Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[C@H:27]([CH:28]=O)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]1[C@H:27]([CH:28]=[CH2:1])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C[C@@H]1Cc2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.07 g, 5.8 mmol) in THF (20 mL) at −78° C. is added KHMDS (11.0 mL, 5.5 mmol) and the mixture is stirred for 1.5 h. A solution of (S)-3-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.94 g, 3.6 mmol) in THF (10 mL) is added and the solution stirred at −78-C for 1.5 h before warming to RT. The reaction is quenched with water (10 mL) and extracted with EtOAc (2×30 mL). The organic extracts are washed with 1N HCl (3×35 mL), brine (2×30 mL) and dried over Na2SO4. Purification by flash chromatography using a gradient of 0-15% EtOAc/hexane affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].[C:13]1(=O)[C:26]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][C:14]1=O>CC(C)=O>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]2[C:3]=1[N:4]=[C:24]1[C:25](=[N:10]2)[C:26]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]1=2
Reactant: Nc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Reactant: O=C1C=Cc2c(ccc3ccccc23)C1=O
Solvent: CC(C)=O
Product: Clc1cc(Cl)c2nc3c4ccccc4c4ccccc4c3nc2c1
Yield: 81 %

Procedure:
When 0.12 mole each of 2,4-dichloro-6-nitroaniline and phenanthrenequinone were reacted by the method of Example 1, 24 g. (81 percent yield) of 10,12-dichlorodibenzo[a,c]phenazine, mp = 221°-222° C. (acetone), were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28]([O:30]C)=O)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][NH2:37]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28]([NH:37][CH3:36])=[O:30])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Reactant: CN
Product: CNC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Yield: 63 %

Procedure:
Using the same procedure as in Example 26, methyl (2S)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.42 mmol) was reacted with methylamine to give the title compound as a white solid (126 mg, 63%) except that the crude material was purified on an HPLC column (C18, 5 microns, 19 mm diameter, 100 mm length) of a preparative HPLC-MS system eluting with a mixture of water and acetonitrile containing 2 g/l of ammonium carbonate (gradient). NMR Spectrum 1.65 (d, 3H), 2.67 (d, 3H), 5.16 (q, 1H), 5.71 (s, 2H), 7.00 (d, 1H), 7.04-7.10 (m, 3H), 7.36 (dd, 2H), 7.71-7.77 (m, 3H), 8.17 (s, 1H), 8.37 (m, 1H), 8.53 (s, 1H), 8.55 (s, 1H), 10.68 (br s, 1H); Mass spectrum MH+ 471.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Temperature: 0 °C

Procedure:
Morpholine (58.2 mg, 0.668 mmol) and triethylamine (116 μl, 0.835 mmol) were placed in a round-bottom flask with a stir bar. Dry dichloromethane (5870 μL) was then added and the solution cooled to 0° C. 4-bromobenzenesulfonyl chloride (150 mg, 0.556 mmol) was added and the reaction was allowed to warm to room temperature overnight. It was quenched with water and extracted in ethyl acetate. The organic layers were washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 4-[(4-bromophenyl)sulfonyl]morpholine as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:27]([N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35])(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:34][CH2:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=4)[CH2:14][CH2:13]3)=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[C:31]1=[O:35])(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)nc1C
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4nc(C)c(C)cc4C)CC3)c(C#N)c2)C1=O
Yield: 82.5 %

Procedure:
Using 5-bromo-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (1.24 g) described in Preparation Example 172 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.14 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:33])[C@@H:20]([NH:25]C(OC(C)(C)C)=O)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([OH:34])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:33])[C@@H:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([OH:34])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCN(C(=O)OCc2ccccc2)CC1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)C[C@H](N)C(=O)NC1CCCN(C(=O)OCc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.2 %

