Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=O.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1/[CH:1]=[CH:16]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:6]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccccc1C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccccc1C#N
Temperature: 110 °C

Procedure:
2-Formylbenzonitrile (5 g, 38.1 mmol) was added to a round bottom flask, equipped with a stir bar, and dissolved in toluene (50 mL). (Carbethoxymethylene)triphenylphosphorane (14.6 g, 41.9 mmol) was then added to the mixture. The reaction was heated at 110° C. for 20 hours. The solution was concentrated under vacuum, and the residue was redissolved in dichloromethane. The solution was passed though a plug of silica (dichloromethane eluent) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.37 (t, 3H, J=7.12 Hz), 4.30 (q, 2H, J=7.12 Hz), 6.61 (d, 1H, J=15.94 Hz), 7.47 (dt, 1H, J=7.71 Hz, J=1.19 Hz), 7.62 (dt, 1H, J=7.80 Hz, J=1.36 Hz), 7.7-7.75 (m, 2H), 7.97 (d, 1H, J=15.94 Hz); MS (DCI+) m/z 218.9 [M+NH3]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C@H:11]1[CH2:16][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[CH2:14][CH2:13][N:12]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:22]2[CH:23]=[C:18]([CH2:17][N:15]3[CH2:14][CH2:13][N:12]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:11]([CH3:10])[CH2:16]3)[CH:19]=[CH:20][CH:21]=2)[CH:7]=1)#[N:9]
Reactant: C[C@H]1CN(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CCN1C(=O)OC(C)(C)C
Reactant: N#Cc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CN(Cc2cccc(-c3cc(C#N)ccn3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 93.4 %

Procedure:
To 2-chloro-4-pyridinecarbonitrile (0.416 g, 3 mmol) was added 1,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (1.499 g, 3.60 mmol) followed by K2CO3 (1.244 g, 9.00 mmol) and Pd(Ph3P)4 (0.139 g, 0.120 mmol) in 1,4-dioxane (15.00 mL) and water (5.00 mL). The mixture was heated in a microwave for 30 min at 140° C. The organic layer was collected and the aqueous layer was extracted once with EtOAc (3 mL). The organic layer was filtered, evaporated on Glas-Coll, redissolved in hexane/DCM 4 mL (3/1), loaded onto Redisep gel column (12 g) (Teledyne Isco Co. Lincoln, Nebr., USA; http://www.isco.com/combiflash/) and purified with Combiflash chromatography. Fractions were collected and the solvent was removed under reduced pressure to afford 1.10 g (94%) of the title compound. LC-MS m/z 393 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)[CH3:5].C(O)C>[C].[Pd].O>[ClH:1].[ClH:1].[CH3:3][N:4]([CH2:6][CH:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:5]
Reactant: CN(C)CC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(C)CC1CNCCO1

Procedure:
A mixture of 22.5 g of 4-benzyl-2-chloromethylmorpholine, 200 ml of ethanol and 200 ml of an aqueouos 26,7% dimethylamine solution is heated at 150° C. for 5 hours in an autoclave. After completion of the reaction, the solvent is distilled off under reduced pressure. After adding water, the residue is extracted with toluene three times. The extract is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is treated with 37% hydrochloric acid-ethanol to give 2-(N,N-dimethylaminomethyl)-4-benzylmorpholine dihydrochloride as white crystals. A mixture of 22.9 g of the hydrochloride compound, 200 ml of ethanol and 100 ml of water is subjected to catalytic reduction with 2.3 g of 10% palladium-carbon at ordinary temperature and atmospheric pressure. After absorbing a theoretical volume of the hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The obtained residue is treated with ethanol to give 2-(N,N-dimethylaminomethyl)morpholine dihydrochloride as white crystals, melting at 270°-271° C.
Reaction SMILES: [CH3:1][C:2]([C:8]1[O:12][N:11]=[C:10]([CH2:13]O)[CH:9]=1)([O:4][CH2:5][C:6]#[CH:7])[CH3:3].S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH2:13][C:10]1[CH:9]=[C:8]([C:2]([CH3:3])([O:4][CH2:5][C:6]#[CH:7])[CH3:1])[O:12][N:11]=1
Reactant: C#CCOC(C)(C)c1cc(CO)no1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C#CCOC(C)(C)c1cc(CCl)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.20 g of {5-[1-methyl-1-(2-propynyloxy)ethyl]isoxazol-3-yl}methanol was dissolved in 5 ml of dichloromethane, and 0.5 ml of thionyl chloride was then added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.21 g of 3-(chloromethyl)-5-[1-methyl-1-(2-propynyloxy)ethyl]isoxazole.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:28])[C:14]([C:25](=O)[CH3:26])=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:29][C:30]([CH3:35])=[CH:31][N+:32]([O-:34])=[O:33]>C(O)(C)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C:14]3[CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=4)[C:31]([N+:32]([O-:34])=[O:33])=[C:30]([CH3:35])[NH:29][C:25]=3[CH3:26])=[O:28])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)N1CCN(c2ccccc2)CC1
Reactant: CC(N)=C[N+](=O)[O-]
Solvent: CC(C)O
Product: CC1=C(C(=O)N2CCN(c3ccccc3)CC2)C(c2cccc([N+](=O)[O-])c2)C([N+](=O)[O-])=C(C)N1

