:21]2[CH:22]=[CH:23][C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:25][CH:26]=2)[CH:8]=[C:9]([C:11]2[C:12](=[O:17])[NH:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncccc1-c1cc(N(C)C(=O)c2ccc(NS(C)(=O)=O)cc2)c(OC)c(C(C)(C)C)c1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1c(N(C)C(=O)c2ccc(NS(C)(=O)=O)cc2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C
Temperature: 60 °C
Yield: 94 %

Procedure:
To a solution of 142 (0.17 g, 0.33 mmol) in HOAc (3 mL) was added concentrated aqueous HBr (48%, 0.11 mL), and the solution was heated in a sealed tube at 60° C. for 15 h. The reaction mixture was cooled to RT, diluted with EtOAc, and washed sequentially with water and saturated aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with DCM/MeOH/NH4OH to afford 0.15 g (93%) of N-[3-tert-butyl-2-methoxy-5-(2-oxo-1,2-dihydropyridin-3-yl)phenyl]-4-methanesulfonylamino-N-methylbenzamide (I-104) as a white powder.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=1[O:16][CH3:17].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].O>C(O)C>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13](=[O:15])[CH:14]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][C:6]=1[O:16][CH3:17]
Reactant: COCOc1ccc(C=CC(C)=O)cc1OC
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C=CC(=O)C=Cc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 114.7 %

Procedure:
1-(4-Methoxymethyloxy-3-methoxyphenyl)-1-buten-3-one (35j, 1.00 g, 4.2 mmol) and benzaldehyde (1b, 0.46 ml, 4.5 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.30 g, 7.5 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to give 1.35 g (99%) of an oil which was used without purification. The oil (36j, 1.30 g, 4.0 mmol) was stirred in methanol (50 ml) for 15 min at 60° C. Concentrated hydrochloric acid (3 drops) was added and the solution stirred for 18 hr at 60° C. The methanol was evaporated and the resulting residue extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a semi-solid. The crude semi-solid was chromatographed on silica gel with ethyl acetate/hexane to give 0.41 g (36%) of a yellow oil; 1H NMR δ 3.92 (s, 3H), 6.08 (s, 1H), 6.91 (d, 1H, J=16.1 Hz), 6.93 (d, 1H, J=8.2 Hz), 7.07 (d, 1H, J=15.9 Hz), 7.10 (s, 1H), 7.15 (d, 1H, J=8.0 Hz), 7.38 (m, 3H), 7.59 (m, 2H), 7.67 (d, 1H, J=15.9 Hz), 7.71 (d, 1H, J=15.9 Hz); 13C NMR: δ 56.0, 109.8, 114.9, 123.4, 125.3, 127.3, 128.3, 128.8, 130.3, 134.9, 142.8, 143.5, 146.8, 148.3, 188.7.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH3:15])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:19])(=O)=O.O>ClCCl>[C:1]([C:5]1[C:9]([Cl:19])=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH3:15])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(Cl)c(C(C)(C)C)nn1C
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A 5-L, four neck round bottom flask equipped with overhead air stirrer, positive pressure nitrogen inlet, thermocouple, and addition funnel was charged with ethyl 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxylate (250 g, 1.19 mol) in dichloromethane (2.5 L). The resulting solution was cooled to 10° C. with a wet-ice bath. Sulfuryl chloride (149 mL, 1.49 mol) was added via addition funnel at such which maintained the temperature between 21-31° C. The resulting mixture was then stirred for 2 h at room temperature. A separate 12-L, four neck flask equipped with overhead air stirrer and thermocouple was charged H2O (3.75 L) and cooled to 10° C. This mixture was then added via addition funnel, while maintaining the temperature below 32° C. and the resulting mixture was stirred for 30 min. The layers were separated, the aqueous layer was extracted with dichloromethane (2×1 L). The organic layer was carefully washed with NaHCO3 (saturated, 2×2 L), brine (1.25 L), dried over Na2SO4, filtered, and evaporated to yield ethyl 3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxylate as a white solid. 1H NMR (CHLOROFORM-d) δ: 4.39 (q, J=7.1 Hz, 2H), 4.07 (s, 3H), 1.29-1.49 (m, 12H)
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8][C:7]1=S)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:17][NH2:18]>O>[CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:17]\[NH2:18])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NN
Reactant: CCCCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Solvent: O
Product: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Temperature: 100 °C
Yield: 79.4 %

