Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([CH:8](O)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[CH:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].COCCN(S(F)(F)[F:42])CCOC>ClCCl>[F:1][CH:2]([CH:8]([F:42])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[CH:18][N:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:24][CH:25]=3)[N:16]=2)=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCOC(=O)C(F)C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(F)C(F)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To the crude ethyl 2-fluoro-3-hydroxy-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoate (0.11 g, 0.26 mmol) in dichloromethane (1.7 mL) at 0° C. was added Deoxo-Fluor® (0.05 mL, 0.28 mmol) and stirred for 30 minutes. The reaction mixture was loaded onto a Celite® cartridge and purified by flash column chromatography using 0-60% ethyl acetate/hexanes as eluent to afford the title compound as a yellow oil (0.054 g, 47%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=1.9 Hz, 1H), 8.32-8.14 (m, 2H), 7.87-7.73 (m, 2H), 7.50 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 6.11-5.76 (m, 1H), 5.52-4.90 (m, 1H), 4.27 (dqd, J=23.6, 7.1, 2.1 Hz, 2H), 1.27 (dt, J=19.4, 7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.04, −187.64, −187.68, −192.41, −192.44, −202.56, −202.60, −204.97, −205.00; ESIMS m/z 442 ([M+H]+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCCCC>C(OCC)C>[OH:21][C:15]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc(Br)cn1
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCC
Product: COc1ccc(C2(O)CCCCC2)cn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 66.9 %

Procedure:
A solution of n-butyllithium (1.6M in hexanes, 150 ml) was added dropwise over 1 hour to a mechanically stirred solution of 5-bromo-2-methoxypyridine (39.3 g) in 800 ml of diethyl ether at -40° C. The resulting slurry was stirred at -40° C. to -45° C. for 45 minutes, and then cyclohexanone (23.5 g) in 50 ml of diethyl ether was added dropwise over 1 hour. The mixture was allowed to warm to 0° C. over about 1 hour, and then the reaction was quenched with saturated ammonium chloride solution. The layers were separated, and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to yield a semi-solid material. Trituration with pentane provided 29.0 g of product as a powder. Recrystallization of 8 g of the product gave 6.2 g of plates, m.p. 74°-75° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:14])=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)(=[O:3])[CH3:2].[CH3:15][O:16]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:4]1[C:5]([OH:14])=[C:6]([CH:15]=[O:16])[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CC(=O)c1cc2c(cc1O)CCCC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1cc2c(c(C=O)c1O)CCCC2
Temperature: 0 °C

Procedure:
To a solution of 5,6,7,8-tetrahydro-3-acetyl-2-naphthol (9.5 g) in dry dichloromethane (50 ml), cooled in an ice bath, was added titanium tetrachloride (38 g) over a period of three minutes. After fifteen minutes stirring dichloromethyl methyl ether (8.05 g) was added over a period of five minutes. The mixture was retained in the ice bath for a further ten minutes, then stirred without cooling for thirty minutes, and finally warmed to 35° for twenty minutes.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:23]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: O[C@@H]1CCNC1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CC[C@@H](O)C3)cc2c1=O
Yield: 60 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (R)-pyrrolidin-3-ol according to the GPA affording 25.6 mg (60%) of a red powder. Rt=3.09 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:46])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]=2[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=2)=[O:22])=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][S:2]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:46])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]=2[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=2)=[O:22])=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(CCc2c(CCNC(=O)CCCCC(=O)NCCc3ccc(N)cc3)ccc(OC)c2OC)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(CCc2c(CCNC(=O)CCCCC(=O)NCCc3ccc(NS(C)(=O)=O)cc3)ccc(OC)c2OC)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Methanesulphonylchloride (0.41 ml) was added to a stirred solution of the Intermediate (a) (2.74 g) and triethylamine (0.74 ml) in dry dimethylformamide. The solution was stirred at room temperature for 10 hours.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[C@@:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13]3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[CH2:2].Br[C:25]1[C:26]([CH3:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:32][C:26]1[C:25](/[CH:2]=[CH:1]/[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C@H:12]4[C@@:14]5([C:22]6[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=6)[NH:16][C:15]5=[O:23])[CH2:13]4)=[CH:9][CH:10]=3)[NH:5][N:4]=2)=[CH:30][CH:29]=[C:28]([CH3:31])[N:27]=1
