Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:12]([C:23]([OH:25])=[O:24])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[H][H]>COC(C)(C)C.CO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C@@H:12]([C:23]([OH:25])=[O:24])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)=C(C(=O)O)C1
Reactant: [H][H]
Agent: O=O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@@H](C(=O)O)C1
Temperature: 25 °C
Yield: 89 %

Procedure:
In a glove box (O2 content≦2 ppm) a 35 ml autoclave equipped with a 15 ml glass insert and a magnetic stirring bar was charged with 4-(4-fluoro-phenyl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid-1-tert-butyl ester (0.300 g, 0.934 mmol), [Ru(OAc)2((S)-3,5-Xyl-4-MeO)-MeOBIPHEP] (9.67 mg, 0.00936 mmol), triethylamine (15 mg, 0.16 mmol, 0.16 eq.) and 5 ml of methanol. The asymmetric hydrogenation was run for 42 h at 80° C. under 40 bar of hydrogen. After cooling to room temperature the pressure was released from the autoclave, the methanol solution was diluted with 50 ml of tert-butyl methyl ether and extracted with two 50-ml portions of a 1 M aqueous sodium hydroxide solution. The aqueous layer was poured on ice, acidified with ice-cold 2 M aqueous hydrochloric acid solution to pH 1 and extracted with two 100-ml portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give (+)-(3R,4R)-4-(4-fluoro-phenyl)-piperidine-1,3-dicarboxylic acid-1-tert-butyl ester in 89% yield (0.27 g) and with 96.6% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].BrC1C=C([CH2:41][S:42](CC2C=CC=C(Br)C=2)(=[O:44])=[O:43])C=CC=1.C[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19]([C:55]4[CH:56]=[CH:57][CH:58]=[C:59]([S:42]([CH3:41])(=[O:44])=[O:43])[CH:54]=4)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCCCCC
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(Cl)c3)n2)cn1
Reactant: O=S(=O)(Cc1cccc(Br)c1)Cc1cccc(Br)c1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3cccc(S(C)(=O)=O)c3)c2)n1
Reaction time: 1 h
Yield: 78 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.4) (0.45 g, 0.76 mmol), commercially available 3-bromo-phenylmethyl sulfone (0.20 g, 0.83 mmol), tetrakis(triphenyl-phosphine)palladium (0.053 g, 0.046 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h. Heptane (10 mL) was added at room temperature and the mixture was stirred for 1 h. The precipitate was collected by filtration, washed with heptane and dried to yield the title compound (0.27 g, 78%) as an off-white solid. MS (ISP) 459.2 [(M+H)+]; mp 213° C.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1/[CH:13]=[CH:14]\[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O.Cl>CCO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1/[CH:13]=[CH:14]\[CH2:15][NH2:16]
Reactant: COc1ccc(F)c(/C=C\CN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(F)c(/C=C\CN)c1
Temperature: 0 °C

Procedure:
Hydrazine hydrate (88%)(1.00 g, 19.2 mmol) was slowly added to a stirring solution of cis-2-[3-(2-fluoro-5-methoxyphenyl)prop-2-en-1-yl]-isoindole-1,3-dione (2.00 g, 6.4 mmol) in EtOH (100 mL) and the solution was heated to reflux for 5h. The resulting mixture was made acidic (pH <2.0) (10N HCl) followed by heating on a steam bath for 60 min. Cooling of the suspension to 0° C. precipitated the hydrazide which was filtered off, the filtrate was then diluted with H2O (20 mL) and extracted with EtOAc (2×). The aqueous layer was made basic (50% NaOH), and extracted with Et2O (3×). The ethereal layers were combined, washed with brine, dried over MgSO4, and concentrated to give a crude white wax. Purification by Kugelrohr distillation afforded the titled compound as a clear oil, 800 mg, 70%: 1H NMR (300 MHz, CDCl3) δ 1.26 (s, 2H, br), 3.421 (m, 2H), 3.78 (s, 3H), 5.81 (m, 1H), 6.40 (d, J=11.0 Hz, 1H), 6.62 (m, 2H), 6.90 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([C:16](=O)[CH:17]([CH3:19])[CH3:18])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N+:13]([O-])=O>[Pd].C(O)C>[CH:17]([C:16]1[N:2]([CH3:1])[C:3]2[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=2[N:13]=1)([CH3:19])[CH3:18]
Reactant: CC(C)C(=O)N(C)c1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1nc2ccc(C(F)(F)F)cc2n1C