Procedure:
To a solution of 4-((S)-2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-3-hydroxy-azepan-1-carboxylic acid benzyl ester of Example 2f (4.0 g) in methanol (20 mL) was added 4M HCl in dioxane (20 mL). The reaction was stirred at room temperature for 2 hours whereupon it was concentrated to provide the title compound (3.8 g): MS(EI) 378 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:22][CH2:23][C:24]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][C@H:27]2[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:25])=[O:19])[NH2:17])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN1CCOCC1.[CH2:52]1[O:72][C:71]2[CH:70]=[CH:69][C:56]([CH2:57][O:58][C:59](ON3C(=O)CCC3=O)=[O:60])=[CH:55][C:54]=2[O:53]1>C(Cl)Cl>[CH2:52]1[O:72][C:71]2[CH:70]=[CH:69][C:56]([CH2:57][O:58][C:59]([NH:17][C@H:16]([C:18]([NH:20][C@@H:21]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:22][CH2:23][C:24]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][C@H:27]3[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:25])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:10][C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)=[O:60])=[CH:55][C:54]=2[O:53]1
Reactant: CCOC(=O)[C@@H](CCC(=O)N1c2ccccc2C[C@H]1C(=O)OCC)NC(=O)[C@@H](N)CCCCNSc1ncccc1[N+](=O)[O-]
Reactant: O=C(OCc1ccc2c(c1)OCO2)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H](CCC(=O)N1c2ccccc2C[C@H]1C(=O)OCC)NC(=O)[C@H](CCCCNSc1ncccc1[N+](=O)[O-])NC(=O)OCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
An aliquot (1.0 g) of the resulting ester was dissolved in 30 ml of methylene chloride, and 0.21 g of N-methylmorpholine and 1.07 g of N-(3,4-methylenedioxybenzyloxycarbonyloxy)succinimide were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed successively with saturated aqueous sodium bicarbonate solution, 5% aqueous potassium hydrogensulfate solution, and water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol/methanol to give 1.1 g of ethyl 1-[N2 -(3,4-methylenedioxybenzyloxycarbonyl)-N6 -(3-nitro-2-pyridinesulfenyl)-L-lysyl-O1 -ethyl-gamma-D-glutamyl]indoline-2(S)-carboxylate. mp. 130°-135° C. [α]D27 : -23.2° (dimethylformamide).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2cccnc2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2cccnc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(pyridin-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 403.00 g/mol.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH2:8])[CH:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C([O-])(=O)C.[NH4+:18]>CO>[NH2:18][C:2]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH2:8])[C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: [NH4+]
Reactant: C=CC1CCC(=O)C1C(=O)OCC
Agent: CC(=O)[O-]
Solvent: CO
Product: C=CC1CCC(N)=C1C(=O)OCC
Temperature: 50 °C
Yield: 37.6 %

Procedure:
Ethyl 2-oxo-5-vinylcyclopentanecarboxylate (0.48 g, 2.79 mmol) was mixed with ammonium acetate (2.15 g, 27.9 mmol) in MeOH (10 mL). The mixture was heated to 50° C. for 2 hours. The contents were concentrated. The residue was partitioned between DCM and water. The DCM layer was separated, and the aqueous layer was extracted with DCM. The combined DCM solutions were dried (Na2SO4). The crude was purified with flash chromatography to give ethyl 2-amino-5-vinylcyclopent-1-enecarboxylate (0.19 g, 41% for 2 steps). 1H NMR (CDCl3, 400 MHz) δ (ppm): 5.59-5.58 (m, 1H), 5.05-4.88 (m, 2H), 3.68 (s, 3H), 3.52-3.46 (m, 1H), 2.66-2.56 m, 1H), 2.38-2.30 (m, 1H), 2.13-2.03 (m, 1H), 1.70-1.62 (m, 1H), 1.61 (br s, 2H). MS: 168.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:20]C(Br)C.O>C1COCC1>[Br:20][C:5]1[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC(Br)Br
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
A solution of N-(6-chloro-2-pyridinyl)-2,2-dimethylpropanamide (4.83 g, 22.7 mmol) in THF (40 ml) at −78° C. under argon was treated with n-butyl lithium (20 ml, 2.5M in Hexanes, 50 mmol) over 10 min and then allowed warm to 0° C., stirred at 0° C. for 3 h and then recooled to −78° C. The reaction was then treated dropwise with dibromoethane (2.057 ml, 23.9 mmol) and the reaction was allowed warm to rt and stirred at rt for 0.5 h. The reaction was then treated with water (5 ml), stirred at rt for 5 min, treated with more water (500 ml) and extracted with diethyl ether (3×500 ml). The organic extracts were dried (MgSO4), filtered, evaporated and the residue chromatographed (0-25% ethyl acetate:Hexane) to give the product as a yellow solid (3.489 g, 53%).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=O)[S:16][CH:17]=1.[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:9][C:10]#[N:11])[S:16][CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1cc(Br)cs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#CC=Cc1cc(Br)cs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
A solution of diethyl(cyanomethyl)phosphonate (2.1 mL, 12.9 mmol) in anhydrous THF (50 mL) was cooled to 0° C. under nitrogen and treated with KN(TMS)2 (11 mmol of a 0.5 M solution in toluene). After stirring for 15 min at 0° C., a solution of 4-bromo-2-thiophenecarboxaldehyde 63 (Aldrich, Wis.) (1.9 g, 10 mmol) in anhydrous THF (50 mL) was added and the resulting mixture was stirred for 30 min at 0° C. Saturated aqueous NH4Cl solution was added and the crude product extracted three times with diethylether. The ether extracts were dried over Na2SO4, filtered, and evaporated, and the product was purified by flash chromatography on a silica gel column (eluent: 5% EtOAc in hexane). The major fractions were combined and concentrated to give 76 (2.1 g) in 9.3 to 1 ratio of trans to cis isomers as a white solid; For trans isomer: 1H NMR (400 MHz, d6-DMSO) δ: 7.90 (s, 1H), 7.77 (d, J=16.5 Hz, 1H), 7.57 (s, 1H), 6.28 (d, J=16.5 Hz, 1H); For cis isomer: 1H NMR (400 MHz, d6-DMSO) δ 7.97 (s, 1H), 7.65 (s, 1H), 7.57 (d, J=11.1 Hz, 1H), 5.82 (d, J=11.7 Hz, 1H). MS (EI) m/z [(M+H+) (79Br)] 214 and [(M+H+) (81Br)] 216.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[CH3:13][C:14](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:15]=O.Cl>>[CH3:13][C:14](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:15]=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1
Reactant: CC(C=O)=Cc1ccccc1
Reactant: NNC1=NCCc2ccccc21
Agent: Cl
Product: CC(C=NNC1=NCCc2ccccc21)=Cc1ccccc1

