Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=1)[CH2:2][CH3:3].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=1>>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:8]2[C:7]([C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]([O:15][CH3:16])=[O:14])[N:5]=[C:4]2[CH2:1][CH2:2][CH3:3])=[CH:24][CH:23]=1)([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Product: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 97.6 %

Procedure:
2-n-Propyl-4,5-dicarbomethoxyimidazole (2.00 g, 8.8 mmol, 1 eq.) was alkylated with 4'-bromomethyl-2-carbomethoxybiphenyl (2.70 g, 8.8 mmol, 1 eq.) by the procedure described in Example 1, Part A. Obtained 3.87 g of a yellow oil which was suitable for further transformation. NMR (DMSO-d6): δ 7.84-7.22 (m, 4H); 7.22 (d, 2H, J=9 Hz); 7.13 (d, 2H, J=9 Hz); 5.50 (s, 2H); 3.77 (s, 3H); 3.75 (s, 3H); 3.55 (s, 3H); 2.67 (t, 2H, J=7 Hz); 1.67 (t of q, 2H, J=7,7 Hz); 0.88 (t, 3H, J=7 Hz).
Reaction SMILES: [CH2:1]([C:8](=[CH2:19])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>C(#N)C>[CH2:1]([CH:8]([CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: O=C(OCc1ccccc1)C(Cc1ccccc1)Cn1ccnc1
Yield: 94.7 %

Procedure:
The resultant compound from Example 73 (10.00 g, 36.93 mmol) and imidazole (5.40 g, 79.3 mmol) in acetonitrile (10 mL) were heated at reflux for 44 h. The mixture was evaporated and the residue was chromatographed on silica gel with 2% methanol in chloroform to afford 11.20 g (88%) of the desired product as an oil: TLC (5% methanol/95% chloroform) Rf =0.35; 1H-NMR (CDCl3) 7.38 (s, 1H), 7.38-7.05 (m, 10H), 7.00 (dd, 1H), 6.80 (dd, 1H), 5.03 (d, 1H), 4.99 (d, 1H), 4.25 (1H), 4.03 (dd, 1H), 3.22-3.09 (m, 1H), 3.02 (dd, 1H), 2.78 (dd, 1H).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:38])[CH3:37])=[CH:31][CH:30]=2)[N:28]=1>>[C:36]([NH:35][C:32]1[CH:33]=[CH:34][C:29]([C:27]2[N:28]=[C:24]([NH:23][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([S:11]([N:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH2:4][CH2:3][CH2:2]4)(=[O:12])=[O:13])=[CH:15][CH:16]=3)[S:25][CH:26]=2)=[CH:30][CH:31]=1)(=[O:38])[CH3:37]
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Product: CC(=O)Nc1ccc(-c2csc(NC(=O)c3ccc(S(=O)(=O)N4CCCc5ccccc54)cc3)n2)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with N-(4-(2-aminothiazol-4-yl)phenyl)acetamide (57 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-60% EtOAc in hexanes to give N-(4-(4-acetamidophenyl)thiazol-2-yl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as a white solid. Yield: 28 mg (22%). 1H-NMR: 10.02 (s, 1H), 8.20 (d, J=8.5 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.75 (d, J=8.5 Hz, 2H), 7.67-7.58 (m, 4H), 7.24-7.18 (m, 1H), 7.14-7.08 (m, 2H), 3.84-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.06 (s, 3H), 1.66-1.59 (m, 2H).
Reaction SMILES: [CH3:1][Si:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(Cl)[Cl:3].[OH2:11]>CCOCC>[CH3:1][Si:2]([Cl:3])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:11][Si:2]([Cl:3])([CH3:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O
Reactant: C[Si](Cl)(Cl)c1ccccc1
Solvent: CCOCC
Product: C[Si](Cl)(O[Si](C)(Cl)c1ccccc1)c1ccccc1
Yield: 33.5 %