Procedure:
Shake 12.0 g. of N-methyl-2'-nitro-5'-trifluoromethylisobutyranilide in 100 ml. of ethanol containing 0.3 g. of 5% palladium on carbon at an initial pressure of approximately 50 lbs. per square inch. Filter, removing the solvent, and add 40 ml. of 4N hydrochloric acid and reflux for 30 minutes. Cool, and basify with sodium bicarbonate. Extract with ether and dry over sodium sulfate. Sublime at 55° C (0.1 mm) obtaining the product of this step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)=[O:11])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]1([C:25]#[C:26][C:2]2[CH:3]=[C:4]([C:8]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:10]#[C:8][C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=4)[CH:13]=3)=[O:11])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(C(=O)c1cccc(Br)c1)c1cccc(Br)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(C(=O)c1cccc(C#Cc2ccccc2)c1)c1cccc(C#Cc2ccccc2)c1
Yield: 131.5 %

Procedure:
A solution of 3,3′-dibromobenzil (5.0 g, 0.0136 mol) and phenylacetylene (3.47 g, 0.0340 mol) in triethylamine (30 mL) is deaerated by bubbling nitrogen through the solution for ten minutes. (PPh3)2PdCl2 (0.067 g, 0.0001 mol) is then added, and the reaction mixture heated at reflux overnight. The mixture is concentrated to dryness, then taken up in CH2Cl2 (100 mL), washed sequentially with 1 M HCl, saturated aqueous NaHCO3 and dried (Na2SO4), then concentrated, giving 3.67 g (66 percent) product as a white solid: m.p. 144° C. to 145° C.; 1H NMR (CDCl3) δ 8.12 (s, 2H), 7.96 (d, J=7.9 Hz, 2H), 7.81 (d, J=7.7 Hz, 2H), 7.52 (m, 6H), 7.36 (m, 6H); 13C NMR (CDCl3) δ 192.83, 137.40, 132.82, 131.52, 129.04, 128.58, 128.25, 124.50, 122.37, 91.11, 87.62.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][C:11](=O)[CH2:10]1.Cl.[NH2:16][OH:17].C(N(CC)CC)C>CCO>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10]1
Reactant: O=C1CCC(c2ccc(O)cc2O)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: ON=C1CCC(c2ccc(O)cc2O)C1

Procedure:
(±)-3-(2,4-Dihydroxyphenyl)cyclopentanone (5 mg), hydroxylamine hydrochloride (2.7 mg) and triethylamine (5.4 μM) were heated in EtOH (4 ml) under reflux for 3 hr. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was extracted with ethyl acetate (10 ml), and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 4:1 v/v) to furnish the title compound as a white solid and a mixture of isomers (3.8 mg, 71%). δH (d4-MeOH) 1.80-1.93 (1H, overlapping m), 2.05-2.20 (0.5H, m), 2.39-2.55 (3H, overlapping m), 2.68-2.74 (1H, overlapping m), 2.94 (0.5H, br dd), 6.26-6.33 (2H, overlapping m), 6.94 (0.5H, d), 6.96 (0.5H, d); m/z (ES−) 266 ((M+60)−1)−.
Reaction SMILES: [C:1]1([CH2:6][NH:7][C:8]([NH2:10])=[S:9])[S:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=O>C(O)C>[ClH:11].[C:1]1([CH2:6][NH:7][C:8]2[S:9][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:10]=2)[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)NCc1cccs1
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: CCO
Product: Cl
Product: Fc1ccc(-c2csc(NCc3cccs3)n2)cc1
Yield: 56.4 %

Procedure:
N-thenylthiourea (0.80 grams, 0.0046 moles) and α-chloro-p-fluoroacetophenone (0.80 grams, 0.0046 moles, Aldrich Chem. Co.) in 11 ml absolute ethanol were heated at reflux temperature under nitrogen for 90 minutes. After cooling, and ethanol was removed under vacuum and the solids triturated with ethanol, filtered and vacuum dried over phosphorous pentoxide, yielding 0.848 grams (56%) of 2-thenylamino-4(p-fluorophenyl)-thiazole hydrochloride, m.p. 184°-187° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:8](N)=[CH:7][C:6]=1[C:16]([F:19])([F:18])[F:17])(=[O:3])[CH3:2].Cl.[N:21]([O-])=O.[Na+].[S:25](=[O:27])=[O:26]>C(O)(=O)C.O>[C:1]([NH:4][C:5]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:8]([S:25]([NH2:21])(=[O:27])=[O:26])=[CH:7][C:6]=1[C:16]([F:19])([F:18])[F:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(F)(F)F)cc(N)cc1C(F)(F)F
Reactant: O=S=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C(F)(F)F)cc(S(N)(=O)=O)cc1C(F)(F)F

