Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCCCC1C(O)=O.C1C=NC2[N:17](O)[N:18]=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C([O:55][C@@H:56]([C:75]1[S:76][CH:77]=[C:78]([C:80](=[O:83])[NH:81][CH3:82])[N:79]=1)[CH2:57][C@@H:58]([N:62]([CH2:71][CH2:72][O:73][CH3:74])[C:63](=[O:70])[C@@H:64]([NH2:69])[C@@H:65]([CH3:68])[CH2:66][CH3:67])[CH:59]([CH3:61])[CH3:60])(=O)C>ClCCl>[N:69]([C@@H:64]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C:63]([N:62]([C@@H:58]([CH:59]([CH3:61])[CH3:60])[CH2:57][C@H:56]([C:75]1[S:76][CH:77]=[C:78]([C:80]([NH:81][CH3:82])=[O:83])[N:79]=1)[OH:55])[CH2:71][CH2:72][O:73][CH3:74])=[O:70])=[N+:17]=[N-:18]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(CCOC)[C@H](C[C@@H](OC(C)=O)c1nc(C(=O)NC)cs1)C(C)C
Reactant: On1nnc2cccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CCCCC1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N=[N+]=[N-])C(=O)N(CCOC)[C@H](C[C@@H](O)c1nc(C(=O)NC)cs1)C(C)C
Reaction time: 0.08 h
Yield: 127.6 %

Procedure:
To a suspension of N-methyl pipecolinic acid (0.15 mmole, 21 mg) in dichlbromethane (5 mL) were subsequently added, in the order, HOAt (0.11 mmole, 15 mg), HATU (0.11 mmole, 42 mg) and Et3N (0.21 mmole, 29 μL). After stirring for 5 minutes, a solution in dichloromethane (1 mL) of the compound obtained in example 15.3 (0.1 mmole, 46 mg) was added. The reaction mixture was stirred for 4 hours, At the end dichloromethane was removed under vacuum. The crude product was dissolved in ethyl acetate (10 mL) and washed, in the order, with a NaHCO3 saturated aqueous solution (1×10 mL) and with brine (1×10 mL). The organic phase were dried over Na2SO4, filtered and concentrated under vacuum. The product was purified by flash chromatography (eluent chloroform:methanol 97:3 volume/volume). 58 mg (99% yield) of pure 2-((1R,3R)-3-((2S,3S)-2-azido-N-(2-methoxyethyl)-3-methylpentanamido)-1-hydroxy-4-methylpentyl)-N-methylthiazole-4-carboxamide were isolated. Rf=0.37 (chloroform/methanol 97:3 volume/volume). 1HNMR (400 MHz, CDCl3) δ: 8.07 (s, 1H), 7.62 (m, 1H), 7.57 (m, 1H), 5.75 (dd, 1H), 4.61 (dd, 1H), 4.11 (m, 1H), 3.70-3.48 (m, 4H), 3.22 (s, 3H), 3, 20-3.08 (m, 1H), 2.92 (m, 3H), 2.88-2.78 (m, 1H), 2.40 (m, 1H), 2.2-2.09 (m, 6H), 2.09-1.81 (m, 5H), 1.69-1.48 (m, 5H), 1.39-1.30 (m, 1H), 1.26-1.09 (m, 1H), 1.08-0.86 (m, 12H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH2:30][CH3:31])[C:24]2=[O:32])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+].C(O)CCC>O>[CH2:30]([N:25]1[C:26](=[O:29])[CH:27]=[CH:28][N:23]([C:20]2[CH:21]=[CH:22][C:17]([N:16]3[CH2:14][CH2:13][N:4]([C:5]4[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=4)[CH2:3][CH2:2]3)=[CH:18][CH:19]=2)[C:24]1=[O:32])[CH3:31]
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Reactant: CCn1c(=O)ccn(-c2ccc(N)cc2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CCn1c(=O)ccn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Reaction time: 24 h
Yield: 37 %