Procedure:
3-Pentyl-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one (6.0 g, 16 mmol) was mixed with hydrazine (10 mL, 300 mmol) and water (10 mL). The mixture was heated at 100° C. for 8 h. The solid formed was filtered and washed with water to give the desired product (3.0 g, 78%). LCMS calculated for C10H17N6O (M+H): 237.1; found: 237.1.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]O>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][CH3:18])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1ccccc1C(=O)c1ccccc1

Procedure:
The ester methyl 2-benzoylbenzoate was prepared from the corresponding acid 2-benzoyl benzoic acid by Fischer esterification. One mole (226.23 grams) of 2-benzoylbenzoic acid was refluxed overnight in 1500 milliliters of methanol containing 2 grams of p-toluenesulfonic acid as catalyst. Cooling and rotary evaporation of the solvent afforded the ester as white crystals (melting point 145° C.) having a purity of about 99 percent. This material was used as such without further purification. Other esters can be prepared from their corresponding acids in a similar fashion.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10](CC)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1[CH:21]=[CH:20]C=CC=1.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:23]([Cl:22])=[O:25])[CH2:12][CH:13]1[CH2:20][CH3:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccncc1
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1CN(C(=O)Cl)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
a solution of (RS) 4-tert-butoxycarbonyl-2-ethylpiperazine (3.95 g) and pyridine (1.64 ml) in DCM (35 ml) was added dropwise to a stirred solution of triphosgene (2.1 g) in DCM (100 ml) at 0° C. under Ar. The mixture was warmed to room temperature, stirred for 30 min then washed with water (100 ml) and brine (100 ml). The organic solution was dried (sodium sulfate) and concentrated in vacuo. The residue was dissolved in isohexane, filtered and concentrated in vacuo to give the product as a clear oil (3.73 g) which was used without further purification; δH (400 MHz, CDCl3) 4.39–3.80 (4H, m), 3.39–2.69 (3H, m), 1.66 (2H, m), 1.47 (9H, s), 0.96 (2.7H, d, J 7 Hz) and 0.89 (0.3H, d, J 7 Hz); GC (150° C.-10 min-320° C.) 83%, 8.72 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:13].C(N(CC)CC)C>CC(C)=O>[CH3:18][O:17][C:15]([CH2:14][C:12]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])=[O:13])=[O:16]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1cnccc1C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)Nc1cnccc1C(=O)O

Procedure:
A solution of 3-aminopyridine-4-carboxylic acid (1.0 equivalent), methyl 2-(chlorocarbonyl)acetate (1.1 equivalents), and triethylamine (2.0 equivalents) in acetone was stirred overnight at room temperature. The solvent was removed in vacuo. The product was used without further purification. LC/MS m/z 239.2 (MH+), Rt 1.40 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O-:30])=O)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[C:28]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:28](=[O:30])[C:27]4[CH:26]=[CH:25][C:24]([N:21]5[CH2:20][CH2:19][O:18][CH2:23][CH2:22]5)=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1)(=[O:30])[CH:27]([CH3:31])[CH3:26]
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Product: CC(C)C(=O)Nc1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc32)cc1

