Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1.O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:33]([C:32]1[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=1)[OH:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc(C(F)(F)F)cc1)c1ccccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 4.0 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.6 g, 9.9 mmol) in THF (100 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 30 minutes. To this solution, 4-trifluoromethylbenzaldehyde (1.6 g, 9.0 mmol) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for two hours, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.6 g, 82%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])=[N:2]1.[H-].[Na+].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1.C(OCC)(=O)C>CN(C=O)C>[CH:20]1([CH2:23][N:1]2[CH:5]=[CH:4][C:3]([CH2:6][N:7]3[C:15](=[O:16])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]3=[O:17])=[N:2]2)[CH2:22][CH2:21]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc[nH]n1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccn(CC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a colorless solution of 2-(1H-pyrazol-3-ylmethyl)-1H-Isoindole-1,3(2H)-dione (CAN 95533-75-8; 3.66 g, 16.1 mmol) in DMF (80 mL) at 0° C. was added in 4 portions sodium hydride (1.29 g, 32.2 mmol) within 15 min. After warming to room temperature the mixture was stirred for 30 min and cyclopropylmethyl bromide (21.7 g, 15.6 mL, 161 mmol) in DMF (20 mL) was added within 30 min. The mixture was stirred for 22 h at room temperature, poured into ethyl acetate (200 mL) and extracted with water (3×100 mL). Water phases were washed with ethyl acetate (200 mL), organic phases were combined, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 100% EtOAc in heptane) and finally by preparative HPLC to give 1.63 g (36%) of the title compound as a white solid; MS (EI): 282.2 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[O:9]([CH:17]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)[CH2:22][CH2:21]1)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[O:9]([CH:17]([CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([N:26]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:22][CH2:21]1)[Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:11])[CH3:12]
Reactant: Cc1ccc(NC2CCN(CCC(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CC2)nc1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
After adding 2-furoyl chloride (0.14 mL, 1.4 mmol) dropwise to a solution of 1-(3-tert-butyldimethylsiloxy-3-cyclohexylpropyl)-4-(5-methylpyridin-2-yl)aminopiperidine (423 mg, 0.95 mmol) and triethylamine (0.264 mL) in methylene chloride (4 mL) while cooling on ice, the mixture was stirred at room temperature for 18 hours. NH silica Chromatorex DM1020 was added to the reaction mixture, which was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 g NH silica Chromatorex DM2035, hexane:ethyl acetate=4:1) to obtain the title compound as an oil (458 mg) (89.4% yield).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:5]
Reactant: O=C(O)c1ccccc1I
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1ccccc1I
Temperature: 25 °C
Reaction time: 23 h
Yield: 87.4 %