Reactant: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Reactant: Cc1ccc(Br)c(C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(/C=C/c2n[nH]c3cc([C@@H]4C[C@@]45C(=O)Nc4ccccc45)ccc23)c(C)n1
Yield: 28.3 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-vinyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (60 mg, 0.2 mmol) and 3-bromo-2,6-dimethylpyridine (37 mg, 0.2 mmol) in DMF (1.5 mL) was added iPr2NEt (0.07 mL), followed by Pd(OAc)2 (2.2 mg, 0.01 mmol) and P(o-tol)3 (6.7 mg, 0.022 mmol). The resulting mixture was purged with argon, and then microwaved 2 h at 125° C. Purification by prep-HPLC gave the title compound as a light yellow solid (23 mg, 22%). NMR indicated 3% of the branched isomer. 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H, partially overlapping with the peak at 7.68 ppm), 7.68 (d, J=16.4 Hz, 1H, partially overlapping with the peak at 7.72 ppm), 7.59 (d, J=16.4 Hz, 1H), 7.50 (s, 1H), 7.06 (d, J=8.8 Hz, 1H, overlapping with the peak at 7.05 ppm), 7.05 (t, J=8.6 Hz, 1H, partially overlapping with the peak at 7.06 ppm), 6.94 (d, J=8.0 Hz, 1H), 6.56 (t, J=7.6 Hz, 1H), 5.98 (d, J=7.6 Hz, 1H), 3.35 (t, J=8.4 Hz, 1H), 2.86 (s, 3H), 2.76 (s, 3H), 2.24 (dd, J=7.6 Hz, 4.8 Hz, 1H), 2.18 (dd, J=9.0 Hz, 5.0 Hz, 1H); MS ESI 407.2 [M+H]+, calcd for [C26H22N4O+H]+ 407.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH2:41]([O:43][C:44]([C:46]1[N:47]([CH3:52])[CH:48]=[C:49]([NH2:51])[N:50]=1)=[O:45])[CH3:42].C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:19])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([NH:51][C:49]4[N:50]=[C:46]([C:44]([O:43][CH2:41][CH3:42])=[O:45])[N:47]([CH3:52])[CH:48]=4)=[O:17])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1nc(N)cn1C
Reactant: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc(NC(=O)c2ccc3cc4n(c3c2)C(C)(C)CNC4=O)cn1C
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
To a solution of 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylic acid (336 mg, 1.3 mmol, Intermediate E) in DMF (1 mL) are added N-hydroxybenzotriazole (351 mg, 2.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (498 mg, 2.6 mmol). After stifling for 10 min, 4-amino-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester (535 mg, 2.6 mmol), N,N-diisopropylethylamine (0.45 mL, 2.6 mmol) and 4-dimethylaminopyridine (32 mg, 0.26 mmol) are added. The reaction mixture is heated at 60° C. for 16 h. DMF is removed under a stream of N2 at 40° C. and EtOAc (2 mL) and water (2 mL) are added. After stirring for 15 min, a white solid is formed and it is filtered and dried to afford the title compound (490 mg, 92%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][NH2:36].C1COCC1>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[S:23]([NH:22][C:20]1[CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH3:35])[N:7]=2)[CH:17]=[CH:18][C:19]=1[F:34])(=[O:25])=[O:24]
Reactant: CN
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Solvent: C1CCOC1
Product: CNc1nccc(-c2sc(C(C)C)nc2-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)n1
Yield: 83 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.10 g, 0.190 mmol) and methylamine in THF (1.0 mL, 2.0 mmol) the title compound was obtained (0.082 g, 0.16 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.75 (1H, s), 8.08-8.00 (m, 1H), 7.59-7.40 (m, 3H), 7.39-7.30 (m, 2H), 7.27-7.11 (m, 2H), 6.16 (br. s., 1H), 3.30-3.21 (m, 1H), 2.71 (br, 3H), 1.31 (d, J=7.0 Hz, 6H). MS (ESI): 520 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13]([C:15]3[C:19]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[C:18]([CH3:31])[S:17][C:16]=3[CH3:32])=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:33]([Sn](CCCC)(CCCC)CCCC)=[N+:34]=[N-:35].CC(O)=O>C1(C)C=CC=CC=1>[CH3:32][C:16]1[S:17][C:18]([CH3:31])=[C:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[C:15]=1[C:13]([NH:12][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]3[N:33]=[N:34][NH:35][N:2]=3)=[CH:8][CH:7]=2)[CH2:11][CH2:10]1)=[O:14]
Reactant: Cc1sc(C)c(C(=O)NC2(c3ccc(C#N)cc3)CC2)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1sc(C)c(C(=O)NC2(c3ccc(-c4nn[nH]n4)cc3)CC2)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of N-[1-(4-cyanophenyl)cyclopropyl]-2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]thiophene-3-carboxamide from Example 14, Step 2 (174 mg, 0.383 mmol) in toluene (2.5 mL), was added azidotributyltin (317 μL, 1.15 mmol) and the mixture was heated at the reflux temperature. After 20 h, the solution then obtained was allowed to cool to r.t. and AcOH (365 μL) was added. The heterogeneous mixture was stirred for 4 h and the precipitated solid was collected by filtration, successively rinsed with toluene and hexane then dried to afford the desired product as an off-white solid. MS (−APCI): m/z 496 (M−1)−.