Procedure:
5.7 G. of 4-acetylamino-3,5-bis-trifluoromethylaniline is dissolved in 16 ml. of acetic acid and cooled to 10° C., 3.2 ml. of concentrated hydrochloric acid is added, and the mixture cooled to 0°-5° C. with stirring. A solution of 1.4 g. of sodium nitrite in 4 ml. of water is added dropwise, with vigorous stirring and the resultant mixture stirred for 1/2 hour. The aqueous diazonium salt solution is then added to a solution of 0.4 g. of cupric chloride in 50 ml. of acetic acid which has been previously saturated at 20° C. with sulfur dioxide. The reaction mixture is stirred for 10 minutes, while sulfur dioxide is bubbled through this mixture and for 20 minutes further. The reaction mixture is poured into ice, extracted with methylene chloride, washed with water, dried and evaporated in vacuo. The residual 4-acetylamino-3,5-bis-trifluoromethylbenzenesulfonylchloride is again dissolved in methylene chloride and added to an excess of liquid ammonia. The contents of the flask is allowed to evaporate at room temperature overnight, affording 4-acetylamino-3,5-bis-trifluoromethylbenzenesulfonamide. This is taken up with 25 ml. of 6N hydrochloric acid and treated on a steam bath for 3 hours. It is cooled in ice and allowed to crystallize. The residue is collected by filtration, washed with water, and crystallized from aqueous ethanol to afford pure 4-amino-3,5-trifluoromethylbenzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([C:20]3[C:25](F)=[CH:24][C:23](C#N)=[CH:22][C:21]=3F)C(OCC)=O)=[CH:10][C:9]=2[CH3:30])=[O:7])=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl.C[O:38][CH:39]([OH:41])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:20]3[CH:25]=[CH:24][C:23]([C:39]([OH:41])=[O:38])=[CH:22][CH:21]=3)=[CH:10][C:9]=2[CH3:30])=[O:7])=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(c1c(F)cc(C#N)cc1F)c1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reactant: COC(C)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cc2ccc(C(=O)O)cc2)n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a slurry of ethyl 2-[5-(4-chlorobenzoyl)-1,4-dimethylpyrrol-2-yl]-2-(2,6-difluoro-4-cyanophenyl)acetate (0.05 g, 0.11 mmol) [prepared as described in Example 9, Step (a)] in methoxyethanol (4 ml) was added an aqueous solution of lithium hydroxide monohydrate (0.02 g in 0.5 ml H2O), and the reaction mixture was heated at reflux under an argon atmosphere. After 24 hr, the reaction mixture was cooled to room temperature and poured into a mixture of ice/water (40 ml) containing 1N HCl (1 ml). The solid was filtered to give crude {4-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]benzoic acid (0.037 g) as a tan solid. Flash chromatography on a silica gel column (0.5% acetic acid-30% acetone:hexane), followed by recrystallization from methanol-acetone gave pure {4-[5-(4-chloro-benzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]benzoic acid (0.032 g, 70.2% yield) as a white solid, mp 245-246.8° C. ##STR48##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C(Cl)(=O)C(Cl)=O.[NH:26]1[CH2:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[N:26]1([C:15]([C:14]2[CH:18]=[CH:19][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[N:7]=[C:2]([Cl:1])[CH:3]=3)=[N:12][CH:13]=2)=[O:17])[CH2:29][CH2:28][CH2:27]1
Reactant: C1CNC1
Reactant: Cn1nc(Cl)cc(Nc2ccc(C(=O)O)cn2)c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 127.4 %

