Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1>>[CH3:29][O:28][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][NH:18][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:25][C:24]=1[OH:27]
Reactant: CCCOc1ccc(-c2ccnc(Cl)n2)cc1
Reactant: COc1cc(CCN)ccc1O
Product: CCCOc1ccc(-c2ccnc(NCCc3ccc(O)c(OC)c3)n2)cc1

Procedure:
Intermediate 50 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 380. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.0 (d, 1H), 7.1-7.0 (m, 4H) 6.8 (s, 1H), δ 6.7-6.6 (m, 3H), δ 4.0 (t, 2H), δ 3.7 (s, 3H), 3.5 (t, 2H), δ 2.7 (t, 2H), δ 1.8-1.7 (m, 2H), 0.9 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][NH2:16].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:16][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCC1CCCN1C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 88.8 %

Procedure:
To a suspension of 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.68 g) in methanol (30 mL) was added a solution of methylamine (0.83 g) in methanol (3 mL). The reaction mixture was stirred for 72 hours and then sodium borohydride (0.76 g) and molecular sieves were added. After stirring for 2 hours, the reaction mixture was filtered and the filtrate reduced in vacuo. The residue was re-dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (30 mL), brine (30 mL), dried (MgSO4) and reduced in vacuo to give 2-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.56 g). To a solution of 2-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g) in dichloromethane (10 mL) was added triethylamine (0.36 mL) followed by methanesulfonyl chloride (0.20 mL). After stirring for 3 hours the reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 2-[(methanesulfonyl-methyl-amino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (0.63 g). Treatment of this compound with HCl in dichloromethane/methanol yielded N-methyl-N-pyrrolidin-2-ylmethyl-methanesulfonamide hydrochloride (0.49 g).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:16][C:17]([NH2:19])=[S:18].II.CCO>N1C=CC=CC=1.CCOC(C)=O>[CH3:14][C:13]1[N:16]=[C:17]([NH2:19])[S:18][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1
Reactant: NC(N)=S
Reactant: CC(=O)Cc1ccc(-n2cccn2)cc1
Agent: II
Solvent: c1ccncc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(N)sc1-c1ccc(-n2cccn2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-pyrazol-1-yl-phenyl)-propan-2-one (6.9 g, 34.46 mmol) in pyridine (30 ml) is treated with thiourea (2.6 g, 34.46 mmol) followed by iodine (8.7 g, 34.46 mmol) and heated to 80° C. After 8 hours, the reaction mixture is allowed to cool to room temperature and the resulting suspension is filtered and washed with EtOAc. The filtrate is concentrated in vacuo to afford an oil. The oil is dissolved in EtOAc (200 ml) and washed with NaHCO3 (2×100 ml), brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford a sticky solid. EtOH is added to the crude residue and the resulting precipitate is filtered and dried to afford the title compound (MH+ 257.29).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])(C)C)=[O:18]>O1CCOCC1>[CH2:3]([O:10][CH2:11][CH2:23][CH2:20][O:19][C:17](=[O:18])[CH2:16][O:14][CH2:13][CH2:12][CH2:11][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(COCCCOCc1ccccc1)OCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.24 g, 6 mmol) in dioxane (20 ml) is added 3-benzyloxypropan-1-ol (1.0, 6 mmol) and the mixture is allowed to stir at room temperature for 1 hour. t-Butyl bromoacetate (1.05 g, 6.5 mmol) is added slowly and the mixture is allowed to stir for 18 hours. The solvent is evaporated and saturated ammonium chloride (20 ml) is added. The mixture is extracted with methylene chloride (3×20 ml) and the combined organic extracts are dried, filtered and evaporated. Purification by flash column chromatography on silica gel using ethyl acetate/hexane (1:4) as eluent yields 3-benzyloxypropyl-2-[(3-benzyloxypropyl)oxy]-acetate; 1H NMR (CDCl3): δ7.3 (m, 10H), 4.48 (q,4H), 4.27 (t,8 Hz,2H), 4.0 (s,2H), 3.56 (m,6H), 1.92 (m,2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+].[I-].[Li+]>CN(C)C=O>[CH:22]1([CH2:21][N:7]2[C:8]([S:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH2:24][CH2:23]1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(CC2CC2)c(=O)[nH]c1=O
Temperature: 90 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
To a solution of 5-ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione 276 mg, 1.0 mmol) and bromomethyl cyclopropane (160 mg, 1.0 mmol, 85%) dissolved in dimethylformamide (5 ml), sodium bicarbonate (126 mg, 1.50 mmol) and lithium iodide (13.0 mg, 0.10 mmol) were added. The resulting mixture was stirred at 90° C. for 24 hrs, distilled under the reduced pressure to remove dimethylformamide and purified with column chromatography to obtain the titled compound as a white solid (152 mg, yield: 46.0%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[C:10]([Cl:25])[N:9]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[NH:17]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:23]2[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)=[N:9][C:10]=2[Cl:25])=[CH:16]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C(O)c2c[nH]c3ncccc23)c(Cl)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Clc1ccc(CNc2ccc(Cc3c[nH]c4ncccc34)c(Cl)n2)cc1

