Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([C:21]([NH2:23])=[O:22])[CH:20]=2)[NH:17][N:16]=[C:15]3[CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[CH3:39][N:40]1[CH:44]=[C:43]([S:45](Cl)(=[O:47])=[O:46])[N:42]=[C:41]1[CH3:49]>CN(C1C=CN=CC=1)C>[CH3:39][N:40]1[CH:44]=[C:43]([S:45]([N:27]2[CH2:28][CH2:29][CH:24]([C:15]3[C:14]4[C:18](=[C:19]([C:21]([NH2:23])=[O:22])[CH:20]=[C:12]([C:8]5[CH:9]=[CH:10][CH:11]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=5)[CH:13]=4)[NH:17][N:16]=3)[CH2:25][CH2:26]2)(=[O:47])=[O:46])[N:42]=[C:41]1[CH3:49]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: CS(=O)(=O)Nc1cccc(-c2cc(C(N)=O)c3[nH]nc(C4CCNCC4)c3c2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5cccc(NS(C)(=O)=O)c5)cc34)CC2)cn1C
Yield: 12.5 %

Procedure:
Following the general procedure of Example 11, 5-{3-[(methylsulfonyl)-amino]phenyl}-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Example 67) (0.07 mmol), diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (33 mg, 0.17 mmol) were reacted to give the title compound (5 mg, 13% for 3 steps).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][OH:27])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: CNCCO
Product: CN(CCO)CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and 2-(Methylamino)Ethanol were converted to yield 2-({4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-methyl-amino)-ethanol, MS: 391 (MH+, 1Cl).
Reaction SMILES: [CH3:1][CH:2]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([C:12]3[N:16](C4CCCCO4)[N:15]=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][NH:3]1.[Cl:23][C:24]1[C:32]([C:33]([F:36])([F:35])[F:34])=[C:31]([F:37])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:23][C:24]1[C:32]([C:33]([F:35])([F:36])[F:34])=[C:31]([F:37])[CH:30]=[CH:29][C:25]=1[C:26]([N:3]1[CH2:4][CH2:5][C:6]2[C:11]([C:12]3[NH:16][N:15]=[CH:14][CH:13]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH:2]1[CH3:1])=[O:27]
Reactant: CC1NCCc2c(-c3ccnn3C3CCCCO3)ncnc21
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CC[SiH](CC)CC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1c2ncnc(-c3ccn[nH]3)c2CCN1C(=O)c1ccc(F)c(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of the product of Example 112, step g (60 mg, 0.20 mmol) in DCM (2 mL) was added 2-chloro-4-fluoro-3-(trifluoromethyl)benzoic acid (49 mg, 0.20 mmol), followed by EDCI (116 mg, 0.607 mmol), HOBt (19 mg, 0.14 mmol) and TEA (2.0 mL, 0.607 mmol). The reaction was stirred at room temperature overnight. The crude mixture was treated directly with TFA (0.8 mL) and triethylsilane (81 L, 0.20 mmol) and stirred for 3 h. The solvents were removed in vacuo and the residue was azeotroped with toluene (1×). Chromatography on SiO2 eluted with EtOAc/Hex afforded the desired product (59 mg, 66%). MS (ESI) mass calcd. C19H14ClF4N5O, 439.1. m/z found 440.1 [M+H]+. 1H NMR (500 MHz, MeOD): 9.08-8.87 (m, 1H), 7.92-7.68 (m, 2H), 7.57-7.44 (m, 1H), 7.10-6.92 (m, 1H), 5.71-5.63 (m, 1H), 3.68-3.33 (m, 3H), 3.19-3.08 (m, 1H), 1.77-1.56 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[NH:5][CH:6]=[N:7]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:30]([O:36][CH2:37]Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:30]([O:36][CH2:37][N:5]1[C:4](=[O:14])[C:3]2[C:8](=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:2]=2[OH:1])[N:7]=[CH:6]1)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1cc(O)c2c(=O)[nH]cnc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(O)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a suspension of 5-hydroxy-7-methoxyquinazolin-4(3H)-one (4.395 g, 22.9 mmol) in DMF (50 mL) at 0° C. was added 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (55 mL, 55 mmol). After it was stirred at room temperature for 1 hour, it was cooled again with an ice-water bath and to it was added chloromethyl pivalate (4.14 g, 27.5 mmol). After it was stirred at room temperature for another hour, it was quenched with a solution of AcOH (10 mL) in water (150 mL) and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated to afford the (5-hydroxy-7-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate solid (5.674 g, 81%). 