Procedure:
A mixture of 17.47 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine, 16.3 parts of 1-(4-aminophenyl)-3-ethyl-2,4(1H,3H)-pyrimidinedione, 11.83 parts of sodium hydrogen carbonate and 240 parts of 1-butanol was stirred for 24 hours at reflux temperature. After cooling, 150 parts of water were added. The product was filtered off and crystallized from methylbenzene. The product was filtered off and dried in vacuo at 60° C., yielding 10.6 parts (37.0%) of 3-ethyl-1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2,4(1H,3H)-pyrimidinedione; mp. 210.2° C. (int. 26).
Reaction SMILES: C(ON=O)(C)(C)C.N[CH:9]1[N:34]([C:35]#[N:36])[CH:12]2[CH:13]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([Br:33])[CH:24]=3)[CH:14]=[C:15]3[C:20]([O:19][C:18](=[O:21])[C:17]([CH3:22])=[CH:16]3)=[C:11]2[O:10]1.[BH4-].[Na+].CCOC(C)=O>C1COCC1.ClCCl>[Br:33][C:25]1[CH:24]=[C:23]([CH:13]2[CH:12]3[N:34]([C:35]#[N:36])[CH2:9][O:10][C:11]3=[C:20]3[C:15]([CH:16]=[C:17]([CH3:22])[C:18](=[O:21])[O:19]3)=[CH:14]2)[CH:28]=[C:27]([O:29][CH3:30])[C:26]=1[O:31][CH3:32]
Reactant: COc1cc(C2C=c3cc(C)c(=O)oc3=C3OC(N)N(C#N)C32)cc(Br)c1OC
Agent: CC(C)(C)ON=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C2C=c3cc(C)c(=O)oc3=C3OCN(C#N)C32)cc(Br)c1OC
Reaction time: 2 h
Yield: 51 %

Procedure:
At 0° C., tert-butylnitrite (62 μL, 0.52 mmol) was added to 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-methyl-8-oxo-4H-oxazolo[4,5-h]chromene (20 mg, 0.044 mmol) in dry THF (1 mL) and was stirred at this temperature for 2 h. Sodium borohydride (19.8 mg, 0.52 mmol) was added and the reaction was stirred at 0° C. for 3 h. Reaction was quenched with NH4Cl saturated aqueous solution (1 mL) and the mixture was partitioned between water (2 mL) and EtOAc (5 mL). The aqueous layer was extracted with EtOAc (2×5 mL). The organic layers were combined, washed with saturated NaHCO3 (5 mL), brine (5 mL), dried over Na2SO4, filtered and concentrated to a yellow oil. The product was isolated by flash chromatography using a 12S SiO2 system by Biotage, Inc., Charlottesville, Va., using 1 to 2% EtOAc in dichloromethane to yield 10 mg (85%) of 4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-methyl-8-oxo-4H-oxazolo[4,5-h]chromene as a light yellow solid. 1H NMR (Acetone-d6) 7.80 (d, J=1.2 Hz, 1H), 7.13-7.11 (m, 2H), 6.99-6.96 (m, 2H), 5.00 (s, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.39 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11](O)[CH2:12][C@H:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].C1(B(O)O)C=CC=CC=1.C(O)(=O)CC.COC1C=CC2C3C(C(C)(C)N(C)C=2C=1)CCC(C)C3>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]2[C@H:11]3[C@H:16]([C:17]([CH3:19])([CH3:18])[N:2]([CH3:1])[C:3]=2[CH:8]=1)[CH2:15][CH2:14][C@@H:13]([CH3:20])[CH2:12]3
Reactant: CNc1cc(OC)ccc1C(O)C[C@H](C)CCC=C(C)C
Agent: COc1ccc2c(c1)N(C)C(C)(C)C1CCC(C)CC21
Agent: OB(O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: CCC(=O)O
Product: COc1ccc2c(c1)N(C)C(C)(C)[C@@H]1CC[C@@H](C)C[C@@H]21