Procedure:
To (4-chloro-benzyl)-6-chloro-5-[hydroxy-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl-carbamic acid tert-butyl ester (542, 1.00 g, 2.00 mmol) in acetonitrile (130.0 mL) were added triethylsilane (11.5 mL, 0.0720 mol) and trifluoroacetic acid (5.5 mL, 0.071 mol). The reaction was heated to reflux for 2 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give a light yellow solid (P-0161, 480 mg, 62%). MS (ESI) [M+H+]+=383.1, 385.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][CH3:24])[N:15]=[C:14]([NH:25][CH3:26])[N:13]=2)[CH:9]=[C:8](F)[C:5]=1[C:6]#[N:7])[CH3:2].CCN(C(C)C)C(C)C.[NH2:37][NH2:38]>CCO>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][CH3:24])[N:15]=[C:14]([NH:25][CH3:26])[N:13]=2)[CH:9]=[C:8]2[C:5]=1[C:6]([NH2:7])=[N:37][NH:38]2)[CH3:2]
Reactant: NN
Reactant: CCOc1cc(-c2cc(N3CCC[C@H]3CC)nc(NC)n2)cc(F)c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOc1cc(-c2cc(N3CCC[C@H]3CC)nc(NC)n2)cc2[nH]nc(N)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
In a microwave tube, 2-(ethyloxy)-4-[6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-(methylamino)-4-pyrimidinyl]-6-fluorobenzonitrile (137 mg, 0.371 mmol), 5 mL of EtOH, Hunig's base (0.065 mL, 0.371 mmol), and hydrazine anhydrous (0.070 mL, 2.225 mmol) were added. The yellow suspension mixture was heated to 100° C. in an oil bath overnight. When the temperature of the reaction reached 100° C., the solid in the mixture was all dissolved. After overnight, there was a white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature, then the white solid was filtered from the yellow solution, washed by CH3CN (2 mL), and dried under reduced pressure to afford the title compound (120 mg) as a white solid. LC-MS (ES) m/z=382 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.90 (t, J=7.3 Hz, 3H), 1.35 (m, 1H), 1.44 (t, J=7.0 Hz, 3H), 1.80 (m, 2H), 1.93 (m, 3H), 2.82 (d, J=4.6 Hz, 3H), 3.39 (m, 1H), 3.40-3.45 (m, 1H), 3.48-3.62 (m, 1H), 4.05 (m, 1H), 4.13-4.25 (q, J=7.0 Hz, 2H), 4.99 (s, 2H), 6.17 (s, 1H), 6.40 (s, 1H), 6.92 (s, 1H), 7.44 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28](=[O:35])[CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[C:16]2[N:15]=[C:14]([CH3:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH:28]([OH:35])[CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[C:16]2[N:15]=[C:14]([CH3:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: COc1cc(C(=O)N2CCCC(=O)c3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(C)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(C(=O)N2CCCC(O)c3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(C)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To an ice-bath-cooled solution of 2-methoxy-N-(2-methyl-1H-benzimidazol-4-yl) -4-(2,3,4,5-tetrahydro-5-oxo-1H-1-benzazepin-1-yl)carbonylbenzamide (123 mg) in methanol (5 ml) was added sodium borohydride (10 mg), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with chloroform and the solution was washed with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was triturated with ether to give 2-methoxy-N-(2-methyl-1H-benzimidazol-4-yl)-4-(2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonylbenzamide (123 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[S-:11][C:12]#[N:13].[K+].BrBr.[NH4+].[OH-]>C(O)(=O)C.O>[NH2:13][C:12]1[S:11][C:6]2[CH:5]=[C:4]([C:2](=[O:3])[CH3:1])[CH:9]=[CH:8][C:7]=2[N:10]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc2nc(N)sc2c1
Yield: 78.5 %