Procedure:
In a manner similar to that of Example 4, condensation of 1-hydrazino-3,4-dihydroisoquinoline (7.3 g.) and α-methylcinnamaldehyde (6.56 g.) and treatment of the reaction mixture with hydrochloric acid gave a solid, which was recrystallized first from ethanol-ether, then twice from N,N-dimethylformamide-ether, affording 1-[2-(2-methyl-3-phenylallylidene)hydrazino]-3,4-dihydroisoquinoline (I: X=C6H5CH=C(CH3), X'=Y=Y'=Z=Z'=H) hydrochloride in two crops (5.6 g. and 4.2 g., m.p. 217°-219° C.).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[C:2]([NH2:4])=[NH:3].[CH2:10]([CH:18]1[CH2:20][CH:19]1[C:21](Cl)=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[CH2:10]([CH:18]1[CH2:20][CH:19]1[C:21]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][NH:1][C:2]([NH2:4])=[NH:3])=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N=C(N)NCCCCN
Reactant: CCCCCCCCC1CC1C(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCC1CC1C(=O)NCCCCNC(=N)N
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To 457.2 mg. of 1-amino-4-guanidinobutane (IV) suspended in 60 ml. of dry pyridine was added 2-(n-octyl)cyclopropanecarbonyl chloride. This suspension was stirred at room temperature for 40 hours. At the end of 40 hours the solid material was filtered and the filtrate concentrated to a viscous oil, which was chromatographed on silica gel using 30% methanol in CHCl3, resulting in 497.7 mg. of desired material, characterised by EIMS with M+ at m/e 310 for C17H34 -N4O.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([Sn](C)(C)C)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].I[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH2:27]1>[Cu]I.C1COCC1>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:27]3[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:42])[CH3:40])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[N:26]=3)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCN1CN(I)c2ccccc21
Reactant: C[Si](C)(C)CCOCn1nc([Sn](C)(C)C)c2ccc([N+](=O)[O-])cc21
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc([N+](=O)[O-])cc21
Yield: 82.2 %