Procedure:
6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)nicotinic acid (100 mg, 356 μmol, Eq: 1.00) was suspended in dichloromethane. Oxalyl chloride (67.8 mg, 46.8 μl, 534 μmol, Eq: 1.5) was added followed by a drop of DMF (10 μl) and the reaction mixture was stirred for 2 hr at room temperature. The reaction mixture was concentrated. The acid chloride was used as is for the next step. It was dissolved in dichloromethane (10 ml). To that was added azetidine (20.3 mg, 24.0 μl, 356 μmol, Eq: 1.00) followed by DIEA (230 mg, 311 μl, 1.78 mmol, Eq: 5) and the reaction was stirred over night at room temperature. The reaction mixture was diluted with dichloromethane, washed with a saturated sodium carbonate solution, washed with brine, dried over sodium sulfate, filtered and concentrated to give a light brown solid (145 mg) which was triturated with DCM/Hex/EtOAc to give the desired product as a yellow solid (56 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:34])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24](C(C)(C)C)=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1.C[Al](C)C.C(OC(=O)C1C=CC([Br:49])=CC=1OCC)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:49][C:24]1[CH:25]=[CH:26][C:21]([C:10]2[NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:34])[N:9]=2)=[C:22]([O:31][CH2:32][CH3:33])[CH:23]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: CCOC(=O)c1ccc(Br)cc1OCC
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOc1cc(Br)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
To a solution of meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (3 g, example 1) in toluene cooled to 0° C. was added dropwise 2 M solution of trimethylaluminum in toluene (5.33 mL, 10.66 mmol). After the addition, the mixture was stirred at 0° C. for 15 min then the ice bath was removed. After 30 min, the mixture was warmed up to 80-100° C. for about 30 min before being slowly cooled down to room temperature. At room temperature, a solution of 4-bromo-2-ethoxy-benzoic acid ethyl ester (3.18 g, 11.64 mmol) in toluene (10 mL) was added, and the yellow reaction mixture was heated at reflux for 48 h. Upon cooling to room temperature, 1 M Rochelle solution (˜20 mL) and ethyl acetate (˜50 mL) were added. The biphasic mixture was stirred rigorously at room temperature for 3 h. The layers were separated and the aqueous layer was extracted with ethyl acetate (1×100 mL). The combined organic layers were washed with saturated solution of sodium bicarbonate (1×20 mL), brine (1×20 mL), dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated to dryness. Purification of the crude residue by flash chromatography (120 g of silica gel, eluting with 5-10%, 20%, 40% then 80% ethyl acetate in hexane) gave the title compound as light yellow foam (3.25 g, 65%). HR-MS (ES, m/z) calculated for C25H24N2OCl2Br [(M+H)+] 517.0444, observed 517.0443.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8](C3CCCCO3)[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[C:18]([NH:23][C:24]3[C:25]4[C:29]([CH:30]=[CH:31][CH:32]=3)=[N:28][N:27](C3CCCCO3)[CH:26]=4)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl.CO>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([C:17]2[C:18]([NH:23][C:24]3[C:25]4[CH:26]=[N:27][NH:28][C:29]=4[CH:30]=[CH:31][CH:32]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: Cc1nc(-c2cccnc2Nc2cccc3nn(C4CCCCO4)cc23)c2cnn(C3CCCCO3)c2n1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2cccnc2Nc2cccc3[nH]ncc23)c2cn[nH]c2n1
Reaction time: 16 h
Yield: 92.1 %

Procedure:
A solution of N-(3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (56.9 mg, 111 μmol) in DCM (1 mL) and MeOH (2 mL) was treated with (+/−)-10-camphorsulfonic acid (57 mg, 2.2 equiv.) and stirred for 16 h. LCMS indicated clean monodeprotection with only a small amount of the fully deprotected compound. Additional (+/−)-10-camphorsulfonic acid (57 mg, 2.2 equiv.) was added and the solution stirred at 60° C. for 1 h after which time reaction was complete. The mixture was concentrated and purified by SCX ion exchange chromatography washing with MeOH and eluting off with 2 N NH3/MeOH to give N-(3-(6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-1H-indazol-4-amine (35 mg, 87% yield) as a brown solid. 1H NMR of free base thus obtained gives broad signals, so a small amount was converted to the HCl salt for better 1H NMR analysis by dissolving in MeOH containing 2 drops 2 M aqueous HCl followed by concentration to dryness. HCl salt: 1H NMR (400 MHz, d6-DMSO) δ 14.18 (br. s., 1H); 11.38 (s, 1H); 10.43 (s, 1H); 9.76 (s, 1H); 9.42 (d, 1H); 9.04 (s, 1H); 8.64 (d, 1H); 8.46 (s, 1H); 7.85-7.98 (m, 2H); 7.69 (d, J=9.54 Hz, 1H); 2.14 (s, 3H). m/z (ESI, +ve) 343.0 (M+H)+.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:72])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:70])[C:57]4[CH:62]=[CH:61][C:60]([O:63][C:64]5[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=5)=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:71])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:72])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56](=[O:70])[C:57]4[CH:62]=[CH:61][C:60]([O:63][C:64]5[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=5)=[CH:59][CH:58]=4)=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:71])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Oc5ccccc5)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Oc5ccccc5)cc4)cc3)cc2C1=O
Yield: 77 %