Procedure:
2.5 g (10 mmol) of crude 2-acetyl-3-(3-nitrophenyl)-2-propenoic acid 4-phenyl-piperazide and 2.5 g (25 mmol) of 2-amino-1-nitro-1-propene are heated in 15 ml of isopropanol at 60° C. for 6 hours. The crude product which has precipitated out is crystallized from isopropanol.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:33]([CH:34]=O)=[CH:32][N:31]=[C:30]([S:36][CH3:37])[N:29]=2)[CH:24]=[CH:25][CH:26]=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.[Cl:38][C:39]1[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[C:40]=1[NH2:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.O1CCCC1.O>[Si:1]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:33]([CH2:34][NH:41][C:40]3[C:42]([CH3:46])=[CH:43][CH:44]=[CH:45][C:39]=3[Cl:38])=[CH:32][N:31]=[C:30]([S:36][CH3:37])[N:29]=2)[CH:24]=[CH:25][CH:26]=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: CSc1ncc(C=O)c(Nc2cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Reactant: Cc1cccc(Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncc(CNc2c(C)cccc2Cl)c(Nc2cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Reaction time: 1 h
Yield: 101 %

Procedure:
A mixture of 2.6 g (5 mmol) of 4-(3-(2-(tert-butyldiphenylsilyloxy)ethyl)phenylamino)-5-formyl-2-methylthiopyrimidine and 0.63 ml (722 mg, 5.1 mmol) of 2-chloro-6-methylaniline in 80 ml of toluene was treated with 170 mg (0.9 mmol) of 4-toluenesulfonic acid monohydrate and then heated at reflux with azeotropic removal of water for 2 hours. The mixture was cooled and evaporated. The residue was dissolved in 20 ml of tetrahydrofuran and added dropwise to a solution of 5 ml (5 mmol) of lithium aluminium hydride (1M solution in tetrahydrofuran) in a further 30 ml of tetrahydrofuran. After stirring for 1 hour the reaction was quenched by the cautious dropwise addition of 1.5 ml of water, 2 ml of 2M aqueous sodium hydroxide and 2.5 ml of water. The mixture was filtered through a filter aid and the filtrate evaporated to give 3.3 g (100%) of 4-[3-(2-(tert-butyldiphenylsilyloxy)ethyl)phenyl]amino-5-(2-chloro-6-methylanilino)methyl-2-methylthiopyrimidine as a yellow oil which was used without further purification. [Mass spectrum (ESI) MH+ =653].
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([O:33]C)=[O:32])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][C:17]4[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([OH:33])=[O:32])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][C:17]4[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCN1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc2C1
Temperature: 25 °C