Procedure:
4-Aminoacetophenone (3.0 g, 22.19 mmol) and potassium thiocyanate (8.87 g, 88.78 mmol) were dissolved in acetic acid (35 mL) and stirred together until they dissolved (˜15-20 min). The solution was then treated with a solution of bromine (1.14 mL, 22.19 mmol) dissolved in acetic acid (15 mL) by slow addition over 20 min. The reaction was then stirred at room temperature for 19 hr and then poured into H2O (100 mL). The solution was then basified to pH=9-10 with NH4OH. The resulting precipitate was collected by vacuum filtration. The solids were then dissolved in hot ethyl acetate and filtered again. The filtrate was concentrated in vacuo to give 3.35 g (76%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.32 (d, J=1.47 Hz, 1H) 7.91 (s, 2H) 7.83 (dd, J=8.46, 1.84 Hz, 1H) 7.37 (d, J=8.46 Hz, 1H) 2.55 (s, 3H). MS m/z (DCI) 193.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[CH:26]=[C:27]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:28]=[CH:29][CH:24]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-Chloro-phenyl)-3-ethynyl-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine (example C.4) (322 mg, 1.0 mmol) and 4-bromo-benzenesulfonamide (236 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (320 mg, 67%). MS (ISP) 477.0 [(M+H)+]; mp 290-293° C.
Reaction SMILES: C=C.[CH3:3][O:4][C:5]1[CH:36]=[CH:35][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH2:31][N+:32]([O-:34])=O)[CH2:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[C:37]1(N=C=O)C=CC=C[CH:38]=1>C1C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:36]=[CH:35][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]([C:31]3[CH2:38][CH2:37][O:34][N:32]=3)[CH2:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:20])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(COC(=O)CC(C[N+](=O)[O-])c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: C=C
Solvent: c1ccccc1
Product: COc1ccc(COC(=O)CC(C2=NOCC2)c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.1 %

Procedure:
Ethylene was bubbled into a mixture of 40.3 (235 mg, 0.5 mmol, see Example 40) in benzene (2 mL) for 20 minutes. Phenyl isocyanate (0.22 mL, 2 mmol) and TEA (3 drops) were then added. The mixture was stirred at room temperature for 2 days. The solid was removed by filtration and washed by benzene. The filtrate was concentrated and purified by flash chromatography to give 42.1 (200 mg). MS ESI (pos.) m/e: 476 (M+H). 1 HNMR (CDCl3) δ 7.37 (d, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 6.92 (m, 6H), 5.05 (dd, 2H), 4.98 (s, 2H), 4.25 (m, 2H), 4.10 (t, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.24 (dd, 1H), 2.79 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4](=[O:17])[CH2:3]1.N(CCCC)(CCCC)CCCC.O>C(Cl)Cl.C(OCCCC)(C)=O>[OH:17][C:4]12[CH2:3][CH:2]([CH3:1])[CH2:15][C:14](=[O:16])[CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: CC1CC(=O)CCCCCCCCCC(=O)C1
Solvent: CCCCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: CC1CC(=O)C2CCCCCCCCC2(O)C1
Reaction time: 1.17 h
Yield: 72.7 %