Procedure:
A mixture of (3R)-1-(2-methylamino-4-methoxy-phenyl)3,7-dimethyl-oct-6-en-1-ol (291 mg, 1 mmol), phenylboronic acid (365 mg, 3 mmol) and propionic acid (22 rag, 0.3 mmol) in benzene (10 mL) was refluxed for 20 h to give, after chromatography, 140 mg (51%) of (6aR,9 R, 10aR)-3-methoxy-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydro-phenanthridine: [α]D +37 (c 4.5, CHCl3); 1H nmr (400 MHz, CD3COCD3), δ 0.83 (q, 1H, J=11.6 Hz, H-10ax), 0.98 (d, 3H, J=6.5 Hz), 1.0 (s, 3H), 1.20 (m, 2H), 1.22 (m, 1H), 1.29 (s, 3H), 1.54 (m, 1H), 1.82 (m, 1H), 1.89 (m, 1H), 2.37 (dr, 1H, J=10.3, 2.7 Hz), 2.45 (m, 1H), 2.83 (s, 3H), 3.71 (s, 3H), 6.12 (d, 1H, J=2.4 Hz), 6.16 (dd, 1H, J=8.3, 2.4 Hz), 7.0 (d, 1H, J=8.3 Hz); 13C nmr (100.6 MHz, CD3COCD3), δ 19.1, 23.1, 26.5, 28.7, 32.4, 33.0, 35.8, 36.0, 41.3, 48.9, 55.1, 57.7, 99.2, 100.7, 120.2, 125.9, 147.8, 160.0. Exact Mass calcd. for C18H28NO (M+1): 274.2170; found: 274.2172.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:19]2[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Oc2ncc(C#N)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1A (1.18 g, 7.75 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (1.1 g, 7.96 mmol), 2-chlorothiazole-5-carbonitrile (CAS 51640-36-9, 1.12 g, 7.75 mmol) and then the reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL). The organics were dried over magnesium sulfate, filtered, and evaporated. The product was purified via silica-gel column chromatography using dichloromethane as the eluent. The title compound was obtained as white solid (2.0 g), 1H NMR (300 MHz, CDCl3) δ ppm 7.76 (s, 1H) 7.12-7.23 (m, 2H) 6.87-7.00 (m, 2H) 4.44-4.65 (heptet, J=6.25 Hz, 1H) 1.36 (d, J=6.25 Hz, 6H), MS (DCI): m/z 261 (M+H)+.
Reaction SMILES: C1CCCCCCC1.N(OC(C)(C)C)=O.ON1[C:21](=O)[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C1(=NO)CCCCCCC1.[N+](C1CCCCCCC1)([O-])=O>C(O)(=O)C>[C:18]1(=[O:27])[CH2:19][CH2:26][CH2:25][CH2:24][CH2:23][CH2:20][CH2:21]1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)(C)ON=O
Agent: O=[N+]([O-])C1CCCCCCC1
Agent: ON=C1CCCCCCC1
Solvent: C1CCCCCCC1
Solvent: CC(=O)O
Product: O=C1CCCCCCC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Cyclooctane (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cyclooctanone oxime, nitrocyclooctane, and cyclooctanone were formed in yields of 55%, 5%, and 4%, respectively.
Reaction SMILES: OC1(C2C=CC=CC=2)CCN(C2N=CC([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:19][C:18]=3[C:28]([F:31])([F:30])[F:29])=[O:16])=CC=2)CC1.N[C:39]1[CH:48]=[CH:47][C:42]2=[N:43][C:44](=[O:46])[N:45]=[C:41]2[CH:40]=1.[N+]([C:52]1C=CC2=NC(=O)N=C2C=1)([O-])=O>>[O:46]=[C:44]1[NH:45][C:41]2[CH:40]=[CH:39][C:48]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([CH3:52])[CH2:23]4)=[N:19][C:18]=3[C:28]([F:30])([F:31])[F:29])=[O:16])=[CH:47][C:42]=2[NH:43]1
Reactant: O=C1N=c2ccc([N+](=O)[O-])cc2=N1
Reactant: O=C(Nc1ccc(N2CCC(O)(c3ccccc3)CC2)nc1)c1oc(N2CCCCC2)nc1C(F)(F)F
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4[nH]c(=O)[nH]c4c3)o2)C1

