Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:17])=[CH:9][C:8]=1[C:18](=[O:20])[CH3:19])(=O)=O.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[Cl:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[C:8]([C:18](=[O:20])[CH3:19])[CH:9]=1
Reactant: CC(=O)c1cc(Cl)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccc(F)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: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Temperature: 100 °C
Yield: 66 %

Procedure:
To a mixture of 2-acetyl-4-chloro-1-naphthyl trifluoromethanesulfonate (0.100 g, 0.284 mmol, from Example 45, Step 2) and (3-fluorophenyl)boronic acid (0.048 g, 0.34 mmol) in 1,4-dioxane (1 mL) was added 1 N solution of sodium carbonate in water (0.43 mL, 0.43 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.014 mmol). The mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 40% ethyl acetate in hexane, to give the desired product (56 mg, 66%). LCMS calculated for C18H13ClFO (M+H)+: m/z=299.1; Found: 299.0.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=1.C(N(CC)CC)C>ClCCl>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([NH:14][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[CH:16][C:17]=1[C:23]([F:24])([F:25])[F:26])#[N:20]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccccc1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-benzoyl chloride was condensed with 4-Amino-2-trifluoromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-Isopropoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[N:12]1C(=O)C2C(=CC=CC=2)C1=O.NN>C(O)C>[CH3:1][O:2][C@@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[NH2:12]
Reactant: CO[C@@H]1Cc2ccccc2[C@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: CO[C@@H]1Cc2ccccc2[C@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a mixture of 2-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione (4.13 g, 0.00141 mol) in ethanol (3.38 mL) under an atmosphere of argon was added hydrazine (0.0442 mL, 0.0580 mol). The reaction mixture was allowed to stir at rt overnight. White solid byproduct crashed out of solution. TLC showed no starting material. The reaction mixture was concentrated, and the residue was suspended in DCM and filtered. The filtrate was concentrated in vacuo. 1H NMR showed that the reaction had not gone to completion. The yellow oil was therefore stirred at reflux for 3 h. LCMS confirmed reaction was complete. The reaction mixture was cooled to rt, concentrated in vacuo, triturated with DCM, filtered, and the filtrate was concentrated in vacuo to give product as a yellow oil (0.154 g, 64%). LC/MS: Rt=0.68 min, ES+ 164 (AA standard).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCCl)CC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCN3CCN(C)CC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(4-chloro-butane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 255) and 1-methyl-piperazine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C26H39N7O4SF [(M+H)+] 564.2767, observed 564.2763.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[CH:8]=[CH:7][CH:6]=[CH:5]2.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:16](Cl)=[O:17]>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:16]([C:10]2[N:9]3[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]3)=[CH:3][C:2]=2[CH3:1])=[O:17])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: Cc1cc2ccccn2c1
Product: COc1cc(C(=O)c2c(C)cc3ccccn23)ccc1[N+](=O)[O-]

Procedure:
This compound is obtained by carrying out the procedure according to the preparation described in Example 1, by benzoylation of 2-methylindolizine, described in Pharmazie; (1980), vol 35(4), pp 203-204, with 3-methoxy-4-nitrobenzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH:11]1([CH:10]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:22][CH:23]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([C:41]4[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=4)=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Br)cc3c2C)C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(-c4cnn(C)c4)cc3c2C)C2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 38.9 %

Procedure:
To a solution (15 mL) of ethyl 3-{[(4-{[(5-bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (0.59 g) synthesized in Example A174(3) in N,N-dimethylacetamide were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.44 g), potassium carbonate (0.29 g) and tetrakistriphenylphosphine palladium (0.06 g), and the mixture was stirred at 70° C. for 24 hr under argon atmosphere. The reaction mixture was cooled to room temperature, and filtered through celite, and the residue was washed with diethyl ether. Water was added to the filtrate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give ethyl 3-[{[4-({cyclohexyl[3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.23 g, 39%) as a pale-yellow oil. The obtained oil was dissolved in ethanol (1 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.04 g, 16%) as a colorless solid.
Reaction SMILES: [I-].[C:2]([C:7]1[CH:12]=[CH:11][C:10]([Zn+])=[CH:9][CH:8]=1)([O:4][CH2:5][CH3:6])=[O:3].Br[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>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.C1COCC1>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([C:10]2[CH:11]=[CH:12][C:7]([C:2]([O:4][CH2:5][CH3:6])=[O:3])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1)#[N:20]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(C#N)cc2)cc1
Reaction time: 3 h
Yield: 80.1 %