Procedure:
Methylphenyl dichlorosilane (765 g; 4.0 mol.) and the same amount of diethyl ether were introduced into a four-necked flask of 2 liters volume equipped with a stirring machine, a reflux condenser, a thermometer and a dropping funnel, followed by stirring the mixture, dropwise adding 36 g (2.0 mol.) of water through the dropping funnel over five hours under nitrogen atmosphere, and then refluxing the mixture for an additional three hours. After refluxing the mixture, ether was distilled off and the starting material, methylphenyl dichlorosilane (184 g; 0.96 mol.) was recovered by distilling the reaction mixture in vacuo to obtain 220 g (0.67 mol.) of 1,3-dimethyl-1,3-diphenyl dichlorodisiloxane. Boiling Point=135°-138° C./2 mmHg.
Reaction SMILES: [Br:1][C:2]1[S:18][C:5]2[C:6]([OH:17])=[C:7]([C:13]([O:15]C)=O)[N:8]([CH3:12])[S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[S:18][C:5]2[C:6]([OH:17])=[C:7]([C:13](=[O:15])[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:8]([CH3:12])[S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: Nc1ccccn1
Reactant: COC(=O)C1=C(O)c2sc(Br)cc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2sc(Br)cc2S1(=O)=O
Temperature: 25 °C

Procedure:
3.54 g. of 6-bromo-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno[2,3-e]-1,2-thiazine-1,1-dioxide are boiled under reflux for 6 hours with 1.42 g. of 2-aminopyridine in 150 ml. of absolute xylene. The reaction mixture is allowed to cool to room temperature. The precipitated crude product is recrystallized from dioxane and 6-bromo-4-hydroxy-2-methyl-3-(2-pyridylcarbamyol)-2H-thieno[2,3-e]-1,2-thiazine-1,1-dioxide having a melting point of 232°-235° is obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:25]>>[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)CC(N)c1ccccn1
Product: CC(C)CC(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1ccccn1

