Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][NH:42][CH:43]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[NH:41]1[CH:40]=[C:39]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]4[CH2:23][CH2:22][N:21]([CH:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[C:20]4=[O:30])=[O:18])=[N:13][C:14]=3[CH3:15])[CH:5]=[CH:4][N:3]=2)[CH:43]=[N:42]1
Reactant: Cc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(Cl)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(-c2cn[nH]c2)c1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
A solution of Example C3 (0.12 g, 0.28 mmol) in dioxane (4 mL) was sparged with Ar, treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.08 g, 0.42 mmol), a solution of K2CO3 (0.077 g, 0.55 mmol) in water (1 mL) and Pd(PPh3)4 (0.032 g, 0.03 mmol) and heated at 90° C. overnight. The mixture was cooled to RT, diluted with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (72 mg, 56%). 1H NMR (400 MHz, DMSO-d6): δ 13.05 (br s, 1 H), 10.89 (s, 1 H), 8.35 (d, J=5.7 Hz, 1 H), 8.31 (brs, 1 H), 8.03 (s, 1 H), 7.89 (d, J=8.8 Hz, 1 H), 7.61 (d, J=8.8 Hz, 1 H), 7.28 (d, J=2.4 Hz, 1 H), 6.56 (dd, J=5.7, 2.4 Hz, 1 H), 3.95-3.77 (m, 5 H), 3.43-3.39 (m, 4 H), 2.24 (s, 3 H), 1.71-1.70 (m, 2 H), 1.60 (d, J=12.4 Hz, 2 H); MS (ESI) m/z: 464.2 (M+H+).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@H:28]3[CH2:32][C@@H:31]([O:33][CH3:34])[C@H:30]([OH:35])[C@@H:29]3[OH:36])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:36][C@H:29]1[C@@H:30]([OH:35])[C@H:31]([O:33][CH3:34])[CH2:32][C@@H:28]1[O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[N:26]=1
Reactant: CO[C@@H]1C[C@H](Oc2nc(N3CCN(C(=O)OCc4ccccc4)CC3)nc3ccccc23)[C@@H](O)[C@H]1O
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1C[C@H](Oc2nc(N3CCNCC3)nc3ccccc23)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.9 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1S,2S,3R,4R)-(2,3-dihydroxy-4-methoxycyclopentan-1-yl)oxy]quinazoline (600 mg) in methanol (12 ml) is added 10% palladium/carbon (120 mg), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 20 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure to give 4-[(1S,2S,3R,4R)-(2,3-dihydroxy-4-methoxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (415 mg) as foam.
Reaction SMILES: CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:32][C:33]1[CH:34]=[C:35]2[C:39](=[C:40]([C:42]([OH:44])=O)[CH:41]=1)[NH:38][CH:37]=[CH:36]2.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][NH:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:58][CH:57]=2)=[CH:48][CH:47]=1>CN(C=O)C.O>[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][N:54]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]([F:63])([F:64])[F:65])=[CH:58][CH:57]=2)[C:42]([C:40]2[CH:41]=[C:33]([Cl:32])[CH:34]=[C:35]3[C:39]=2[NH:38][CH:37]=[CH:36]3)=[O:44])=[CH:48][CH:47]=1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: Fc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(Cl)cc2cc[nH]c12)N(CCc1ccc(F)cc1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
121 mg (1.2 mmol) of N-methyl morpholine and then 227 mg (0.6 mmol) of HBTU were added to 78 mg (0.40 mmol) of 5-chloro-1H-indol-7-carboxylic acid and 142 mg (0.48 mmol) of [2-(4-fluoro-phenyl)-ethyl]-(4-trifluoromethyl-benzyl)-amine dissolved in 4 ml DMF at rt under nitrogen. The reaction mixture was stirred at rt over night. Water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layers were washed once with 1N aqueous HCl solution, once with saturated aqueous NaHCO3 solution and once with saturated aqueous NaCl. Solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 7:3) to yield 178 mg (94%) product as a yellow viscous oil. MS (ISP) 475.