Procedure:
6-Nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-(trimethyl-stannanyl)-1-H-indazole (7.50 g, 16.4 mmol), 3-iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzimidazole (6.50 g, 17.4 mmol), and copper(I) iodide (313 mg, 1.64 mmol) were combined with dry THF (150 mL) in a flask purged with argon. Tetrakis(triphenylphosphine)palladium(0) was added, and the reaction stirred at reflux under argon for 23 h. The reaction was cooled and adsorbed directly onto silica gel (˜16 g). Purification by silica gel chromatography (4% to 15% ethyl acetate/hexanes) gave 7.28 g (82%) of 6-nitro-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.91 (d, 1H, J=9.0 Hz), 8.59 (d, 1H, J=1.8 Hz), 8.22 (dd, 1H, J=8.7, 1.8 Hz), 7.92-7.89 (m, 1H), 7.66-7.62 (m, 1H), 7.40-7.36 (m, 2H), 6.24 (s, 2H), 5.90 (s, 2H), 3.68-3.59 (m, 4H), 0.94 (t, 2H, J=8.1 Hz), 0.86 (t, 2H, J=8.1 Hz), −0.04 (s, 9H), −0.15 (s, 9H). Anal. (C26H37N5O4Si2) C, H, N. Calculated: C, 57.85; H, 6.91; N, 12.97. Found: C, 57.60; H, 6.81; N, 12.82.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[F:18][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=2)=[N:3][CH:4]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2[nH]ccc2c1
Reactant: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(Nc3ccc4[nH]ccc4c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[(1H)-indol-5-yl]-4-pyrimidineamine and 3-hydroxyaniline were reacted to provide 5-fluoro-N2-(3-hydroxyphenyl)-N4-[(1H)-indol-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 11.13 (s, 1H), 10.25 (bs, 1H), 9.87 (bs, 1H), 9.43 (bs, 1H), 8.16 (d, 1H, J=5.1 Hz), 7.89 (d, 1H, J=0.09 Hz), 7.39-7.27 (m, 3H), 7.03-6.94 (m, 2H), 6.83 (s, 1H), 6.48 (d, 1H, J=7.5 Hz), 6.40 (t, 1H, J=2.1 Hz); LCMS: purity: 92%; MS (m/e): 336(MH+).
Reaction SMILES: OCC1C=CC([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=CC=1.[OH:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1>>[OH:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:47][CH:46]=1
Reactant: OCCCc1ccc(B(O)O)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CO)cc5)cc4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CCCO)cc5)cc4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 65, using 4-(3-hydroxypropyl)phenylboronic acid in place of 4-(hydroxymethyl)phenylboronic acid. ES/MS calcd. for C33H32N3O5S+ 582.2. Found m/z=582.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][C@H:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)(Cl)Cl>[C:29]([O:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][C@H:8]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CN1CC[C@@H](Oc2ccc(O)cc2)[C@H](c2ccccc2)C1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(O[C@@H]2CCN(C)C[C@H]2c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
A suspension of 3.21 g of trans-4-(4-hydroxyphenoxy)-1-methyl-3-phenylpiperidine in 150 ml of dry chloroform containing 1.72 ml of triethylamine is cooled in a cold water bath under nitrogen while 0.88 ml of acetyl chloride is added via syringe. After 3.5 hours at room temperature another 0.43 ml of triethylamine and 0.22 ml of acetyl chloride are added. After an additional 30 minutes stirring, the solvent is removed in vacuo and the residue is triturated with a mixture of ether (150 ml) and hexane (100 ml). The mixture is then filtered and the solid washed once with ether. The filtrate is concentrated in vacuo to an oil which crystallizes upon standing to a pale yellow oily solid. The oil is dissolved in 50 ml of boiling hexane and filtered. The filtrate is concentrated in vacuo to an oil which crystallizes under high vacuum to a nearly colorless, crystalline solid. The solid is dissolved in 25 ml of boiling hexane and the solution is allowed to cool. After standing overnight at room temperature the mixture is filtered, the solid washed with hexane and dried to afford product as colorless crystals, mp 79.5°-82° C.
Reaction SMILES: [CH2:1]([C@@H:3]1[NH:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)[CH3:2].[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>C(Cl)Cl>[CH2:1]([C@H:3]1[CH2:4][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH3:2]
Reactant: CC[C@H]1CN(Cc2ccccc2)CCN1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the product from example 69 part b) (4.74 g) in DCM (150 ml) was added (BOC)2O (5.52 g) and the reaction stirred at RT for 48 h. The reaction was concentrated under reduced pressure. The crude product was purified by chromatography (silica, (0-10% EtOAc/isohexane as eluent)), to give the sub-titled compound as a colourless oil (6.09 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[C:28]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[N:29]=2)[CH:26]=1>CN(C)C=O.O1CCCC1>[CH:33]1([C:31]([NH:30][C:28]2[N:29]=[C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]4[CH:18]=[C:17]([NH:16][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=5)=[O:9])[CH:38]=[CH:37][CH:36]=4)=[CH:26][N:25]3[CH:27]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Reactant: Cn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1nccc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Yield: 50.5 %

Procedure:
In the same manner as in Example 7-4 and using 1-methyl-1H-pyrazole-5-carboxylic acid (73.6 mg, 0.584 mmol), oxalyl chloride (102 μL, 1.17 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop) and N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (60.0 mg, 0.195 mmol) as starting materials, the title compound (41.0 mg, 50%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[C:3]([Cl:9])[C:4](OCC)=[O:5].[CH:16]([NH2:18])=O.C[O-].[Na+]>CO>[Cl:9][C:3]1[C:4]([OH:5])=[N:18][CH:16]=[N:1][C:2]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(Cl)=C(N)c1ccccc1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Oc1ncnc(-c2ccccc2)c1Cl

Procedure:
45.73 g (0.20 mol) of ethyl 3-amino-2-chloro-3-phenyl-propenoate are reacted with 31.9 g (0.71 mol) of formamide and 93 ml of sodium methylate solution in 120 ml of methanol and worked up in analogy to Example 9 (reaction time 16 h). Yield: 32.9 g (79.7%)