Procedure:
A solution of 3-methyl-1,5-cyclotetradecanedione 29 (500 mg, 2.1 mmol) in CH2Cl2 (4 ml) was treated at 22-24° C. with a solution of ZrCl3OPr (36% in AcOBu) (1.79 g, 3.86 mmol). After 15 minutes the solution was treated at −10° C. with NBu3 (0.68 g, 0.88 ml, 3.68 mmol). After 70 minutes, the reaction mixture was poured into 5 ml water and 7 ml of a aqueous 2 NHC1 solution were added. After extraction with 25 ml diethyl ether the combined organic phases were washed (saturated aqueous NaHCO3 solution, H2O), dried (Na2SO4) and the solvent was evaporated (crude 531 mg). Flash chromatography, using SiO2 (25 g) and n-pentane/diethyl ether=6:4 as eluent, afforded 364 mg (yield: 73%) of (30).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(OCC)(=O)C.[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]([CH3:32])[CH2:24][C:25]2([CH3:31])[CH3:30]>N1C=CC=CC=1.C(N(CC)CC)C>[CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]([CH3:32])[CH2:24][C:25]2([CH3:31])[CH3:30])=[O:9]
Reactant: CC1CC(C)(C)c2cccc(N)c21
Reactant: Cc1nnsc1C(=O)O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1nnsc1C(=O)Nc1cccc2c1C(C)CC2(C)C
Yield: 74.2 %

Procedure:
A mixture of 1.5 g (10.4 mmols) of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid, 5 ml of thionyl chloride, and one drop of pyridine was refluxed for 1 hour. The resultant solution was distilled under reduced pressure to remove excess thionyl chloride. The obtained residue was dissolved in 10 ml of ethyl acetate. This solution was added to 10 ml of ethyl acetate solution of 1.7 g (9.7 mmols) of 4-amino-1,1,3-trimethylindane and 4 ml of triethylamine, and the resultant solution was stirred at room temperature for 3 hours. The resultant reaction solution was sequentially washed with water, aqueous sodium hydrogen carbonate solution, water, and a saturated brine, and then concentrated under reduced pressure. The concentrated residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane =1/9), to obtain 2.17 g of white crystals (Compound No. 14 shown in Table 6). The yield was 69.1%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[N:7][C:6]=1[CH3:12])[CH3:2].Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:17][N:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([NH:11][C:15]2[N:16]=[CH:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)=[CH:19][N:20]=2)[CH:8]=[N:7][C:6]=1[CH3:12])[CH3:2]
Reactant: COc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: CCOC(=O)c1cc(N)cnc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(Nc2ncc(-c3ccc(OC)cc3)cn2)cnc1C
Temperature: 100 °C

Procedure:
A vial is charged with 5-amino-2-methyl-nicotinic acid ethyl ester 8 (1.25 mmol), 2-chloro-5-(4-methoxy-phenyl)-pyrimidine 3 (1.25 mmol), Pd(OAc)2 (0.187 mmol), xanthphos (0.187 mmol), Cs2CO3 (1.25 mmol), and anhydrous 1,4-dioxane (8 mL). The vial is evacuated and refilled with N2 twice and the mixture is heated in an oil bath at 100° C. for 2 h. The vial is cooled down to rt and the reaction mixture is diluted with DCM, washed with 10% NH4Cl solution, brine and dried over Na2SO4. The solvent is removed under vacuum and the crude is purified by short silica gel chromatography using DCM:MeCN:MeOH=8:2.5:0.5 to afford 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-nicotinic acid ethyl ester 9 as pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ10.13 (s, 1H), 9.10 (d, J=4.0 Hz, 1H), 8.94 (s, 2H), 8.78 (d, J=4.0 Hz, 1H), 7.79-7.77 (m, 2H), 7.16-7.14 (m, 2H), 4.45 (q, J=8.0 Hz, 2H), 3.90 (s, 3H), 2.75 (s, 3H), 1.45 (t, J=8.0 Hz, 3H). MS (m/z) (M+1)+: 365.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:13][N:14]=[C:7]1[N:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:5]2=[O:27].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH2:20]([N:6]1[C:5](=[O:27])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:1]([S:36]([CH3:35])(=[O:38])=[O:37])[S:36]([CH3:35])(=[O:38])=[O:37])[CH:3]=2)[N:8]2[C:12]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[N:13][N:14]=[C:7]12)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)c(=O)n(Cc1ccccc1)c1nnc(N3CCCC3)n21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1ccc2c(c1)c(=O)n(Cc1ccccc1)c1nnc(N3CCCC3)n21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.9 %