Procedure:
Compound 55 was prepared by the general procedure for compound 1, by using compound A-10 and 5-aminobenzimidazolone as starting materials (5-aminobenzimidazolone was prepared by reduction of 5-nitrobenzimidazolone according to Regan, J. and coll. J. Med. Chem. 2002, 45, 2994-3008). 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 1H), 10.60 (s, 1H), 10.01 (s, 1H), 7.42 (s, 1H), 7.17 (br d, 1H, J=8.2 Hz), 6.89 (d, 1H, J=8.5 Hz), 4.10 (m, 2H), 3.04 (br t, 1H, J=12.5 Hz), 2.74 (m, 1H), 1.77 (m, 2H), 1.67 (m, 1H), 1.53 (m, 1H), 1.15 (m, 1H), 0.93 (d, 3H, J=6.6 Hz). MS (M+1): 410.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])=[N:5][C:6]([CH:18]2[CH2:20][CH2:19]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)#[N:2].O.O.[Sn](Cl)Cl>CCO>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[CH:7]=[C:6]([CH:18]3[CH2:19][CH2:20]3)[N:5]=[C:4]([O:21][S:22]([C:25]([F:27])([F:28])[F:26])(=[O:24])=[O:23])[C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)cc(C2CC2)nc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: N#Cc1c(-c2ccc(N)cc2)cc(C2CC2)nc1OS(=O)(=O)C(F)(F)F
Yield: 86.1 %

Procedure:
In analogy to GP 3, reaction of 1.49 g trifluoromethanesulphonic acid 3-cyano-6-cyclopropyl-4-(4-nitro-phenyl)-pyridin-2-yl ester (3.6 mmol, 1 eq.) with 4.1 g tin(II) chloride dihydrate (18.19 mmol, 5 eq.) in 20 mL EtOH yielded 1.2 g of the desired aniline (3.1 mmol, 86% yield).
Reaction SMILES: [N:1]([N:3]1[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:2].C(N(CC)CC)C.[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl.O>[CH2:17]([O:24][C:25]([N:6]1[CH2:7][CH2:8][CH2:9][N:3]([N:1]=[O:2])[CH2:4][CH2:5]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=NN1CCCNCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=NN1CCCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-nitrosohomopiperazine (4.174 g) and triethylamine (9 ml) in dichloromethane (25 ml) was added dropwise benzyloxycarbonyl chloride (5 ml) at 0° C. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water and separated. The organic layer was washed with water (×2), brine, dried over magnesium sulfate and concentrated to give 1-benzyloxycarbonyl-4-nitrosohomopiperazine (6.0 g). This product was used for the next step without purification.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])=[C:4]1[CH3:23])[CH3:2].C(N1C2[C:29](=[CH:30][CH:31]=CC=2)[C:28]([C:35](C2C(C(O)=O)=NC=CC=2)=[O:36])=[C:27]1[CH3:46])C.C1([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[CH:55]=2)C=CC=CC=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:35]([O:22][C:20](=[O:21])[CH3:19])(=[O:36])[CH3:28].[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([NH:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]4[CH:46]=[CH:27][CH:28]=[CH:29][C:30]=4[CH3:31])[CH:55]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:20](=[O:21])[O:13]2)=[C:4]1[CH3:23])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Reactant: CCn1c(C)c(C(=O)c2cccnc2C(=O)O)c2ccccc21
Reactant: Cc1cccc(Nc2ccccc2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(Nc3cccc(-c4ccccc4C)c3)OC(=O)c3cccnc32)c2ccccc21