Procedure:
4-Carbethoxyphenylzinc iodide (2.16 mmol, in about 10 mL THF) was transferred via a cannula to a THF solution of 5 mole-% Pd(PPh3)4 (0.127 g, 0.11 mmol) and 4-bromobenzonitrile (0.400 g, 2.19 mmol) at room temperature under an argon atmosphere. The solution was then stirred for 3 hours. The reaction product was isolated by a procedure similar to that described in Example 3. Ethyl 4-(4-cyanophenyl)benzoate (Entry 4 in Table VIII, 0.433 g, 1.73 mmol) in 80% yield was obtained as a crystalline solid: mp 114°-115° C.; 1H NMR (360 MHz) δ7.60-8.21 (m, 8H), 4.42 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H); 13C NMR δ165.9, 144.2, 143.1, 132.5, 130.4, 130.1, 127.7, 127.0, 118.5, 111.6, 61.0, 14.2; IR (CCl4) ν2981, 2231, 1722, 1608, 1276, 1109 cm-1. HREI calcd. for C16H13NO2 m/e 251.0947, found 251.0949. Anal. calcd. for C16H13NO2 : C, 76.48; H, 5.21; N, 5.57, Found: C, 76.25; H, 5.17; N, 5.31.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[C:7]([S:22](=[O:25])(=[O:24])[NH2:23])[N:8]3S(C3C=CC=CC=3)(=O)=O)=[CH:4][C:3]=2[O:2]1.[OH-].[Na+]>O>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[C:7]([S:22](=[O:24])(=[O:25])[NH2:23])[NH:8]3)=[CH:4][C:3]=2[O:2]1
Reactant: NS(=O)(=O)c1cc2cc3c(cc2n1S(=O)(=O)c1ccccc1)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc2cc3c(cc2[nH]1)OCO3
Temperature: 90 °C
Yield: 78.9 %

Procedure:
An initial suspension of 5,6-methylenedioxy-1-benzenesulfonyl-2-sulfamoylindole (2.21 gm, 5.8 mmol) in 40% sodium hydroxide (4 ml, 40 mmol) and water (11 ml) was warmed at 90° C. for 1 hour to give a homogeneous solution. The reaction was cooled to room temperature and the product salt precipitated. This mixture was acidified with conc. HCl and the precipitated producted collected by filtration. This solid was dissolved in ethyl acetate/acetonitrile, and dried (anhydrous Na2SO4). This solution was filtered through a charcoal pad and the solvents evaporated. The residue was triturated with diethyl ether to give the crystalline product (1.1 gm), mp 234°-237° C.
Reaction SMILES: [OH-].[Mg+2:2].[OH-].[CH3:4][P:5](=[O:10])([O:8]C)[O:6][CH3:7]>>[Mg+2:2].[CH3:7][O:6][P:5]([CH3:4])(=[O:8])[O-:10].[CH3:7][O:6][P:5]([CH3:4])(=[O:8])[O-:10]
Reactant: COP(C)(=O)OC
Agent: [Mg+2]
Agent: [OH-]
Product: COP(C)(=O)[O-]