Reaction SMILES: [CH3:1][N:2]1[C@H:8]([CH2:9][OH:10])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:18][S:19]([O:10][CH2:9][C@@H:8]1[CH2:7][CH2:6][C:3]2([CH2:5][CH2:4]2)[N:2]1[CH3:1])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CN1[C@H](CO)CCC12CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1[C@H](COS(C)(=O)=O)CCC12CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of (5S)-4-methyl-5-(hydroxymethyl)-4-azaspiro[2.4]heptane (0.2 g, 1.42 mmol) and triethylamine (0.287 g, 2.84 mmol, Shantou Xilong chemical factory) in 5 mL of dichloromethane was stirred at 0° C. for 30 min. To the mixture was added methanesulfonyl chloride (0.325 g, 2.84 mmol, Shanghai Haiqu chemical. Ltd.) via a syringe. The reaction mixture was stirred at 0° C. for 4 hrs and quenched with a mixture of 5 mL of saturated Na2CO3 aqueous solution and 5 mL of water. The resulted mixture was extracted with dichloromethane (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give ((5S)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methyl methanesulfonate as yellow oil (150 mg, 48%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][OH:18].C(=O)([O-])O.[Na+]>C(O)(C)(C)C.O>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:8]=[CH:9][C:10]([CH:13]=[N:14][O:18][NH2:17])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)OC(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(C=NON)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
In a mixture of 21.2 ml of t-butanol and 2.1 ml of water were dissolved 4.3 g of 4-cyanobenzoic t-butyl ester, 1.84 g of hydroxylamine hydrochloride and 2.31 g of sodium hydrogencarbonate. The solution was stirred for 2 hours at 80° C. To the reaction mixture was added water, and the mixture was subjected to extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (hexane/ethyl acetate=1/1), followed by crystallization from hexane to afford 4.41 g of the titled compound as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.O>CN1CCCC1=O>[ClH:11].[Cl:11][C:8]1[CH:9]=[CH:10][C:3]2[C:2]([NH:1][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:6][S:5][C:4]=2[CH:7]=1
Reactant: Nc1csc2cc(Cl)ccc12
Reactant: Clc1ccncc1
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ccc2c(Nc3ccncc3)csc2c1
Yield: 174.5 %

Procedure:
A solution of 3-amino-6-chlorobenzo[b]thiophene (5 g, 27 mmol) and 4-chloropyridine hydrochloride (6 g, 40 mmol) in 75 mL of 1-methyl-2-pyrrolidinone was stirred at 80° for 1.5 h, and then was cooled, stirred with water and extracted with ether. The aqueous layer was basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution and then was dried (anhydrous magnesium sulfate), filtered and concentrated to a dark oil. Elution through silica with ethyl acetate via flash column chromatography yielded 7 g of an amber oil. Conversion to the hydrochloride salt in 20% methanol in ether yielded 4.2 g of yellow crystals, mp 264-266° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([C:19]4[CH:20]=[CH:21][C:22]([CH2:25][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[CH:23][CH:24]=4)[CH:17]=[CH:18][C:13]=3[N:12]3[C:27]([CH3:30])=[N:28][N:29]=[C:11]3[C@H:10]([CH2:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(C=O)cc3)ccc2-n2c(C)nnc21
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(CN4CCN(C)CC4)cc3)ccc2-n2c(C)nnc21
Reaction time: 0.08 h

Procedure:
(S)-2-(6-(4-Chlorophenyl)-8-(4-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (for a preparation see Intermediate 6) (90 mg) was dissolved in DCM (5 ml). 1-Methylpiperazine (30 μl) and acetic acid (10.35 μl) were added and the reaction mixture was stirred for 5 min. Sodium triacetoxyborohydride (192 mg) was added and the reaction mixture was stirred at room temperature, under nitrogen, over the weekend. Saturated sodium hydrogen carbonate solution (5 ml) was added and the reaction mixture was stirred for 10 min. The organic phase was separated and the saturated sodium hydrogen carbonate solution was extracted with DCM (10 ml). The DCM extracts were combined, dried and the solvent was evaporated. The residue was chromatographed (0-15% methanol:DCM), triturated with diethyl ether and dried in a vacuum dessicator at 40° C. overnight to give (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (66.5 mg) as a white solid. LCMS (formate): MH+ 582, RT 0.65 min