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:15]3[C@H:11]([CH2:12][NH:13][CH2:14]3)[C@:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])([OH:16])[C@H:9]([OH:25])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@@H:40]([CH3:44])[C:41](O)=[O:42]>>[C:26]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:15]3[C@H:11]([CH2:12][N:13]([C:41](=[O:42])[C@@H:40]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][CH3:32])[CH3:44])[CH2:14]3)[C@:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])([OH:16])[C@H:9]([OH:25])[CH2:8]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1[C@@]1(O)[C@H](O)CC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reactant: COc1ccccc1[C@@H](C)C(=O)O
Product: COc1ccccc1[C@@H](C)C(=O)N1C[C@@H]2[C@H](C1)[C@@](O)(c1ccccc1OC)[C@H](O)CC2(c1ccccc1)c1ccccc1
Yield: 43.2 %

Procedure:
By working according to the procedure of Example 1, starting from 0.2 g of (3aR,4R,5R,7aR)-7,7-diphenyl-4-(2-methoxyphenyl)perhydro-4,5-isoindolediol and 0.11 g of (R)-2-(2-methoxyphenyl) propionic acid, 0.12 g of (3aR,4R,5R,7aR)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(R)-2-(2-methoxyphenyl) propionyl]perhydro-4,5-isoindolediol is obtained, melting at 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:5]([CH2:11]Cl)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.Cl.Cl.[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][NH2:32].C(N(CC)CC)C.C(O)(=O)C>C(#N)C.ClCCl>[NH:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][N:32]1[C:15](=[O:17])[C@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:4]2[CH:3]=[C:2]([Cl:1])[C:10]3[NH:9][N:8]=[CH:7][C:6]=3[C:5]=2[CH2:11]1
Reactant: NCc1ncc[nH]1
Reactant: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)C(=O)OC
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ncc[nH]2)C1=O
Temperature: 25 °C
Yield: 24 %

Procedure:
(S)-Dimethyl 2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (250 mg, 0.63 mmol) and (1H-imidazol-2-yl)methanamine dihydrochloride (170 mg, 1.0 mmol) were combined and suspended in acetonitrile (10 mL). Triethylamine (800 μL, 5.7 mmol) was added to the mixture. Reaction was warmed to reflux for 3 hours. Acetic acid (1.5 mL) was added to the mixture. Reaction was heated at reflux for 20 hours. Mixture was cooled to room temperature then diluted with dichloromethane. Mixture was extracted twice with water. Aqueous layer was concentrated in vacuo. Residue was purified by preparatory HPLC. Water was lyophilized off. Remaining residue was passed through a column of Dowex 1×4-200 ion exchange resin eluting methanol. Title compound was recovered as amber residue in 24% yield. MS m/e (M+H)+=388.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:14])[C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.[CH3:16][O:17][C:18]1[C:26]2[O:25][C:24](C)(C)C[C:22]=2[C:21]([C:29]2[C@@H:38]3[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]3)[C:32](=[O:39])[N:31]([C:40]3[CH:45]=[CH:44][C:43]([C:46](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:47])=[CH:42][CH:41]=3)[N:30]=2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:14])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:46]([C:43]2[CH:44]=[CH:45][C:40]([N:31]3[N:30]=[C:29]([C:21]4[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[C:26]([O:25][CH3:24])[CH:22]=4)[C@@H:38]4[C@@H:33]([CH2:34][CH:35]=[CH:36][CH2:37]4)[C:32]3=[O:39])=[CH:41][CH:42]=2)=[O:47])[CH2:10][CH2:9]1