Procedure:
A solution of methyl 14-cyclohexyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (0.16 M, 1 eq, from Step 4) in MeOH and 1N NaOH (4 eq) was heated to 80° C. for 6 h. After cooling to RT, the MeOH was removed under reduced pressure and the resulting aqueous solution acidified with aqueous 3N HCl until pH 1-2 resulting in formation of a pale yellow precipitate. This was filtered off and dried on the filter overnight to afford the crude hydrochloride salt of the product as a yellow solid. Purification was by RP-HPLC (stationary phase: column Waters XTERRA prep. MS C18, 5 μm, 30×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried (2×) in the presence of 3N aqueous HCl to afford the bis-HCl salt of the title compound as a white powder (65% over steps 3, 4 and 5).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)[C:6]([N+:19]([O-])=O)=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:19][C:6]1[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N)c(Nc2ccc(CCO)cc2)n1

Procedure:
A mixture of 2-{4-[(6-methoxy-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1, 3.52 g, 12.17 mmol), iron powder (3.4 g, 60.84 mmol) and ammonium chloride (325 mg, 6.08 mmol) in ethanol/water (v/v, 2:1, 90 mL) was heated at reflux temperature for 1 h. After cooling, the catalyst was removed and the filtrate was concentrated. The residue was extracted with ethyl acetate (100 mL) and washed with water. The organic layer was dried (MgSO4), and concentrated to give 3.41 g (quant.) of the title compound as a black oil: 1H-NMR (CDCl3) δ 7.48 (2H, d, J=8.4 Hz), 7.14 (2H, d, J=8.4 Hz), 7.04 (1H, d, J=8.2 Hz), 6.75 (1H, br.s), 6.13 (1H, d, J=8.2 Hz), 3.87 (3H, s), 3.83 (2H, t, J=6.6 Hz), 2.81 (2H, t, J=6.6 Hz).
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=1)C.O=P(Cl)(Cl)[Cl:17]>CN(C=O)C>[Cl:17][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1ccnc(N2CCCC2)n1
Solvent: CN(C)C=O
Product: Clc1ccnc(N2CCCC2)n1

Procedure:
4-Ethoxy-2-pyrrolidin-1-ylpyrimidine (2.0 g, 10 mol) was added to 15 mL of POCl3, followed by the addition of 0.5 ml of DMF. The reaction mixture was irradiated under microwave at 160° C. for 1.5 h. Most of the solvent was evaporated in vacuo. The residue was added in portions to ice-water containing ammonia. The precipitate was filtered off. The aqueous filtrate was extracted with EtOAc. The organic phase was dried over sodium sulfate, filtered, and concentrated. The solid precipitate was combined with the crude residue and purified by silica gel column chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH3:17])([C:12]([O:14]CC)=[O:13])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+:18].[OH-]>C1COCC1.O>[Li+:18].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH3:17])([C:12]([O-:14])=[O:13])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(C)(C)Nc1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Nc1ccc(Cl)c(Cl)c1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 50-mL round bottom flask equipped with a magnetic stirring bar was charged with ethyl N-(3,4-dichlorophenyl)-2-methylalaninate (790 mg, 2.9 mmol) and dissolved in 3 mL of THF. A solution of LiOH (132 mg, 5.8 mmol) dissolved in 1.0 mL of H2O was added and the mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure. A total of 846 mg (90%) of N-(3,4-dichlorophenyl)-2-methylalanine as a yellow solid was recovered as the lithium salt, after drying under vacuum for 24 h. MS (ES) m/z 248 [M+H]+
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:25][CH:26]=1)=[O:7]
Reactant: COC(=O)C(=O)Cl
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(NC(=O)C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl chlorooxoacetate (72 μL, 0.77 mmol) was added in one portion to a stirred solution of ethyl cis-4-(4-aminophenoxy)cyclohexanecarboxylate (204 mg, 0.77 mmol) and pyridine (76 μL, 0.93 mmol) in DCM (5 mL) and the reaction mixture was stirred at room temperature for 1 h. Concentration in vacuo left a residue which was taken up in EtOAc (50 mL) and an aqueous solution of hydrochloric acid (1M, 30 mL) was added. The layers were separated and the organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to leave an oil. The oil was purified by column chromatography, using a gradient of 10-70% ethyl acetate:isohexane as eluent, to give the title compound (Intermediate 108) (188 mg, 70%) as an oil; 1H NMR (CDCl3) δ 1.23-1.28 (3H, t), 1.57-1.68 (2H, m), 1.71-1.78 (2H, m), 1.92-2.04 (4H, m), 2.36-2.43 (1H, m), 3.96 (3H, s), 4.14 (2H, q), 4.43-4.45 (1H, m), 6.89-6.93 (2H, d), 7.51-7.55 (2H, d), 8.76 (1H, s); MS m/e (M−H)− 348.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=1.B>>[NH2:25][CH2:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:4]2[C:5]3[C:6]4[CH:16]=[CH:15][S:14][C:7]=4[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])=[CH:22][CH:21]=1)([CH3:27])[CH3:26]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)C#N)cc1
Agent: B
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)CN)cc1
Yield: 39.4 %