Procedure:
In a 20 ml balloon flask, we resuspend 0.55 g (1.5 mmol) of 7-amino-4-benzyl-1-(pyrrolidin-1-yl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (described in example 225) in 10 ml methylene chloride. We add 0.42 ml (3.0 mmol) of triethylamine then 0.24 ml (3.0 mmol) of methanesulfonyl chloride. The obtained solution is shaken for 24 hours at ambient temperature. After cooling down, the obtained solution is washed in water, dried on Na2SO4 then evaporated under vacuum. The crude mixture of the 2 obtained compounds (0.85 g) is chromatographied on silica column by elution with the mixture CH2Cl2 99/CH3OH 1/NH4OH 0.1. The fractions containing the first product by elution order are joined and evaporated under vacuum to give 0.65 g of 4-benzyl-7-(N,N-dimethylsulfonylamino)-1-(pyrrolidin-1-yl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH2:23][O:24][C:25]2[C:30]([N+:31]([O-])=O)=[CH:29][CH:28]=[CH:27][C:26]=2[F:34])[O:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[NH2:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([F:34])[C:25]=1[O:24][CH2:23][C@H:13]1[O:12][CH2:11][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[N:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](COc2c(F)cccc2[N+](=O)[O-])OC[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](COc2c(N)cccc2F)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Dissolved tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-[(2-fluoro-6-nitrophenoxy)methyl]morpholine-4-carboxylate (1.68 g, 3.36 mmol) in ethyl acetate (11.19 mL) and to this solution, carefully added 10% Pd/C (0.714 g, 0.671 mmol). A hydrogen filled balloon was attached and the contents were evacuated and backfilled with H2 several times. Stirred at room temperature for 4 hours. Complete at this time by LC/MS. The solids were filtered off through a pad of celite and washed with ethyl acetate and ethanol. The contents were concentrated and then purified on silica gel (40 g) eluting with a gradient of 0-90% EtOAc/hexanes afforded the title compound (1.57 g, 3.34 mmol, 100% yield) as a yellow oil,
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[O:7][CH2:6]1)[CH2:2][CH3:3].BrCCCCN1C(=O)C2=CC=CC=C2C1=O.Br[CH2:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39]>>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH2:14][CH:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH2:6][O:7]2
Reactant: Cc1ccc(S(=O)(=O)NCCCBr)cc1
Reactant: CCCNC1COc2cccc(OC)c2C1
Agent: O=C1c2ccccc2C(=O)N1CCCCBr
Product: CCCN(CCCNS(=O)(=O)c1ccc(C)cc1)C1COc2cccc(OC)c2C1
Reaction time: 72 h
Yield: 65 %

Procedure:
Using the procedure described in Example 1, but replacing 3-amino-5-methoxychroman by 3-(N-propylamino)-5methoxychroman and N-(4-bromobutyl)phthalimide by 1-bromo-3-(4-toluenesulfonylamino)propane, and leaving stirring for 72 hours, the expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([CH3:21])=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:16]=1)=[O:8].[O:25]([C:27]#[N:28])[K]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([CH3:21])=[C:15]([S:17]([NH:18][C:27]([NH2:28])=[O:25])(=[O:19])=[O:20])[CH:16]=1)=[O:8]
Reactant: N#CO[K]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1cc(S(N)(=O)=O)c(C)s1
Product: COc1ccc(Cl)cc1C(=O)NCCc1cc(S(=O)(=O)NC(N)=O)c(C)s1

Procedure:
Analogously to Example 2 from 2-[2-(5-chloro-2-methoxybenzoylamino)ethyl]-4-sulfamoyl-5-methylthiophene and KOCN.