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(c5c(Cl)cncc5Cl)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from intermediate product A6 and 1-(3,5-Dichloropyridin-4-yl)piperazine as described for compound 8. Crystallised as the free base from methanol. M.p. 137–139° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.Cl.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)[N:40]2[CH2:43][CH:42]([CH:44]([C:48]3[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=3)[C:45](O)=[O:46])[CH2:41]2)=[CH:35][CH:34]=1>ClCCl.C(N(CC)CC)C>[Cl:62][C:59]1[CH:60]=[CH:61][C:56]([CH:39]([C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][CH:37]=2)[N:40]2[CH2:43][CH:42]([CH:44]([C:48]3[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=3)[C:45]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[O:46])[CH2:41]2)=[CH:57][CH:58]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CCCNC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
(RS)-2-{1-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(3-dimethyl-aminopropyl)acetamide may be prepared in the following manner: 0.015 cm3 of N,N-dimethylpropane-1,3-diamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20° C. The solution obtained is stirred at a temperature in the region of 20° C. for about 12 hours. The reaction medium is deposited on a Varian cartridge (of 12 mm in diameter) filled with 4 cm3 of silica (0.060-0.200 mm) conditioned with dichloromethane with the aid of a vacuum apparatus, eluting with dichloromethane between 0 and 6 cm3 and then with a dichloromethane-methanol (95-5 by volume) mixture. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 33 mg [lacuna] (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(3-dimethylamino-propyl)acetamide are thus obtained in the form of white crystals [1H NMR spectrum (300 MHz, CDCl3, with addition of a few drops of CD3COOD d4, δ in ppm): 1.91 (mt: 2H); 2.71 (s: 6H); 2.95 (mt: 2H); from 3.15 to 3.40 (mt 2H); from 3.40 to 3.60 (mt: 1H); from 3.60 to 3.80 (mt: 2H); 4.00 (mt: 2H); 4.28 (d, J=10.5 Hz: 1H); 5.22 (s 1H); 6.68 (tt, J=9 and 2.5 Hz: 1H); 6.90 (mt: 2H); 7.33 (mt: 4H); 7.46 (d, J=8 Hz: 4H)].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:26])[CH2:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:3][CH2:2]1.[CH3:27][C:28](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:29]>>[C:28]([O:26][CH:11]([CH2:12][C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:21])([F:20])[C:16]([F:19])([F:17])[F:18])[CH2:10][O:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:29])[CH3:27]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: OC(COCCN1CCOCC1)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CC(=O)OC(COCCN1CCOCC1)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 10 h
Yield: 273.5 %

Procedure:
To 40.7 g of 1-(2-morpholinoethoxy)-4,4,5,5,6,6,7,7,7-nonafluoro-2-heptanol was added 11.2 g of acetic anhyride. The mixture was stirred at 50° C. for 10 hours, followed by conventional aqueous work-up and purification by silica gel column chromatography. There was obtained 42.7 g of 1-(2-morpholinoethoxy)-4,4,5,5,6,6,7,7,7-nonafluoro-2-heptyl acetate (yield 95%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Temperature: 100 °C
Yield: 89.8 %

Procedure:
To a mixture of 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.3 g, 0.61 mmol), Pd(PPh3)2Cl2 (0.086 g, 0.122 mmol) and pyridine-4-ylboronic acid (0.165 g, 1.342 mmol) in dioxane (3 mL) was added a solution of Na2CO3 (0.2 g, 1.83 mmol) in water (1.5 mL). After degassing, the mixture was heated at 100° C. for 1.5 h. The mixture was purified by flash column chromatography (Hexane/EtOAc=1:1) to give 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.241 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12](Cl)([Cl:14])=[O:13]>C(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:12]([Cl:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)Nc1cccc2cccnc12

Procedure:
8-Aminoquinoline (2.0 g., Pfaltz & Bauer, A28560) in methylene chloride (10 ml) was added dropwise to a 0° C. solution of 2.2M phosgene in methylene chloride (12 ml). The resulting precipitate was filtered and dried. The dark solid thus obtained is unstable and in practice it was immediately used in the next reaction.