Procedure:
In analogy to the procedure described in Example 293, 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69 b) and 3-methyl-1-(pyridin-2-yl)butan-1-amine (CAN 825647-69-6) were condensed to the title product. MS (EI): m/e=431.4 [M+H]+.
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][C:9]1[N:10](C(OCC(C)C)=O)[C:11]2[C:12]([N:28]=1)=[N:13][CH:14]=[C:15]([C:17]1[CH:18]=[CH:19][C:20]3[O:26][CH2:25][CH2:24][NH:23][CH2:22][C:21]=3[CH:27]=1)[CH:16]=2.[C@H:36]([N:40]([CH2:51][C:52]1[N:61]=[C:60](Cl)[C:59]2[CH2:58][C:57]([CH3:64])([CH3:63])[CH2:56][CH2:55][C:54]=2[N:53]=1)C(=O)OCC1C=CC=CC=1)([CH2:38][CH3:39])[CH3:37]>>[CH3:64][C:57]1([CH3:63])[CH2:56][CH2:55][C:54]2[N:53]=[C:52]([CH2:51][NH:40][C@@H:36]([CH2:38][CH3:39])[CH3:37])[N:61]=[C:60]([N:23]3[CH2:22][C:21]4[CH:27]=[C:17]([C:15]5[CH:16]=[C:11]6[NH:10][C:9]([CH3:8])=[N:28][C:12]6=[N:13][CH:14]=5)[CH:18]=[CH:19][C:20]=4[O:26][CH2:25][CH2:24]3)[C:59]=2[CH2:58]1
Reactant: CC[C@@H](C)N(Cc1nc(Cl)c2c(n1)CCC(C)(C)C2)C(=O)OCc1ccccc1
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Agent: O=C([O-])C(F)(F)F
Product: CC[C@@H](C)NCc1nc2c(c(N3CCOc4ccc(-c5cnc6nc(C)[nH]c6c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared as a trifluoroacetate salt according to the method of example 6 by using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and (R)-benzyl sec-butyl((4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)methyl)carbamate (reagent preparation 17) in step 3 followed by Cbz deprotection. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (br s, 3H), 8.24 (br s, 1H), 7.80 (s, 1H), 7.62 (d, 1H), 7.09 (d, 1H), 4.79 (s, 2H), 4.43-4.36 (m, 2H), 4.17-4.11 (m, 2H), 4.00-3.94 (m, 2H), 3.15 (br s, 1H), 2.75 (t, 2H), 2.67 (s, 2H), 2.50 (s, 2H, buried), 1.79-1.66 (m, 1H), 1.62 (t, 2H), 1.46-1.33 (m, 1H), 1.17 (d, 3H), 0.89-0.78 (m, 9H); MS (EI) for C31H39N7O: 526 (MH+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)=[CH:7][CH:8]=2)[N:3]=1.[CH3:24][N:25]([CH3:53])[C:26](=[O:52])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)=[O:35])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:24][N:25]([CH3:53])[C:26](=[O:52])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([C:2]3[N:11]=[C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:9]4[C:4](=[CH:5][C:6]([C:18]5[CH:19]=[N:20][CH:21]=[N:22][CH:23]=5)=[CH:7][CH:8]=4)[N:3]=3)=[CH:41][CH:42]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: Clc1nc(N2CCOCC2)c2ccc(-c3cncnc3)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(-c5cncnc5)cc4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 12.7 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-4-morpholin-4-yl-7-pyrimidin-5-yl-quinazoline (150 mg, 0.00046 mol), N,N-Dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide (168 mg, 0.00041 mol), cesium carbonate (300 mg, 0.00092 mol), DMF (10 mL) and water (3 mL) were added. The reaction mixture was degassed with N2 for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (16 mg, 0.000023 mol) was added and again degassed with N2 for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 4% MeOH in chloroform) followed by preparative TLC (10% MeOH in chloroform) to yield the title compound [30 mg, 11%]. 1H NMR (400 MHz, DMSO-d6): δ 9.36 (s, 2H), 9.29 (s, 1H), 9.05 (s, 1H), 8.98 (s, 1H), 8.46 (d, J=8.8 Hz, 2H), 8.31 (d, J=2.0 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.93 (dd, J′=8.4 Hz, J″=1.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 3.87 (s, 8H), 2.96 (s, 6H); LC-MS (ESI): Calculated mass: 574.2; Observed mass: 575.1 [M+H]+ (RT: 0.26 min).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].[CH2:16](Br)/[CH:17]=[C:18](/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])\[CH3:19].O>CS(C)=O>[CH2:16]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])/[CH:17]=[C:18](/[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])\[CH3:19]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)=CCC/C(C)=C/Cn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
This example illustrates a synthesis of 1-(3,7-Dimethyl-2,3,6,7-dioxidoctyl)-3,7-dimethylxanthine (inventive compound no. 2552). Sodium hydride (95%) (0.28 g, 12 mmol) was added to a solution of theobromine (2.16 g, 12 mmol) in dimethylsulfoxide (50 mL). After 20 minutes of stirring, geranyl bromide (2.17 g, 10 mmol) was added. After 6 hours of stirring at room temperature, the reaction mixture was warmed to 60° C. for 3 hours and then poured into a separatory funnel containing 150 mL of water and extracted with dichloromethane (5×75 mL). The organic extracts were combined, washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 30% acetone/petroleum ether eluant to yield 2.1 g (66.5% yield) 1-(Geranyl)-3,7-dimethylxanthine (inventive compound no. 2545).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=O)=[O:30])[CH:11]=1)=[O:9].C(N(C(C)C)CC)(C)C.[NH2:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][O:67][CH2:68][CH2:69][O:70][CH2:71][CH2:72][O:73][CH2:74][CH2:75][O:76][CH2:77][CH2:78][O:79][CH2:80][CH2:81][OH:82].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:82][CH2:81][CH2:80][O:79][CH2:78][CH2:77][O:76][CH2:75][CH2:74][O:73][CH2:72][CH2:71][O:70][CH2:69][CH2:68][O:67][CH2:66][CH2:65][O:64][CH2:63][CH2:62][O:61][CH2:60][CH2:59][NH:58][C:38](=[O:40])[CH2:37][CH2:36][S:35][CH2:34][C:33]1[CH:32]=[C:31]([CH:43]=[CH:42][CH:41]=1)[C:29]([NH:28][C:17]1[CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:21][C:16]=1[C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=1)[C:8]([NH:7][CH2:6][C:5]1[CH:44]=[CH:45][CH:46]=[C:3]([C:2]([F:1])([F:48])[F:47])[CH:4]=1)=[O:9])=[O:30]
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: NCCOCCOCCOCCOCCOCCOCCOCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1)NCCOCCOCCOCCOCCOCCOCCOCCO
Yield: 6.8 %