Procedure:
Compound 386 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-morpholinobenzoate. [M+H]+ calcd for C28H29N5O3: 484.23; found: 484.01.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=O)[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:22].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([NH2:29])[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:22]
Reactant: CC(=O)c1cc(Cl)c2cnn(C)c2c1-c1cc(F)cc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cnn(C)c2c1-c1cc(F)cc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-7-(3,5-difluorophenyl)-1-methyl-1H-indazol-6-yl]ethanone (0.438 g, 1.36 mmol), ammonium acetate (1.05 g, 13.6 mmol) and sodium cyanoborohydride (0.172 g, 2.73 mmol) in methanol (5 mL) and acetonitrile (5 mL) was heated at 65° C. overnight, in a sealed tube. The mixture was then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness to give the desired product. LCMS calculated for C16H12ClF2N2 (M−NH2)+: m/z=305.1; Found: 305.0.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][CH:16]=O)[CH:12]=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C(Cl)(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC=O)cc1S(=O)(=O)NC(C)(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNc1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.92 g (0.032 mol) of N-tert-butyl-5-formylamino-2-methoxycarbonylbenzenesulfonamide are dissolved in 50 ml of CHCl3, and then 5 ml (0.053 mol) of boranedimethyl sulfide complex are added at 0° C. After 1 h at 0° C. and 3 h at room temperature the reaction mixture is cooled to 0° C. 30 ml of methanol are added and the mixture is washed with water. The organic phase is dried over magnesium sulfate, the solvent is removed by distillation, and 9.23 g (98% of theory) of N-tert-butyl-2-methoxycarbonyl-5-methylaminobenzenesulfonamide are obtained. m.p.: 120°-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[C:13]2[S:17][CH3:18])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.Cl.[CH2:21]([O:23][CH2:24][CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[N:35]1[CH2:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][C@:44]2([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:48][CH2:47][NH:46][CH2:45]2)[CH2:37][CH2:36]1)[CH3:22].O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:21]([O:23][CH2:24][CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[N:35]1[CH2:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][C@:44]2([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:48][CH2:47][N:46]([C:5]([C:4]3[CH:8]=[C:9]([N:12]4[CH:16]=[N:15][N:14]=[C:13]4[S:17][CH3:18])[CH:10]=[CH:11][C:3]=3[O:2][CH3:1])=[O:7])[CH2:45]2)[CH2:37][CH2:36]1)[CH3:22]
Reactant: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnc2SC)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnc5SC)ccc4OC)C3)CC2)nc2ccccc21
Yield: 17.1 %

Procedure:
To a mixture of 2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid (0.27 g, 0.42 mmol), 1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole dihydrochloride (0.23 g, 0.42 mmol), 1-hydroxybenzotriazole hydrate (0.068 g, 0.51 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.97 g, 0.51 mmol), add via syringe under argon anhydrous dichloromethane (15 mL). Add diisopropylethylamine (0.22 mL, 1.26 mmol) and stir at room temperature for 20 hours. Dilute with dichloromethane and wash twice with water. Wash with saturated NaHCO3 solution, dry (MgSO4) the organic phase, filter and concentrate to an oil. Purify the oil by flash chromatography (silica gel, 3.5×15.2 cm) eluting with dichloromethane and then with 10% methanol in dichloromethane. Concentrate the appropriate fractions to afford 0.051 g of the title compound, Rf=0.26 (silica gel, 10% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:10]=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12]=2[OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.OC[CH2:28][S:29][CH2:30][CH2:31][OH:32]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].CO>[CH:14]1([C:11]2[CH:10]=[C:9]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH2:28][S:29][CH2:30][CH2:31][O:32][C:22](=[O:23])[CH2:21][CH2:20][C:9]3[CH:10]=[C:11]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:12]([OH:13])=[C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)=[O:23])[CH:8]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:12]=2[OH:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)CCc1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1
Reactant: OCCSCCO
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: CO
Product: O=C(CCc1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1)OCCSCCOC(=O)CCc1cc(C2CCCCC2)c(O)c(C2CCCCC2)c1

Procedure:
0.2 mol of methyl 3-(3,5-dicyclohexyl-4-hydroxyphenyl)propionate, 0.1 mol of 1,5-dihydroxy-3-thiapentane and 2 ml of tetrabutyl titanate are heated for 8 hours at 150° C. as described in Example 2, during which time the methanol forming distills off. After working up, the yield of product is 25.5% of theory.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH:31]1([NH:37][CH3:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([N:37]([CH3:38])[C:26]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[O:25])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CNC1CCCCC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: CN(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)C1CCCCC1

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and cyclohexyl-methyl-amine. MS (ESI): 454.4 (MH+).