1H NMR (300 MHz, CDCl3) δ 11.36 (s, 1H), 8.16 (s, 1H), 6.69 (d, 1H), 6.51 (d, 1H), 5.88 (s, 2H), 3.89 (s, 3H), 1.21 (s, 9H); LC-MS (ESI) m/z 307 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=3)[C:39]([O:41]C)=[O:40])[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.O.CO>[C:1]([O:5][C:6]([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=3)[C:39]([OH:41])=[O:40])[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc(-c2ccc3c(c2)CC[C@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(-c3cccc(C(=O)O)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
The product from Example 85 (3.0 g, 4.8 mmol) was diluted with 10 mL each of tetrahydrofuran, water, and methanol; 15 mL of 1 N sodium hydroxide (14.4 mmol) was added; and allowed solution to stir overnight at room temperature. The solution was concentrated, water added, and neutralized with 1 N phosphoric acid. The aqueous layer was extracted with methylene chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purified by Biotage in gradient 10-30% ethyl acetate/hexanes, then flushed column with ethyl acetate to 5% methanol/ethyl acetate. Yielded 2.3 g (78%) of product. MH+=619.6
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14]O)=[CH:4][CH:3]=1.[Li+].[Br-].P(Br)(Br)[Br:19].O>CN(C=O)C>[Br:19][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCc1ccccc1-c1ccc(Cl)cc1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2ccccc2CBr)cc1
Reaction time: 1 h

Procedure:
To a mixture of Example 37A (7.9 g) and LiBr (3.45 g) in DMF (100 mL) at 0° C. was added PBr3 (3.77 mL) and the reaction was stirred for 1 hour. The reaction was poured into water (400 mL), and the mixture was extracted with ether (3×200 mL). The combined ether layers were washed with 3× water, and brine, dried over Na2SO4, and condensed to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5]C[CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.[C:16](Cl)(=[O:18])[CH3:17].CS(Cl)(=O)=O>>[C:16]([N:1]1[CH2:6][CH2:5][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:2]1)(=[O:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Reactant: CC(=O)Cl
Agent: CS(=O)(=O)Cl
Product: CC(=O)N1CCC(CNC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by substituting tert-butyl pyrrolidin-3-ylmethylcarbamate for tert-butyl piperidin-3-ylmethylcarbamate and acetyl chloride for methanesulfonyl chloride in EXAMPLE 147A.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:8][C:7]=12.[C:18]1([N:24]2[C:28]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][N:26]=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([N:32]3[CH2:33][CH2:34][N:29]([C:28]4[N:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:25]=[N:26][N:27]=4)[CH2:30][CH2:31]3)=[O:14])=[CH:9][NH:8][C:7]=12