Procedure:
Following the procedure outlined for Example 265, 2-[4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl]-2-methylpropanenitrile (250 mg, 0.67 mmol) was reacted with borane (1.0 M in THF, 10 mL, 10.0 mmol) to afford the desired product (100 mg, 40%) as a yellow solid: ESI MS m/z 379 [C22H22N2O2S+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]2[CH:3]=1.[C:26]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]3[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=3)[N:5]3[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]3[CH:3]=2)=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Cl)cc2n1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(-c3ccc(C(C)(C)C)cc3)cc2n1

Procedure:
In analogy to the procedure described for Example 7, 34 mg (23% of theory) of the product are obtained starting from 120 mg (0.32 mmol) of N6-{2-[(7-chloro-2-methylimidazo[1,2-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 31A) by coupling with 68 mg (0.38 mmol) of (4-tert-butylphenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:20])=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([N+:21]([O-])=O)[CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]2[C:6]([F:20])=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:13])[C:9]=2[CH:10]=1
Reactant: O=[N+]([O-])c1cc(Br)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(Br)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Reaction time: 0.08 h

Procedure:
6-Bromo-3-fluoro-4-nitro-1-(phenylsulfonyl)-1H-indazole (5.9 g) was suspended in acetic acid (60 ml) and iron powder (4.12 g) was added. The suspension was heated to reflux. After 2 h the reaction mixture was diluted with ethyl acetate (100 ml) and filtered through celite. The filter cake was washed well with ethyl acetate then the filtrate basified to pH 8-9. The biphasic system was then stirred for ˜5 min. The layers were then separated, the aq washed with ethyl acetate and the combined organics washed with brine, dried (magnesium sulphate), filtered and concentrated in vacuum to yield a crude loaded onto a 330 g silica cartridge, purified on a 0-100% ethyl acetate:cyclohexane gradient and the relevant fractions combined and concentrated to yield the title compound, 2.4 g as a yellow solid.
Reaction SMILES: Cl.[CH2:2]([C:4]1[S:5][CH:6]=[C:7]([C:9]([NH2:11])=[NH:10])[N:8]=1)[CH3:3].[O-]CC.[Na+].C(O[CH:19]=[CH:20][C:21]#[N:22])C>>[CH2:2]([C:4]1[S:5][CH:6]=[C:7]([C:9]2[N:11]=[C:21]([NH2:22])[CH:20]=[CH:19][N:10]=2)[N:8]=1)[CH3:3]
Reactant: CCc1nc(C(=N)N)cs1
Reactant: CCOC=CC#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCc1nc(-c2nccc(N)n2)cs1

Procedure:
This material was obtained as described in example 2, step A] from 2-ethyl-thiazole-4-carboxamidine hydrochloride (3 g) by treatment with sodium ethoxide (3.13 mL of a 5.4 M solution) and 3-ethoxyacrylonitrile (1.73 mL) to give 2-(2-ethyl-thiazol-4-yl)-pyrimidin-4-ylamine (2.56 g) as a brown solid. MS (ESI): 193.3 (MH+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][C@@H:6]2[CH2:8][CH2:9][C@H:3]1[C@@H:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:5]2[C@@H](C1C=CC=CC=1)C>C(O)C.[OH-].[OH-].[Pd+2]>[OH:1][C@@H:2]1[CH2:7][C@@H:6]2[CH2:8][CH2:9][C@H:3]1[C@@H:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:5]2
Reactant: CCOC(=O)[C@@H]1[C@@H]2CC[C@@H](C[C@H]2O)N1[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@H]1N[C@H]2CC[C@@H]1[C@H](O)C2
Reaction time: 3 h