Procedure:
Following a procedure similar to that described in Example 3 but employing 1.6 g. of an isomer mixture comprising 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-3-pyridinecarboxylic acid and 3-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-2-pyridinecarboxylic acid, 0.95 g. of N-phenyl-m-toluidine, 0.5 ml. of pyridine and 6 ml. of acetic anhydride there was obtained 7-(1-ethyl-2-methyl-3-indolyl)-7-(m-tolylphenylamino)furo[3,4-b]pyridine-5(7H)-one as a yellow solid, m.p. 178°-190° C. (dec.) A toluene solution of the product contacted with acidic clay or phenolic resin developed an orange image.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH2:30][CH3:31]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][CH3:31])[CH2:23][CH2:24]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Reactant: CCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(CCC)CC3)c2n1

Procedure:
Prepared similarly to Example 82 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:18]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[C:3]([O:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[C:4]([Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Oc2c(F)cccc2F)c(Br)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1ncc(Br)c(Oc2c(F)cccc2F)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-bromo-4-(2,6-difluorophenoxy)pyridin-2-amine (301 mg, 1.0 mmol) and N-chlorosuccinimide (1.1 mmols) in acetonitrile (50 mL) is stirred at room temperature for one hour then heated at reflux for 24 hours. The reaction mixture is cooled and concentrated. The residue is purified via column chromatography to afford 5-bromo-3-chloro-4-(2,6-difluorophenoxy)pyridin-2-amine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:6][NH:5][N:4]=1.CC(C)([O-])C.[K+].Cl[CH2:21][C:22]1[NH:23][C:24](=[O:32])[C:25]2[CH:30]=[C:29]([CH3:31])[S:28][C:26]=2[N:27]=1>C1COCC1>[OH:11][C:8]([C:7]1[C:3]([C:2]([F:1])([F:12])[F:13])=[N:4][N:5]([CH2:21][C:22]2[NH:23][C:24](=[O:32])[C:25]3[CH:30]=[C:29]([CH3:31])[S:28][C:26]=3[N:27]=2)[CH:6]=1)([CH3:9])[CH3:10]
Reactant: Cc1cc2c(=O)[nH]c(CCl)nc2s1
Reactant: CC(C)(O)c1c[nH]nc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc2c(=O)[nH]c(Cn3cc(C(C)(C)O)c(C(F)(F)F)n3)nc2s1
Reaction time: 0.03 h
Yield: 3.7 %

Procedure:
A mixture of 2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)propan-2-ol (73 mg, 0.376 mmol) and potassium tert-butoxide (127 mg, 1.13 mmol) in THF (2 mL) was stirred for ˜2 min. To this was added 2-(chloromethyl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (81 mg, 0.376 mmol) and the resultant mixture was stirred for 18 h. The reaction mixture was quenched with saturated NH4Cl solution and concentrated in vacuo. The residue was partitioned between DCM and water and the organic layer was separated. The aqueous layer was extracted with further DCM and the combined organics were washed with saturated brine, dried over MgSO4, filtered and concentrated in vacuo to give a light yellow gum. The gum was purified by preparative LCMS to give the product as a white solid (5 mg, 0.014 mmol, 4%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[O:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[NH:21][CH2:20][CH:17]1[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1)#[N:2]
Reactant: NCC1CCOCC1
Reactant: N#Cc1cc(S(N)(=O)=O)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc(S(N)(=O)=O)ccc1NCC1CCOCC1