Procedure:
A solution of 50 mg of 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoic acid 1.1, 57 mg of diisopropylethylamine, 27 mg of 23-amino-3,6,9,12,15,18,21-heptaoxatricosan-1-ol, 18 mg of EDCI, and 19 mg of HOBt in 2 mL of DMF was stirred for 24 h. The product was isolated by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to give 5.1 mg of product. MS (ES, m/z): 1028 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].C([O-])(O)=O.[Na+].Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH3:29])[CH2:27][CH:26]2[NH2:28])=[CH:21][CH:20]=1.CCOC(C)=O>ClCCl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C@@:25]2([CH3:29])[CH2:27][C@H:26]2[NH:28][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])=[CH:23][CH:24]=1
Reactant: CC1(c2ccc(Cl)cc2)CC1N
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@]1(c2ccc(Cl)cc2)C[C@H]1NC(=O)c1c(F)cccc1F

Procedure:
2,6-difluorobenzoyl chloride (156 mg, 0.881 mmol) was added to a rapidly stirred mixture of NaHCO3 (1 M aq., 4 ml) and a solution of racemic (1R,2R)-2-(4-chlorophenyl)-2-methyl-cyclopropanamine hydrochloride (172 mg, 0.735 mmol) in dichloromethane (4.5 ml). After stirring for 30 minutes EtOAc was added, the organic phase was separated, washed with brine, dried over MgSO4, and the solvent evaporated to give 241 mg, 100%) of racemic N-[(1R,2R)-2-(4-chlorophenyl)-2-methyl-cyclopropyl]-2,6-difluoro-benzamide. M.p. 140-142° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:18](Br)([CH3:20])[CH3:19]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(I)c2c(N)ncnc21
Yield: 72 %

Procedure:
A solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2 g, 0.0077 mol) and K2CO3 (4.2 g, 0.031 mol) in DMF (50 mL) was brought to 80° C. under an argon atmosphere. Isopropylbromide (1.0 g, 0.0084 mol) was added with a syringe. Reaction was refluxed under argon atmosphere for 2 hours. Solid K2CO3 was removed by filtration. Solvent was partially removed in vacuo. Sodium citrate (50 mL) was added and reaction was extracted with EtOAc. Organic phases concentrated in vacuo and purified using silica gel column chromatography [MeOH—CH2Cl2, 5:95] yielding BA12 (1.68 g, 72% yield). ESI-MS (M+H)+ m/z calcd 304.0, found 304.1.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[OH:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>N1C=CC=CC=1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Oc1c(-c2ccccc2)nc2ccccc2c1C(=O)N[C@@H](CC)c1ccccc1
Reaction time: 8 h
Yield: 42.3 %