Procedure:
To a stirred mixture of 2-iodobenzoic acid (8.70 g, 35.1 mmol) and potassium carbonate (20.2 g, 176 mmol) in 100 mL of acetone was added benzyl bromide (5.00 g, 29.2 mmol). The mixture was stirred at room temperature for 23 hours and the solid was filtered off. The solid was rinsed with acetone (2×30 mL). The filtrate was concentrated in vacuo. The residue was dissolved in 200 mL of ether and washed with saturated sodium bicarbonate solution (2×50 mL) and brine (1×50 mL). The ether layer was dried (magnesium sulfate), filtered and concentrated in vacuo to give 8.63 g (87%) of benzyl 2-iodobenzoate A.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)=[C:8]([CH3:26])[C:6]=2[N:7]=1.[NH:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][N:40]=2)[CH:35]=[CH:34]1>>[CH3:26][C:8]1[C:6]2[N:7]=[C:2]([C:38]3[CH:37]=[C:36]4[CH:35]=[CH:34][NH:33][C:41]4=[N:40][CH:39]=3)[N:3]=[C:4]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:5]=2[S:10][C:9]=1[C:11]1[CH:12]=[C:13]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Cc1c(-c2cccc(C(=O)N3CCN(C)CC3)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(-c2cccc(C(=O)N3CCN(C)CC3)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with 1-methylpiperizine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-methylpiperazin-1-yl)methanone. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-methylpiperazin-1-yl)methanone (67 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 19.8 mg of 427. MS (Q1) 554.0 (M)+
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[CH:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].C[Si](Cl)(C)C>O1CCCC1.O>[OH:18][CH:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]#[C:7][C:6]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(C)CC=O
Reactant: C#CC(=O)OCC
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5M in hexanes, 22.5 ml) was added dropwise over 40 minutes with stirring to fresh ethyl propiolate (6.0 ml) in dry tetrahydrofuran (75 ml) under nitrogen, with the temperature being maintained below −68° by external cooling. After 30 minutes, isovaleraldehyde (6.5 ml) in dry tetrahydrofuran (15 ml) was added over 15 minutes with the temperature maintained below −69°. After one hour, trimethylsilyl chloride (10 ml) was added and the reaction was allowed to warm to room temperature. Water was added and the mixture was extracted with ethyl acetate, which was washed with brine, dried, and evaporated to give ethyl 4hydroxy-6-methyl-2-heptynoate as an oil (9.5 g).
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=O)[CH3:2].C[SiH](C)O[SiH](C)C>C1(C)C=CC=CC=1>[CH2:14]([CH:3]([CH2:1][CH3:2])[CH2:4][CH:5]=[CH:6][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:15]
Reactant: CCC(CC)CCC(=O)N1CCCCC1
Agent: C[SiH](C)O[SiH](C)C
Solvent: Cc1ccccc1
Product: CCC(CC)CC=CN1CCCCC1
Reaction time: 3 h
Yield: 177.5 %

Procedure:
4-Ethyl-1-piperidin-1-ylhexan-1-one (59.8 g) was dissolved in toluene (500 mL). To the solution was added (Ph3P)IrCl(CO) (95.9 mg). To the mixture was added 1,1,3,3-tetramethyldisiloxane (82.3 mL) in a water-bath. The mixture was stirred in a water-bath for 3 hr. The reaction mixture was concentrated in vacuo to give the title compound (98.1 g) as a crude product.
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[S:14][C:15]4[C:16]([N:21]=3)=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][C:6]=2[O:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH:28]12[NH:35][CH:32]([CH2:33][CH2:34]1)[CH2:31][N:30]([C:36](=[O:38])[CH3:37])[CH2:29]2>CC#N.CN(C=O)C>[S:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:21]=[C:13]1[O:12][C:10]1[CH:9]=[CH:8][C:7]2[C:3]([CH2:2][N:35]3[CH:28]4[CH2:34][CH2:33][CH:32]3[CH2:31][N:30]([C:36](=[O:38])[CH3:37])[CH2:29]4)=[CH:4][O:5][C:6]=2[CH:11]=1
Reactant: ClCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Reactant: CC(=O)N1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)N1CC2CCC(C1)N2Cc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.9 %

Procedure:
To a solution of 2-(3-chloromethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine (120 mg, 0.31 mmol) in CH3CN/DMF (4:1, 3 mL) was added K2CO3 (169 mg, 1.2 mmol) followed by 1-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethanone (47 mg, 0.31 mmol) and the reaction mixture was stirred (rt, 48 h). The reaction mixture was partitioned between DCM (10 mL) and sat. NaHCO3 (5 mL). The organic layer was separated and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to provide the title compound as a colorless solid (47 mg, 35%). MS (ESI): mass calcd. for C23H22N4O3S, 434.14; m/z found, 435.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.7, 1H), 8.02 (dd, J=7.9, 1.7, 1H), 7.84 (d, J=8.5, 1H), 7.63-7.56 (m, 2H), 7.29 (dd, J=8.5, 2.1, 1H), 7.21 (dd, J=7.9, 4.8, 1H), 4.20 (dd, J=12.7, 1.5, 1H), 3.72-3.58 (m, 2H), 3.48-3.19 (m, 4H), 2.89 (d, J=12.3, 1H), 2.06 (s, J=2.8, 3H), 2.03-1.93 (m, 2H), 1.72-1.63 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Br:13][C:3]1[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:11][C:10]([Cl:12])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cc(Cl)cc(N)c1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1Br
Reaction time: 21 h
Yield: 68.2 %