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of 2-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (5.3 g, 20.8 mmol) (prepared as described on US20050090522A1) in DMF (100 mL) was added 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (4.8 g, 20.8 mmol), TBTU (7.4 g, 23.0 mmol), and N,N-diisopropylethylamine (12.0 mL, 68.9 mmol). The mixture was stirred at rt for 16 hr. The solvent was removed under reduced pressure, and the remaining residue was dissolved in hot MeOH. Upon cooling, precipitate formed. The precipitate was collected by filtration, and was washed with H2O (3×75 mL). The mother liquor was concentrated under reduced pressure, then subjected to a second crystallization using the same method. The combined precipitates gave 1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione as a light brown solid (7.3 g, 15.6 mmol). 1H NMR (500 MHz, CDCl3) δ 9.64 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.62-7.50 (m, 5H), 4.00 (s, 3H), 3.83-3.81 (m, 2H), 3.57-3.56 (m, 2H), 3.43-3.41 (m, 2H), 3.33-3.32 (m, 2H). LCMS: m/e 467.3 (M+H)+, ret time 1.99 min (method 2).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.C(#N)C.Br[C@H:22]([CH3:37])[C:23]([N:25]1[C@@H:33]2[C@@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27][C@H:26]1[C:34]([OH:36])=[O:35])=[O:24]>ClCCl>[CH2:6]([O:5][C:3]([C@@H:2]([NH:1][C@@H:22]([CH3:37])[C:23]([N:25]1[C@@H:33]2[C@@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27][C@H:26]1[C:34]([OH:36])=[O:35])=[O:24])[CH2:8][CH2:9][CH3:10])=[O:4])[CH3:7]
Reactant: CCC[C@H](N)C(=O)OCC
Reactant: C[C@@H](Br)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC

Procedure:
Introduce into a reactor 105 g of ethyl (2S)-2-aminopentanoate, 135 ml of triethylamine and 135 ml of acetonitrile, and then bring the mixture to 60° C. and slowly add a solution of 200 g of the compound obtained in Step A in 1.3 liters of dichloromethane, and subsequently reflux for 4 hours. After returning to ambient temperature, wash the mixture with water and with a dilute acetic acid solution, and then evaporate off the solvents to yield (2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propionyl}octahydro-1H-indole-2-carboxylic acid.
Reaction SMILES: O.[OH-].[Li+].O1CCCC1.C(OP([CH:17]1[C:26](=[O:27])[N:25]2[C@H:20]([CH2:21][O:22][CH2:23][C@H:24]2[C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=2)[CH2:19][CH2:18]1)(=O)OCC)C.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[N:47]1[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]1)[CH:42]=O>O.C(OCC)(=O)C.C(O)C>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[N:47]1[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]1)/[CH:42]=[C:17]1\[CH2:18][CH2:19][C@@H:20]2[N:25]([C:26]\1=[O:27])[C@H:24]([C:28]1[CH:29]=[C:30]([F:36])[C:31]([F:35])=[C:32]([F:34])[CH:33]=1)[CH2:23][O:22][CH2:21]2
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2COC[C@@H](c3cc(F)c(F)c(F)c3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CC[C@H]3COC[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
Lithium hydroxide monohydrate (63.4 mg) was added to a solution mixture of tetrahydrofuran (6 mL) and ethanol (2 mL) of [(4R,9aS)-6-oxo-4-(3,4,5-trifluorophenyl)octahydropyrido[2,1-c][1,4]oxazin-7-yl]phosphonic acid diethyl ester (372 mg) and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (229 mg) at room temperature. The resulting reaction solution was stirred at room temperature for 2 hr, and ethyl acetate and water were added thereto. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH, eluting solvent: heptane-ethyl acetate system) to give 163.2 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:8]([C:9]#[C:10][Si](C)(C)C)=[CH:7][N:6]=[C:5]([NH2:15])[CH:4]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:9]([C:8]1[C:3]([C:2]([F:17])([F:1])[F:16])=[CH:4][C:5]([NH2:15])=[N:6][CH:7]=1)#[CH:10]
Reactant: C[Si](C)(C)C#Cc1cnc(N)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(N)cc1C(F)(F)F

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 5.9 g (22.6 mmol) 4-trifluoromethyl-5-trimethylsilanylethynyl-pyridin-2-ylamine and 1.56 g (11.3 mmol) K2CO3 in 50 mL MeOH. The product is purified by chromatography on silica gel using a DCM/MeOH gradient. Yield: 2.97 g (71%).