Reaction SMILES: C[O:2][C:3]1C=CC2CCN(C(OC(C)(C)C)=O)CC[C:5]=2[CH:4]=1.C[O:22][C:23]1[CH:39]=[CH:38][C:26]2[CH2:27][CH2:28][N:29]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)(=O)CC.Cl>ClC(Cl)C.C(OCC)C>[OH:22][C:23]1[C:39]([C:3](=[O:2])[CH2:4][CH3:5])=[CH:38][C:26]2[CH2:27][CH2:28][N:29]([C:32](=[O:37])[C:33]([F:34])([F:35])[F:36])[CH2:30][CH2:31][C:25]=2[CH:24]=1
Reactant: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: CCC(=O)c1cc2c(cc1O)CCN(C(=O)C(F)(F)F)CC2
Reaction time: 4 h

Procedure:
1,1-Dimethylethyl 7-(methyloxy)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (15 mmol) was converted to 7-(methyloxy)-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine as described in the initial steps of Preparation 23. This material (14 mmol) dissolved in dichloroethane (10 mL) was added at 0° C. to a previously prepared suspension of AlCl3 (4 eq) and propionyl chloride (1.3 eq) in dichloroethane (20 mL). The reaction mixture was stirred in a defrosting ice bath. After 4 h it had reached 12° C. when aqueous HCl (2 M, 40 mL) was carefully added over 20 min. Diethyl ether was added, layers separated and the organic layer washed with water and brine and dried over MgSO4. Volatiles were evaporated and the residue triturated with diethyl ether: cyclohexane 1:1 and then with diethyl ether to give a colourless powder (1-[8-hydroxy-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-1-propanone, 1.2 g). To a solution of this material (0.43 g) in pyridine (2 mL) hydroxylamine hydrochloride (0.10 g) was added at room temperature and the reaction mixture was kept for 16 h. Additional hydroxylamine hydrochloride (0.03 g) was added. After 5 h the solvent was removed under vacuum, the residue treated with water (2 mL) and methanol (4 mL) with stirring until a solid started to form. Additional water (6 mL) was added. The resulting solid was collected by filtration, washed (water) and dried to give a white powder (0.39 g). This material (0.10 g) was dissolved in THF (1 ml) and Ph3P (0.13 g) was added. The reaction mixture was stirred at 50° C. while diisopropyl azodicarboxylate (94 μL) was added over 1 min, resulting in an orange solution. The reaction mixture was stirred at 50° C. for 15 min, then cooled to room temperature, and water (4 μL) was added. Solvent was removed under vacuum and the residue was submitted to column chromatography to provide the title compound (21 mg, colourless solid/film) of acceptable purity for further conversion.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6](=[NH:10])[O:7][CH2:8][CH3:9].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23](/[N:10]=[C:6](\[O:7][CH2:8][CH3:9])/[C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([F:2])[CH:4]=1)=[O:24]
Reactant: CCOC(=N)c1cccc(F)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO/C(=N\C(=O)CCl)c1cccc(F)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
To a suspension of ethyl 3-fluorobenzimidate hydrochloride (400 mg, 1.96 mmol) in dichloromethane (15 mL) was added triethylamine (497 mg, 684 μL, 4.91 mmol) at RT. The reaction mixture was cooled to 0-5° C. and 2-chloroacetyl chloride (333 mg, 234 μL, 2.95 mmol) was added dropwise over a period of 5 min. After 20 min the ice bath was removed and the mixture was stirred at RT for 2 h. The reaction mixture was poured into KHSO4 (10% aqueous solution, 25 mL) and extracted with dichloromethane (3×50 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give the product as light brown oil (537 mg, 1.98 mmol, 101%) which was used without further purification for the next step.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(CN3CCN(C(OC(C)(C)C)=O)CC3)=C(C)C=2N=1.Cl.[CH3:33][C:34]1[C:38]2[N:39]=[C:40]([C:49]3[CH:50]=[CH:51][C:52]([C:55]#[N:56])=[N:53][CH:54]=3)[N:41]=[C:42]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[C:37]=2[S:36][C:35]=1[CH2:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1.[C:64](O)(=[O:68])[C@H:65]([CH3:67])[OH:66]>>[OH:66][C@@H:65]([CH3:67])[C:64]([N:61]1[CH2:60][CH2:59][N:58]([CH2:57][C:35]2[S:36][C:37]3[C:42]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:41][C:40]([C:49]4[CH:50]=[CH:51][C:52]([C:55]#[N:56])=[N:53][CH:54]=4)=[N:39][C:38]=3[C:34]=2[CH3:33])[CH2:63][CH2:62]1)=[O:68]