Procedure:
To a solution of methyl 3-amino-2-bromo-5-chlorobenzoate (1.0 g, 3.8 mmol) in 1,2-dichloroethane (15 ml) at room temperature under nitrogen was added oxan-4-one (0.7 ml, 7.6 mmol) followed by acetic acid (1.3 ml, 23 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (2.4 g, 11 mmol) at room temperature. After 21 h, additional oxan-4-one (0.7 ml, 7.6 mmol) was added to the reaction mixture, with stirring for 10 minutes before adding sodium triacetoxyborohydride (2.4 g, 11 mmol). After stirring for 20 h, deionized water (30 ml) was added and the mixture was neutralised with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×30 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (25 g silica, Isolute cartridge, gradient of eluents; 9:1 Heptane:EtOAc to 8:2 Heptane:EtOAc) to give 903 mg (68%) of the title compound as a white solid. LC-MS 92%, 2.11 min (3 minute LC-MS method), m/z=348.2/350.2/351.9, 1H NMR (500 MHz, Chloroform-d) δ 6.94-7.07 (1H, m), 6.70 (1H, d, J=2.36 Hz), 4.72 (1H, d, J=7.57 Hz), 3.96-4.15 (2H, m), 3.87-3.96 (3H, m), 3.40-3.67 (3H, m), 2.05 (2H, d, J=13.08 Hz), 1.49-1.69 (2H, m).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:18]([O:19][CH2:20][C:21]#[CH:22])=[CH:17][C:16]([C:23]2[C:27]([CH3:28])=[C:26]([S:29][CH3:30])[N:25]([CH3:31])[N:24]=2)=[C:15]([F:32])[CH:14]=1>ClCCl>[Cl:12][C:13]1[C:18]([O:19][CH2:20][C:21]#[CH:22])=[CH:17][C:16]([C:23]2[C:27]([CH3:28])=[C:26]([S:29]([CH3:30])=[O:9])[N:25]([CH3:31])[N:24]=2)=[C:15]([F:32])[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CCOc1cc(-c2nn(C)c(SC)c2C)c(F)cc1Cl
Solvent: ClCCl
Product: C#CCOc1cc(-c2nn(C)c(S(C)=O)c2C)c(F)cc1Cl
Temperature: 22 °C
Reaction time: 8 h

Procedure:
A solution of 1.57 g (0.005 mol) of 50-60% 3-chloroperbenzoic acid in 30 ml of dichloromethane is added dropwise at 0-5° C. to a solution of 1.7 g (0.005 mol) of 3-(4-chloro-2-fluoro-5-propargyloxyphenyl)-4-methyl-5-(methylthio)-1-methyl-[1H]-pyrazole (Example P12) in 20 ml of dichloromethane. After being stirred overnight at 22° C., the reaction mixture is washed with a dilute sodium hydrogen carbonate solution, then with water and concentrated by evaporation, and the resulting residue is recrystallised in petroleum ether/diethyl ether. 1.5 g (88.2% of the theoretical yield) of the desired compound are isolated in the form of crystals having a melting point of 93-96° C.
Reaction SMILES: [CH3:1][C:2]([S:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1)([CH3:8])[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+].CO>O1CCOCC1.O>[CH3:8][C:2]([S:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)SCC[C@H]1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(SCC[C@H]1CCOC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.9 %