Procedure:
0.5 g (1.3 mmol) of (S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Description 1) were dissolved in 10 ml of pyridine; 0.5 ml (5.2 mmol) of ethyl chloroformate were added dropwise and the solution was refluxed under magnetical stirring for 8 hours. The reaction mixture was allowed to reach room temperature and left overnight. 1.0 ml (10.4 mmol) of ethyl chloroformate were added and the solution refluxed for 4 hours. The pyridine was evaporated off with toluene; the residue was dissolved in CH2Cl2, washed with H2O and the organic layer dried over na2SO4 and evaporated in-vacuo to dryness. The crude product was triturated with warm i-Pr2O to yield 0.25 g of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1cnc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1cnc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-5-methylpyrazine following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 2 tR=1.257 min, m/z=388; 1H NMR (CDCl3) 1.07 (s, 3H), 1.12 (s, 3H), 1.49 (d, 3H), 2.01-2.13 (m, 4H), 2.28-2.39 (m, 1H), 2.57 (s, 3H), 2.80 (m, 1H), 5.68 (m, 1H), 7.02 (d, 2H), 7.21-7.33 (m, 5H), 7.67 (d, 2H), 8.41 (s, 1H), 8.76 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:3]=2)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: COC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1ccc(-c2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 17.8 %

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of methyl 4-bromo-2-(4-fluoroanilino)benzoate 70 mg were added 4-(acetamido)phenylboronic acid 77 mg, sodium carbonate 69 mg and polymer-carried di(acetato)dicyclohexylphenylphosphine palladium(II) 31 mg, and it was stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, 4-(acetamido)phenylboronic acid 39 mg and sodium carbonate 22 mg were added, and it was stirred at 95° C. for 14 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Ethanol 2.0 mL and 2.0 mol/L sodium hydroxide aqueous solution 1.0 mL were added to the obtained residue, and it was stirred at room temperature for 1 hour. 6.0 mol/L hydrochloric acid 0.50 mL, water 3.0 mL and ethyl acetate 4.0 mL were added to the reaction mixture. The organic layer was separated and collected, and the solvent was removed under reduced pressure. The obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 40-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 4-(4-(acetamido)phenyl)-2-(4-fluoroanilino)benzoic acid 14 mg of a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]([NH:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:3]=1.ClC(Cl)(O[C:22](=[O:28])OC(Cl)(Cl)Cl)Cl.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:22](=[O:28])[N:16]([CH3:17])[CH:9]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNC(c1ccccn1)c1cc(Br)ccc1N
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude 4-Bromo-2-(methylamino-pyridin-2-yl-methyl)-phenylamine (500 mg) in THF (20 mL) is added triphosgene (493 mg, 1.87 mmol), then the mixture is stirred at room temperature for 2 h. TLC showed the reaction is completed. Water (20 mL) is added and the mixture is extracted with EtOAc, the organic layer is dried over Na2SO4 and concentrated to give the desired compound as a crude mixture. This is used in next step with no further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[CH3:12][NH:13][CH3:14]>>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:13]([CH3:14])[CH3:12])=[O:6]
Reactant: CNC
Reactant: Cc1c(O)cccc1C(=O)O
Product: Cc1c(O)cccc1C(=O)N(C)C
Yield: 42 %

Procedure:
The title compound was prepared from 3-hydroxy-2-methylbenzoic acid and dimethylamine, using the same method as that described for preparation 75, as a solid in 42% yield. 1H NMR(400 MHz, CDCl3) δ: 1.95(s, 3H), 2.70(s, 3H), 2.95(s, 3H), 6.55(d, 1H), 6.80 (d, 1H), 7.00(m, 1H), 9.50(s, 1H); LRMS APCI m/z 180 [M+H]+
Reaction SMILES: [ClH:1].O1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:30])[CH:9]=1>CO>[ClH:1].[ClH:1].[ClH:1].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][NH:20][CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:30])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC2CCNCC2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(OC1CCNCC1)N1CCNCC1COc1cccnc1
Reaction time: 16 h
Yield: 99 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of 4-tert-butyl 1-piperidin-4-yl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (101.5 mg, 0.241 mmol) in MeOH (1 mL). After 16 h, the reaction mixture was concentrated under reduced pressure, yielding 103.3 mg (99%) of the desired product. LC-MS: RT=1.26 min, [M+H]+=321.2.