Reactant: C[C@H](O)C(=O)O
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3ccc(C#N)nc3)nc12
Agent: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3ccc(C#N)nc3)nc12

Procedure:
Tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (75 mg) was reacted with 6-cyanopyridin-3-yl-3-boronic ester via General Procedure A. This crude intermediate was subjected to General Procedure D in which the crude HCl salt of 5-(7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyridine-2-carbonitrile was reacted with L-Lactic acid via General Procedure B to give 8.6 mg of 405 after reverse phase HPLC purification. MS (Q1) 508.2 (M)+.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][N:15]([S:17]([C:20]3[S:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)(=[O:19])=[O:18])[CH2:14][CH2:13][NH:12]2)[CH2:8][CH2:7][NH:6][C:5]1=[O:28])[CH3:3].Cl[C:30]1[N:35]=[CH:34][C:33]([C:36]([OH:45])([C:41]([F:44])([F:43])[F:42])[C:37]([F:40])([F:39])[F:38])=[CH:32][N:31]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:3][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][N:15]([S:17]([C:20]3[S:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)(=[O:19])=[O:18])[CH2:14][CH2:13][N:12]2[C:30]2[N:31]=[CH:32][C:33]([C:36]([OH:45])([C:37]([F:38])([F:39])[F:40])[C:41]([F:43])([F:44])[F:42])=[CH:34][N:35]=2)[CH2:8][CH2:7][NH:6][C:5]1=[O:28])[CH3:1]
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)C1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 55.6 %

Procedure:
To a 20-mL vial, 3-(1-methylethyl)-4-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-2-piperazinone (262 mg, 0.607 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (170 mg, 0.607 mmol, Intermediate D) and Hünig's base (323 μL, 1.852 mmol) were dissolved into dioxane (3.77 mL). The vial was sealed and the reaction mixture was stirred at 100° C. for 12 h. After cooling to room temperature, the mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (40 to 100% EtOAc in hexanes gradient) to give the title compound (228 mg).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Br:24]>>[Br:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1sccc1Cc1ccccc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2sccc2Cc2ccccc2)c1Br
Yield: 24 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulfonamide was prepared in the same manner as described in Example 2 by reacting 2-chlorosulfonyl-3-benzylthiophene with 5-amino-4-bromo-3-methylisoxazole resulting in a 24% yield, m.p. 180-183° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:25])[C:13]([N:15]([CH3:24])[N:16]=CC1C=CC=CC=1)=[O:14])[CH3:2]>Cl.CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:25])[C:13]([N:15]([CH3:24])[NH2:16])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=Cc1ccccc1
Agent: Cl
Solvent: CO
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a test tube (outside diameter 21 mmφ×overall length 160 mm), 100 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5), 0.5 ml of methanol, 10 mg of 10 wt % Pd-c and one drop of concentrated hydrochloric acid were added and the mixture was stirred at 0° C. for 7 hours under hydrogen atmosphere. An unsolved substance was removed by filtration and washed with methanol. The filtrates were combined and concentrated under reduced pressure to give 70 m g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39)