Procedure:
To a solution of 0.43 g (1.75 mmol) of ethyl 2-methyl-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanoate in THF/water (4/1, 6.5 mL) are added 84 mg (3.49 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 18 h. Then methanol (0.5 mL) is added and the reaction is heated to 45° C. for 16 h. Additional lithium hydroxide monohydrate (83 mg, 3.49 mmol) is added and the reaction is heated to 55° C. for 3 h. The reaction mixture is partitioned between DCM (8 mL) and water (10 mL). The aqueous layer is cooled in an ice bath, acidified with 6M aqueous HCl solution to pH 1 and extracted with DCM (3×15 mL). The combined organic extracts are dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to afford 351 mg of 2-methyl-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanoic acid. Yield: 92%; ES-MS: m/z 219 [M+H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.43-1.76 (9H, m), 1.96-2.16 (1H, m), 2.31 (1H, quin, J=7.31 Hz), 2.56-2.77 (2H, m), 3.37 (1H, dd, J=8.22, 7.16 Hz), 3.68-4.05 (3H, m), 7.62 (1H, br. s.)
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[O:51][C:52]([F:55])([F:54])[F:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[O:51][C:52]([F:55])([F:54])[F:53])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: FC(F)(F)Oc1ccccc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3OC(F)(F)F)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(trifluoromethoxy)benzene and isolated as light-yellow gum (7.3 mg, 39%). MS(m/e): 457.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][N:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2.Cl[C:22]1[CH:30]=[CH:29][N:28]=[C:27]2[C:23]=1[CH:24]=CN2>>[CH3:10][O:11][C:12]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:16][CH:15]=[C:14]([CH2:24][C:23]3[CH:22]=[CH:30][C:29]([NH:7][CH2:6][C:5]4[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:28][CH:27]=3)[C:13]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1ccnc2[nH]ccc12
Product: COc1ccnc2[nH]cc(Cc3ccc(NCc4ccc(Cl)cc4)nc3)c12

Procedure:
was prepared following the protocol of Scheme 12, substituting 4-trifluoro-benzylamine with 4-chloro-benzylamine in Step 1 and 4-methoxy-7-azaindole with 4-chloro-7-azaindole (24, prepared as described in Example 11) in Step 4. MS (ESI) [M+H+]+=381.1 and 383.0.
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]([CH3:23])([CH2:10][C:11](=[O:22])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][NH:7][CH:8]=[O:9]>[Pt]=S>[Cl-:1].[CH3:23][N+:3]([CH3:2])([CH2:10][C:11](=[O:22])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH2:6][NH:7][CH:8]=[O:9]
Reactant: C[N+](C)(CCCNC=O)CC(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: S=[Pt]
Agent: [Cl-]
Product: C[N+](C)(CCCNC=O)CC(=O)Nc1ccc(N)cc1

Procedure:
Following the procedure described in 1c above, N,N-dimethyl-N-(4-nitrophenyl)carbamylmethyl-N-3-formamidopropylammonium chloride was catalytically hydrogenated in aqueous solution at 70°-75° C. and at 600 pounds per square inch in the presence of a 5 percent platinum sulfide on charcoal mixture to obtain N,N-dimethyl-N-(4-aminophenyl)carbamylmethyl-N-3-formamidopropylammonium chloride.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COc1ccccc1Nc1nc(Cl)nc2ccccc12
Product: COc1ccccc1N(C)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-amine and methyl iodide by a procedure similar to example 36 (72% yield). 1H NMR (CDCl3): 7.72 (d, J=8.1 Hz, 1H), 7.54 (ddd, J=8.4, 6.6 and 1.5 Hz, 1H), 7.20 (dd, J=8.4 and 1.8 Hz, 1H), 6.87-7.04 (m, 4H), 3.67 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:19])[C@@H:4]([NH2:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Br[C:21]1[C:22]([O:33][CH3:34])=[C:23]([C:27]([O:31][CH3:32])=[C:28]([Cl:30])[CH:29]=1)[C:24]([OH:26])=O.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:18][C:24]([C:23]2[C:22]([O:33][CH3:34])=[C:21]([C:40]3[CH:41]=[CH:42][C:37]([C:36]([F:47])([F:46])[F:35])=[CH:38][CH:39]=3)[CH:29]=[C:28]([Cl:30])[C:27]=2[O:31][CH3:32])=[O:26])[C:3]([OH:2])=[O:19])=[CH:7][CH:8]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: COc1c(Cl)cc(Br)c(OC)c1C(=O)O
Product: COc1c(Cl)cc(-c2ccc(C(F)(F)F)cc2)c(OC)c1C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Yield: 61.6 %