Procedure:
To a solution of ethyl (1S,3S,4S,5R)-5-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]octane-3-carboxylate obtained in Example 2-3 (22 g) in ethanol (300 mL), was added Pearlman's catalyst (4 g). The mixture was stirred for 3 hrs under H2 atmosphere on 4 atm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:8][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(C(C)C)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-isopropylphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 421.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=[O:7].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:20][CH:19]=1.C(N(CC)CC)C.C(O)C>CCOCC>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=3)=[O:7])[CH2:31][CH2:32]2)=[CH:20][CH:19]=1
Reactant: Clc1ccc(CCCN2CCNCC2)cc1
Reactant: N#Cc1ccc(NC(=O)NCCCCl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: N#Cc1ccc(NC(=O)NCCCN2CCN(CCCc3ccc(Cl)cc3)CC2)cc1
Yield: 42 %

Procedure:
A mixture of 1-(3-chloropropyl)-3-(4-cyanophenyl)urea (3.57 g; 15 mmole), 1-[3-(4-chlorophenyl)propyl]piperazine (3.58 g; 15 mmole), triethylamine (1.52 g; 15 mmole), and ethanol (100 ml) was refluxed for 35 hours. The solvent was removed in vacuo and water added to the residue. The product was extracted with ether, dried, and concentrated in vacuo. The resulting reddish-yellow oil was purified on a silica gel column (methylene chloride/methanol 9:1) to give the product as a free base (2.8 g; 42% yield). The product was dissolved in ether and precipitated with ethereal hydrochloric acid to provide, after recrystallization from water, the title compound as colorless crystals, m.p. 219°-221° C.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[CH3:16][C:13]1([CH3:17])[CH2:14][O:15][CH:10]([CH2:9][OH:8])[O:11][CH2:12]1
Reactant: [H][H]
Reactant: CC1(C)COC(COCc2ccccc2)OC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC1(C)COC(CO)OC1
Yield: 85 %

Procedure:
The 2-((benzyloxy)methyl)-5,5-dimethyl-1,3-dioxane (7.6 g, 32.2 mmol) obtained by the step (1a) was mixed with 20% palladium hydroxide (700 mg) and ethyl acetate (70 ml). The mixture was stirred in a hydrogen atmosphere overnight. The reaction mixture was allowed to stand for further 5 days in the same hydrogen atmosphere. The reaction vessel was purged with nitrogen, the catalyst was filtered off, and the solvent was distilled off to obtain the title compound (4 g, yield: 85%) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1B(O)O.OP([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH3:11][N:8]1[CH:7]=[C:6]2[C:10]([C:2]([C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])=[CH:3][CH:4]=[CH:5]2)=[N:9]1
Reactant: Cn1cc2cccc(Br)c2n1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cccc3cn(C)nc23)c(C)c1
Temperature: 69 °C
Reaction time: 156 h
Yield: 60.4 %

Procedure:
A mixture of 7-bromo-2-methyl-2H-indazole (6: R=Me; 2.01 g, 9.53 mmol), 2,4,6-trimethylphenyl boronic acid (1.70 g, 10.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.657 g, 0.569 mmol), 70 mL of DMF, and 33 mL of a 2 M aqueous K2HPO4 solution was stirred at 69° C. for 6.5 d. The mixture was partitioned between 350 mL of diethyl ether and 350 ML of water. The organic layer was washed with 350 mL of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to a pale yellow oil. Column chromatography (0→33% EtOAc/hexanes) afforded of impure 2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazole (5: R=Me, Ar=2,4,6-trimethylphenyl; 1.44 g) as a white solid that was used without further purification.