Procedure:
Using the procedure described in Example 1, 29.0 parts (0.5 mole) of finely divided magnesium hydroxide and 500 milliliters of dimethyl methylphosphonate are heated at reflux for 4 hours. The solid product is collected, washed with acetone and dried at 100° C. under vacuum to constant weight. There are obtained 62.6 parts of monomethyl methylphosphonic acid magnesium salt melting >230° C. and having micro analysis % Mg, 9.36; % P, 23.70; Calculated for C4H12O6P2Mg.H2O: % Mg, 9.23; % P, 23.85.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25].Br[C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][C@H:34]([CH2:53][O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[N:35]([C:42](=[O:52])[CH2:43][C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:51])[C@H:36]2[CH3:41].C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Si:55]([O:54][CH2:53][C@H:34]1[CH2:33][C:32]2[C:37](=[CH:38][CH:39]=[CH:40][C:31]=2/[CH:25]=[CH:24]/[C:23]([O:27][CH2:28][CH3:29])=[O:26])[C@H:36]([CH3:41])[N:35]1[C:42](=[O:52])[CH2:43][C:44]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:51])([C:58]([CH3:61])([CH3:59])[CH3:60])([CH3:57])[CH3:56]
Reactant: C=CC(=O)OCC
Reactant: C[C@H]1c2cccc(Br)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
Bubble nitrogen through acetonitrile. Place tri-o-tolylphosphine (72.3 mg, 0.23 mmol), palladium (II) acetate (11.8 mg, 0.052 mmol) and acetonitrile (0.96 mL) in a microwave vessel. Stir 10 min. Add ethyl acrylate (0.31 mL, 2.88 mmol). Add 1-[(1S,3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone (0.54 g, 0.96 mmol). Add triethylamine (0.40 mL, 2.88 mmol) and stir vigorously. Blow nitrogen across the surface of the reaction. Seal the vessel and heat to 160° C. for 35 min in a microwave. Cool to room temperature and dilute with ethyl acetate. Filter the precipitate and wash with ethyl acetate. Concentrate the filtrate under reduced pressure to give a brown oil. Combine with the crude product from a substantially same reaction run with 0.27 mmol of 1-[(1S,3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone. Purify the combined residues by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 0-10%) to give the title compound (0.54 g, 0.93 mmol). MS (m/z): 576 (M+1). The following compound is prepared essentially by the method of Preparation 14.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[CH:3]=1
Reactant: NC1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CCOCC1
Temperature: 120 °C
Yield: 90.9 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (2 g, 9.137 mmol) in DMF (10 mL) was added tetrahydro-2H-pyran-4-amine (1.108 g, 10.964 mmol) and TEA (2.772 g, 27.410 mmol). The reaction mixture was heated at 120° C. in microwave reactor for 30 mins. The reaction mixture was diluted with H2O then extracted with EA. The combined organic layers were dried over sodium sulfate, filtered and concentrated to yield a crude product (2.5 g) which was used in next step without further purification. LCMS (m/z): 301.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13][CH2:12]1>>[CH:11]1([C:18]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCC=CCC1
Reactant: Nc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(NC(=O)C2CCC=CCC2)cc1

Procedure:
4-(4-cycloheptene-1-carbonylamino)-benzoic acid was prepared as described in Example 3 from 4.45 g (0.0324 mol) of p-aminobenzoic acid and 5.7 g (0.0359 mol) of 4-cycloheptene-1-carboxylic acid chloride.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH:37]2[CH2:46][CH2:45][C:40]3([O:44][CH2:43][CH2:42][O:41]3)[CH2:39][CH2:38]2)(=O)=O)=CC=1>CC(N(C)C)=O>[O:41]1[C:40]2([CH2:45][CH2:46][CH:37]([N:16]3[C:17]4=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]4[C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:9][CH:10]=4)=[N:15]3)[CH2:38][CH2:39]2)[O:44][CH2:43][CH2:42]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound 15) (4.9 g) in 200 mL dry dimethylacetamide was treated under nitrogen with 60% sodium hydride (2.0 g) and stirred 30 minutes. 1,4-dioxaspiro[4.5]dec-8-yl 4-methyl-1-benzenesulfonate (Intermediate Y) (15 g) was added and the mixture heated at 105° C. for 42 hours. Evaporation in vacuo and treating with water gave solid which was collected and washed well with water then dried in air. The solid was boiled with diethyl ether (6×120 mL) and the filtered solution evaporated. Treatment with acetone gave 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine as an off-white solid which was collected and washed with acetone then dried in air m.p. 200-202.5° C. Calculated for C25H25N5O3 C 67.7 H 5.6 N 15.8 Found C 67.6H5.8 N15.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N+:11]([O-])=O.O.O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.8 %