Procedure:
2-(S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (128 mg, 0.5 mmol) was reacted with 3-bromo-5-chloro-2,6-dimethoxybenzoic acid (148 mg, 0.5 mmol) as described in general procedure A. The resulting crude compound was reacted with 195 mg (1.0 mmol) of 4-(trifluoromethyl)phenylboronic acid as described in general procedure D. The product thus obtained was hydrolyzed according to general procedure C to afford the title product (180 mg) as a pure white solid.
Reaction SMILES: [C:1]12(CC(O)=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)Cl.[C:18](Cl)(=[O:22])[C:19](Cl)=O.[NH2:24][C:25]1[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][N:29]([C@H:37]([CH3:41])[C:38]([NH2:40])=[O:39])[C:30]2=[O:36]>CN(C)C=O>[Cl:35][C:34]1[C:25]([NH:24][C:18](=[O:22])[CH2:19][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH2:9][CH:3]([CH2:2][CH:1]2[CH2:8]4)[CH2:4]3)=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:36])[N:29]([C@H:37]([CH3:41])[C:38]([NH2:40])=[O:39])[CH:28]=[CH:27]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H](C(N)=O)n1ccc2c(N)c(Cl)ccc2c1=O
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](C(N)=O)n1ccc2c(NC(=O)CC3C4CC5CC(C4)CC3C5)c(Cl)ccc2c1=O
Reaction time: 1 h

Procedure:
To a solution of 1-adamantaneacetic acid (600 mg, 0.003 mol) in methylene chloride (5 mL, 0.08 mol) was added oxalyl chloride (0.3 mL, 0.003 mol) and a drop of N,N-dimethylformamide at 0° C. The reaction was stirred at that temperature for 1 h. the solvent was removed under reduced pressureunder reduced pressure and dried under nitrogen. The residue was redissolved in methylene chloride (5 mL, 0.08 mol) and added to a solution of (R)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propanamide (420 mg, 0.0016 mol) in methylene chloride (5 mL, 0.08 mol) and N,N-dimethylformamide (2 mL, 0.02 mol), and stirred for 2 hours. the solvent was removed under reduced pressure and the residue was dissolved in 1:3 isopropyl alcohol/chloroform and washed with 1N hydrochloric acid. the solvent was removed under reduced pressure and the residue was purified by flash chromatography to afford the product as an off white solid.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][S-:15].[Na+]>CN(C)C=O>[CH3:14][S:15][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(SC)cc1F
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC)cc1SC
Temperature: 50 °C
Reaction time: 18 h
Yield: 44.7 %

Procedure:
A mixture of methyl 2-fluoro-4-methylsulphenylbenzoate (4.1 g), sodium thiomethoxide (1.48 g) and N,N-dimethylformamide (16 ml) was stirred at 50° C. for 18 hours, poured onto water and extracted (ethyl acetate). The extract was washed (water), dried (magnesium sulphate) and evaporated to give methyl 2-methylsulphenyl-4-methylsulphenylbenzoate (2.09 g) as an orange oil, NMR (CDCl3) 2.0 (s,3H), 2.4 (s,3H), 3.65 (s,2H), 3.9 (s,3H), 7.05 (dd,1H), 7.15 (d,1H), 7.9 (d,1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=1.[Br:17][C:18]1[C:19]([CH2:24][S:25][CH2:26][CH2:27][NH2:28])=[N:20][CH:21]=[CH:22][CH:23]=1>>[BrH:17].[BrH:17].[BrH:17].[Br:17][C:18]1[C:19]([CH2:24][S:25][CH2:26][CH2:27][NH:28][C:11]2[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:13][N:12]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCSCc1ncccc1Br
Reactant: CSc1ncc(Cc2ccccn2)c(=O)[nH]1
Product: Br
Product: O=c1[nH]c(NCCSCc2ncccc2Br)ncc1Cc1ccccn1
Yield: 44.5 %

Procedure:
An intimate mixture of 5-(2-pyridylmethyl)-2-methylthio-4-pyrimidone (1.5 g) and 2-(3-bromo-2-pyridylmethylthio)ethylamine (1.6 g) was heated at 130° for 6 hours. After cooling, the residue was triturated with hot water and treated with dilute hydrobromic acid to give the title compound, in 44.5% yield, m.p. 225°-230° (decomp.) (ex methanol-water).