Procedure:
The compound of example 150 was prepared analogous to compound of example 98 by hydrolysis of compound of example 149.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23].N1C=CN=C1>CN(C=O)C>[CH3:23][C:22]([Si:26]([CH3:29])([CH3:28])[O:17][CH2:16][C:13]1[CH:12]=[C:11]([C:18]([O:20][CH3:21])=[O:19])[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:15][CH:14]=1)([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cc(CO)ccc1-c1cc(OC)ccc1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)ccc1-c1cc(OC)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A 50 mL round bottom flask was charged with 66.13E (1.19 g, 4.1 mmol), tert-butyldimethylchlorosilane (commercially available from Aldrich) (0.68 g, 4.5 mmol), DMF (4 mL), and imidazole (0.70 g, 10 mmol). The mixture was stirred overnight at 25° C. and then diluted with hexanes. The organic phase was washed with 1 N HCl, water, and brine, dried (MgSO4), and concentrated to afford 83.18A (1.6 g, 96% yield) as a colorless oil. The product thus obtained was used without further purification.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([NH:11][NH2:12])[CH:7]=[CH:8][C:9]=1[F:10])#[N:3].ClC1C=C(N2[C:25]([C:26]3[CH:31]=[C:30](F)[CH:29]=[C:28]([Cl:33])[CH:27]=3)=[CH:24][C:23]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=N2)C=CC=1F>>[Cl:33][C:28]1[CH:27]=[C:26]([C:25]2[N:11]([C:6]3[CH:7]=[CH:8][C:9]([F:10])=[C:4]([C:2]#[N:3])[CH:5]=3)[N:12]=[C:23]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:24]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: N#Cc1cc(NN)ccc1F
Agent: Cl
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)n(-c2ccc(F)c(C#N)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 3A and 3-cyano-4-fluorophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 0.76 g of the title compound with 46% purity (23% of theory) are obtained.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([O:12][CH3:13])[CH:9]=2)[NH:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25](Cl)=[O:26].[NH:28]([CH3:30])[CH3:29]>C1COCC1>[CH3:29][N:28]([CH3:30])[CH2:24][C:25]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([O:12][CH3:13])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=2)[CH2:11][C@@H:3]1[CH3:2])=[O:26]
Reactant: CNC
Reactant: COc1cc2c(cc1[N+](=O)[O-])N[C@@H](C)C2
Reactant: O=C(Cl)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)[C@@H](C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A slurry of (2S)-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole hydrogen chloride (4.43 g, 18.11 mmol) and K2CO3 (10.01 g, 72.4 mmol) in THF (200 mL) at 0° C. was treated with bromoacetyl chloride (3.02 mL, 36.2 mmol). After 2 h the resulting mixture was allowed to warm to rt. A 2M Me2NH solution in THF (54.3 mL, 109 mmol) was added. After 18 h the resulting thick slurry was filtered and the solids were washed with EtOAc. The filtrate was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2. The foamy oily product was chased using CH2Cl2 and hexanes, CH2Cl2 and Et2O, then Et2O to obtain N,N-dimethyl-2-[(2S)-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethanamine as an orange solid (2.50 g, 47%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.04 Hz, 3H), 2.28 (s, 6H), 2.75 (d, J=17.21 Hz, 1H), 3.14 (d, J=14.65 Hz, 1H), 3.44 (d, J=14.65 Hz, 2H), 3.90 (s, 3H), 4.75-4.92 (m, 1H), 7.37 (s, 1H), 8.43 (s, 1H); ESIMS (M+H)+=293.88.