Procedure:
3-Cyano-4-fluorobenzenesulfonamide (500 mg), (tetrahydropyran-4-yl)methylamine (288 mg), and N,N-diisopropylethylamine (1.3 mL) were heated at 80° C. in tetrahydrofuran (15 mL) overnight. The mixture was diluted with ethyl acetate, washed with NaHCO3 solution and brine, and dried (Na2SO4), filtered and concentrated. The product was triturated from ethyl acetate.
Reaction SMILES: [C:1]1([C:7]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]3[CH: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])[CH:9]([OH:25])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][C:42]=1[CH2:51][C:52](Cl)=[O:53].O>ClCCl>[C:26]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:52](=[O:53])[CH2:51][C:42]4[CH:43]=[CH:44][C:45]5[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=5)[CH:41]=4)[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])[CH:9]([OH:25])[CH2:8]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Cc1ccc2ccccc2c1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccc4ccccc4c3)CC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a solution of 0.42 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydro-4,5-isoindolediol in 10 cm3 of dichloromethane is added 0.21 cm3 of diisopropylethylamine, followed by 0.23 g of 2-naphthylacetyl chloride in 5.5 cm3 of dichloromethane. After stirring at room temperature for 1 hour, 25 cm3 of water are added. The organic phase is separated off after settling, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 50 cm3 of ethyl acetate, 3 cm3 of 1N aqueous hydrochloric acid and 40 cm3 of water. The organic phase is separated off after settling, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized a first time in 5 cm3 of 2-propanol and then a second time in 5 cm3 of isopropyl ether. 0.3 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2-naphthyl)acetyl]perhydro-4,5-isoindolediol is obtained, melting at 188°-190° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:24].[NH4+].[OH-]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:24])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:16][CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1ccc(NC(C)=O)cc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(NC(C)=O)ccc3nc21
Temperature: 0 °C

Procedure:
A mixture of N-(1-ethylpyrazole-5-yl)-5-acetamido anthranilic acid (2 g) and POCl3 (20 ml) was refluxed overnight. The reaction mixture was poured into ice-water (400 ml), neutralized with NH4OH and extracted with CH2Cl2 (3×100 ml). The CH2Cl2 layers were combined and concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate to afford 0.2 g of 1-ethyl-4-chloro-6-acetamido-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][C:18]([O:20]C)=[O:19])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.[H][H].C(O)(=O)C>CO.[OH-].[Na+]>[C:18]([CH2:17][CH:6]([CH2:5][SH:4])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])([OH:20])=[O:19]
Reactant: [H][H]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h

Procedure:
To a solution of the product from Example 81 (3.0 g.) in methanol (60 ml.), 1N sodium hydroxide (60 ml.) is added. After 4 hours, the solution is applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle, and the desired material is eluted with water to yield 2.3 g. of the named product Rf : 0.2 (silica gel-benzene:acetic acid, 75:25).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:9]Br)=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:11]([O:19]CC)(=[O:18])[CH2:12][C:13](OCC)=O.C[O-].[Na+].C(O)C>CCOCC.CO.S(=O)(=O)(O)O>[CH3:2][CH:3]1[CH2:8][C:7]2[C:13](=[CH:9][CH:4]=[CH:5][CH:6]=2)[CH:12]1[C:11]([OH:19])=[O:18]
Reactant: BrCc1ccccc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: CO
Product: CC1Cc2ccccc2C1C(=O)O
Temperature: 200 °C
Yield: 54.2 %

Procedure:
A solution of α,α′-dibromo-o-xylene (203.51 g, 0.77 mol) in 1.5 l of ether is added to a solution of diethyl malonate (127 g, 0.79 mol), sodium methoxide (314 ml, 1.70 mol), ethanol (100 ml) and ether (500 ml). The mixture is refluxed for 5 hours, then filtered, and finally concentrated. The residue is taken up in 500 ml of water. 173 g of potassium hydroxide are added, and the mixture is refluxed for 18 hours. The reaction medium is poured into a hydrochloric acid solution and the precipitate formed is filtered off by suction and then dried. The solid obtained is maintained at 200° C. for 20 minutes and the new solid obtained is recrystallised from 400 ml of heptane. The crystals obtained are taken up in 400 ml of methanol and, after 5 drops of concentrated sulfuric acid have been added, the mixture is refluxed for 4 hours and then concentrated. The residue is dissolved in 600 ml of ether. This ether phase is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over sodium sulfate and concentrated, giving 73.6 g (54%) of a clear oil.