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]/[CH2:4][OH:5].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].O>CN(C=O)C>[Si:12]([O:5][CH2:4]/[CH:3]=[CH:2]/[CH2:1][OH:6])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC/C=C/CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC/C=C/CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of (2E)-2-butene-1,4-diol (8.22 mL, 0.10 mol) and imidazole (8.50 g, 0.125 mol) in DMF (50 mL) at 0° C., was added tert-butyldimethylsilyl chloride (7.50 g, 0.050 mol) in several portions over 10 minutes. The resulting mixture was warmed to room temperature and stirred (2 h), then poured into H2O (200 mL) and extracted with EtOAc (2×150 mL). The organic layer was washed (brine), dried (Na2SO4) and purified by silica gel column chromatography (hexanes:EtOAc) to yield 5 as a colorless oil (9.0 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ 5.60-5.50 (m, 2H), 4.18 (m, 2H), 4.09 (m, 2H), 2.76 (br, 1H), 0.83 (s, 9H), 0.01 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 136.3, 135.4, 64.8, 63.8, 31.1, 23.6.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(OCCCCCBr)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
To a stirred solution of 3-nitrophenol (4.17 g, 30.0 mmol) and 1,5-dibromo-pentane (7.59 g, 33.0 mmol) in N-methylpyrolidinone (100 mL) was added potassium carbonate (6.21 g, 45.0 mmol), and the resulting mixture was stirred at 90° C. for 6 hours. The reaction mixture was quenched with water (30 mL) followed by extraction with ethyl acetate (30 mL×3). The combined organic layers were washed with brine and then concentrated under vacuum. The residue was purified by silica gel column chromatography to give 1-(5-bromo-pentyloxy)-3-nitro-benzene (5.10 g, 17.7 mmol, 59%) as a yellow liquid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH2:28][C:29]([O:31]CC)=[O:30])([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>CO.[OH-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH2:28][C:29]([OH:31])=[O:30])([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC1(Cc2ccc(OCCCNc3ccccn3)cc2)CCCN(C(C)=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(=O)N1CCCC(CC(=O)O)(Cc2ccc(OCCCNc3ccccn3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from STEP 10 (125 mg) was dissolved in 10 ml methanol and 10 ml 1N sodium hydroxide solution. The reaction was stirred at room temperature for 18 h, then acidified with trifluoroacetic acid (0.77 ml), and concentrated. The residue was purified on reverse phase HPLC using acetonitrile gradient 10-50% in 30 min to yield 90.7 mg. MS: (M+1)=426.2. 1H NMR (CD3CN) δ1.39-1.76 (cmplx bnd, 4H); 2.15, 2.07 (s, 3H); 2.12 (p, 2H); 2.14, 2.10 (d, 1IH); 2.17, 2.28 (d, 1H); 2.68, 2.75 (d, 1H); 2.73, 2.77 (d, 1H); 3.23, 3.14 (ddd, 1H); 3.11, 3.28 (d, 1H); 3.54 (t, 2H); 3.76, 3.68, (d, 1H); 3.61, 3.86 (dd, 1H); 4.08 (t, 2H); 6.82 (t, 1H); 6.85, 6.87 (d, 2H); 7.01 (d, 1H); 7.17, 7.13 (d, 2H); 7.73 (d, 1H); 7.86 (t, 1H). Note: many signals are doubled due to restricted rotation about amide bond. Two chemical shifts are listed for protons which have different shifts in the rotamers, with chemical shift of major rotamer listed first. Anal Calcd. for C24H31N3O4 plus 2.2 CF3COOH: C, 49.77; H, 5.03; N, 6.13. Found: C, 49.47; H, 5.11; N, 6.49.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[N:7]=1.[C:13](O)(=[O:16])[CH:14]=[CH2:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:12][C:8]1[N:7]=[C:6]([NH:5][CH2:4][CH2:3][NH:2][C:13](=[O:16])[CH:14]=[CH2:15])[CH:11]=[CH:10][CH:9]=1
Reactant: NCCNc1cccc(N)n1
Reactant: C=CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NCCNc1cccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