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12.C([Mg]Cl)(C)C.[CH:24](=[O:27])[CH2:25][CH3:26]>C1COCC1>[OH:27][CH:24]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:18])[CH:12]=[C:7]12)[CH2:25][CH3:26]
Reactant: CCC=O
Reactant: O=C1C=C2c3cccc(I)c3CCN2C(=O)CN1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCC(O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
124-1. A mixture of 9-iodo-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (2.2 g, 6.21 mmol) in dry THF (150 mL) was cooled to −78° C. under Ar, and a 2M solution of iPrMgCl in THF (18.6 mL, 37.3 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and propionaldehyde (3.61 g, 62.1 mmol) was then added. The mixture was stirred at −78° C. for another 30 min and then allowed to warm to RT overnight. The reaction mixture was poured onto a saturated aq. solution of WWI and extracted with AcOEt. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, heptane to AcOEt/MeOH 9:1) to give the title compound (231 mg). UPLC-MS: MS 287.2 (M+H+); UPLC rt 0.59 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1>C(O)(=O)C.[Pt]=O>[NH:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1
Reactant: OCCc1ccncc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: OCCC1CCNCC1
Reaction time: 20 h
Yield: 0 %

Procedure:
A solution of 4-(2-hydroxyethyl)pyridine (1.8 g, 14.6 mol) in acetic acid (15 ml) containing platinum oxide (200 mg) was hydrogenated for 20 hours at 3.3–4 atmospheres pressure. After filtration, the filtrate was evaporated and azeotroped twice with toluene. The residue was triturated with 2N sodium hydroxide and solid sodium hydroxide was added to adjust the pH to 13. The volatiles were removed under vacuum and the residue was triturated with ether, filtered, washed with methylene chloride, and dried under vacuum to give 2-(piperidin-4-yl)-1-ethanol (860 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]1[N:25]1[CH2:29][CH2:28][S:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C.Cl>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]2[N:25]2[CH2:29][CH2:28][S:27][CH2:26]2)=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Nn1c(N2CCSC2)nc2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1c(N2CCSC2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.8 %

Procedure:
3,5-Difluorophenylacetic acid (0.152 g, 0.88 mmol), 3-Amino-2-thiazolidin-3-yl-3H-quinazolin-4-one (0.146 g, 0.59 mmol) and HATU (0.268 g, 0.71 mmol) were dissolved in dry DMF (2.5 mL), followed by addition of 2,6-lutidine (205 μL, 1.76 mmol). The reaction mixture was stirred at RT for 48 h and then poured into 1 M HCl (20 mL). The formed precipitate was collected by filtration and washed with water and heptane, which after drying gave the title compound (0.180 g, 76%). LC-ESI-HRMS of [M+H]+ shows 403,1047 Da. Calc. 403,104028 Da.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:23])=O.ClCCl>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:17]([Cl:23])=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1
Reactant: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
To a mixture of 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (0.33 g, 1.13 mmol), oxalyl chloride (0.45 mL, 5.16 mmol) and dichloromethane (10 mL) was added a drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 6 hours. The volatiles were removed in vacuo to obtain 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carbonyl chloride (0.34 g, 1.1 mmol)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](N)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17].C(I)[I:21].N(OCCC(C)C)=O>C1COCC1.[Cu]I>[Cl:1][C:2]1[N:10]=[C:9]([I:21])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(N)nc21
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(I)nc21
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a mixture of 117a (2.99 g, 10.0 mmol), CH2I2 (4.0 ml, 51.0 mmol), and CuI (1.91 g, 10.0 mmol) in THF was added isoamyl nitrite (4.0 mL, 30.0 mmol). The mixture was heated at reflux for 1.0 h and cooled to room temperature. The reaction mixture was partitioned between ethyl acetate and 1N aqueous HCl solution. The organic phase was washed with saturated aqueous NH4Cl, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate to afford 117b (2.02 g, 49%) as a yellow solid. MS-ESI: [M+H]+ 411.0