Procedure:
A mixture of 1-chloro-2,4-dinitro-benzene (100 mg, 0.5 mmol) and SnCl2.2H2O (1.12 g, 5 mmol) in ethanol (2.5 mL) was stirred at room temperature overnight. Water was added and then the mixture was basified to pH 7-8 with saturated NaHCO3 solution. The solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to yield 4-chloro-benzene-1,3-diamine (D-1) (79 mg, quant.). HPLC ret. time 0.38 min, 10-99% CH3CN, 5 min run; ESI-MS 143.1 m/z (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][C:6]([C:14]2[C:22]3[C:21]([NH:23][C@H:24]([C:26]4[N:31]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:30](=[O:38])[C:29]5=[C:39]([CH3:42])[CH:40]=[CH:41][N:28]5[N:27]=4)[CH3:25])=[N:20][CH:19]=[N:18][C:17]=3[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[CH:5][N:4]=1.FC(F)(F)C(O)=O.N>>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:10]([CH3:13])(=[O:11])=[O:12])=[CH:7][C:6]([C:14]2[C:22]3[C:21]([NH:23][C@H:24]([C:26]4[N:31]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:30](=[O:38])[C:29]5=[C:39]([CH3:42])[CH:40]=[CH:41][N:28]5[N:27]=4)[CH3:25])=[N:20][CH:19]=[N:18][C:17]=3[NH:16][CH:15]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1NS(C)(=O)=O
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1NS(C)(=O)=O
Yield: 31.3 %

Procedure:
(S)—N-(2-Methoxy-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-3-yl)methanesulfonamide (82.5 mg, 0.12 mmol) was treated with trifluoroacetic acid (1.4 ml, 18.17 mmol) and a solution of ammonia (7N in methanol, 1.4 ml, 9.8 mmol) according to the method described in Example 27 to give 22 mg (32% yield) of the title compound as a white solid. Purity 95%.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:23])[CH2:6][N:7]([C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])C>C(O)(=O)C.[Fe]>[Cl:22][C:15]1[N:16]=[CH:17][C:18]2[NH:19][C:4](=[O:3])[CH:5]([CH3:23])[CH2:6][N:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:13]=2[N:14]=1
Reactant: CCOC(=O)C(C)CN(CCC(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)CCN1CC(C)C(=O)Nc2cnc(Cl)nc21
Yield: 69.6 %

Procedure:
To a solution of 1.06 g (0.0031 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(3-methyl-butyl)-amino]-2-methyl-propionic acid ethyl ester (IV-27) in 20 mL of acetic acid, was added 1.0 g (0.0179 g-atom) of iron powder. The mixture was heated at 80 degrees for 2 hours and then filtered through Celite while still hot. The filtercake was washed with 100 mL of ethyl acetate (100 mL), and the combined filtrate washed successively with 100 mL of water 100 mL of 7.4 M ammonium hydroxide, 100 mL of water and 100 mL of brine. The aqueous layers were extracted with 100 mL of ethyl acetate, and the combined ethyl acetate layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate—dichloromethane (1:1) to give 0.61 g of (rac)-2-chloro-7-methyl-9-(3-methyl-butyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-27) as white crystalline solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(O)C.[CH3:14][NH:15][CH3:16]>O1CCCC1.O>[CH3:14][N:15]([CH3:16])[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: CNC
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(N(C)C)nc1
Yield: 99 %

Procedure:
500 mg (2.89 mmol) of 1-(6-chloropyrid-3-yl)ethanone, 2 mL of ethanol and 7.23 mL (14.46 mmol) of 2 M dimethylamine in tetrahydrofuran are placed in a 20 mL microwave reactor. The solution is irradiated with microwaves for 10 minutes at 130° C. The mixture obtained is taken up in water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to dryness to give 470 mg of 1-(6-dimethylaminopyrid-3-yl)ethanone, the characteristics of which are as follows:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][CH:7]=1)=[O:4].[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:2][C:3]([NH:5][C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][NH:12]3)=[CH:8][CH:7]=2)=[O:4])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2cn[nH]c2c1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2cn[nH]c2c1

Procedure:
The title compound is prepared from 2-chloro-N-(1H-indazol-6-yl)-acetamide (Example 149a) and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 165-169° C. (diethylether)
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=1)[CH3:2].[CH2:16](OC(C1C=C(CCC)N=C(SC)N=1)=O)C>>[CH3:12][S:9]([C:7]1[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=[C:3]([CH2:1][CH2:2][CH3:16])[N:8]=1)(=[O:11])=[O:10]
Reactant: CCc1cc(C(=O)O)nc(S(C)(=O)=O)n1
Reactant: CCCc1cc(C(=O)OCC)nc(SC)n1
Product: CCCc1cc(C(=O)O)nc(S(C)(=O)=O)n1

Procedure:
The title compound is obtained as a yellow solid (371 mg) in analogy to 6-ethyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid starting from 2-methylsulfanyl-6-propyl-pyrimidine-4-carboxylic acid ethyl ester; LC-MS: tR=0.65 min, [M+H]+=244.95.