A mixture of 105c (1.88 g, 10 mmol), acrylic acid (720 mg, 10 mmol), HATU (3.80 g, 10 mmol) and DIPEA (6.97 mL, 40 mmol) in DCM (50 mL) was stirred at rt for 16 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (EA/MeOH=4/1) to give N-(2-(6-aminopyridin-2-ylamino)ethyl)acrylamide 105d (1.07 g, 52%) as pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].N1C=CN=C1.[C:21]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([O:15][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
4-Bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate A2, 5 g, 18.658 mmol) was dissolved in DCM (50 ml); imidazole (2.54 g, 37.3 mmol) and tert-butyl(chloro)dimethylsilane (5.624 g, 37.3 mmol) were added and the mixture was stirred at RT for 1 hr. The mixture was washed with brine, the organic phase was dried over sodium sulfate and solvent removed under reduced pressure to afford a crude which was purified by flash chromatography on silica gel Biotage column (cyclohexane:EtOAc=95:5 to 60:40) affording title compound as a white solid (6.5 g, 16.97 mmol, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][CH3:13])[CH2:4][N:3]=1>[Pd].CC1C=CC(C(C)C)=CC=1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH3:13])=[CH:4][N:3]=1
Reactant: CCC1CN=C(N)c2ccccc21
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Product: CCc1cnc(N)c2ccccc12
Yield: 27 %

Procedure:
A stirred mixture of (±)-1-amino-4-ethyl-3,4-dihydroisoquinoline (6.83 g.) and 10% palladium on carbon (1.5 g.) in p-cymene (80 ml.) was refluxed for 4 hours. The mixture was filtered and the filtrate reduced to dryness in vacuo to leave an oil which when crystallized successively from Skellysolve B and cyclohexane gave 1.84 g. (27% yield) of the product, m.p. 84°-85°.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[C:19]([Cl:22])[CH:20]=2)[N:15]=[CH:14][C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[C:2]1([CH2:1][O:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:23])=[C:19]([Cl:22])[CH:20]=3)[NH:15][C:14](=[O:25])[C:13]2=[O:24])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: O=C(Cn1c(=O)cnc2cc(Cl)c(Cl)cc21)OCc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(Cn1c(=O)c(=O)[nH]c2cc(Cl)c(Cl)cc21)OCc1ccccc1

Procedure:
The above ester (12.0 g, 33 mmol) was reacted with 30% H2O2 (50 ml) in glacial acetic acid (350 ml) at 55° C. for 24 h. The mixture was cooled and 600 ml of icecold water was added. The precipitate was filtered off and recrystallized from DMF-water to afford 7.16 g of the title compound. M.p. 286°-289° C. 1H-NMR(DMSO-d6):δ5.08(s, 2H), 5.22(s, 2H), 7.28-7.45(m, 6H), 7.75(s, 1H), 12.35(s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[C:10]2Br)[CH2:6]1)=[O:4].[CH3:34][Sn](C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[C:10]2[CH3:34])[CH2:6]1)=[O:4]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)[C@H]1C[C@@H](n2c(Br)c(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](n2c(C)c(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
The title compound is prepared in analogy to Example 104 starting from 6.6 g (12.6 mmol) cis-3-[4-amino-5-(3-benzyloxy-phenyl)-6-bromo-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutane-carboxylic acid methyl ester of Example 113, 0.364 g (0.315 mmol) tetrakistriphenyl palladium, and 4.39 ml (31.52 mmol) tin tetramethyl (Fluka, Buchs, Switzerland) in 20 ml dry N,N-dimethylformamide (T=100-110° C., sealed tube; reaction time=25 h). Analytical HPLC: tR=11.67 min (Grad 1); ES-MS: m/eo=443.2; NMR (DMSO-d6; not all signals reported): 8.07/s (1H), 7.25-7.5/several m's (6H), 7.03/“d” (1H); 6.95/s (1H); 6.90/“d” (1H); 5.5-6.0/b (NH2); 5.14/s (2H); 4.90/m (1H); 3.65/s (3H); 2.25/s (3H).