Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[C:12]([O-:16])(=[O:15])[CH2:13][CH3:14].[Na+]>C(O)(=O)CC>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([O:16][C:12](=[O:15])[CH2:13][CH3:14])[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: CCC(=O)[O-]
Agent: [Na+]
Solvent: CCC(=O)O
Product: C=CCC1=C(C)C(OC(=O)CC)CC1=O
Yield: 302.9 %

Procedure:
In the same apparatus as in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g), propionic acid (60 ml) and sodium propionate (3 g) were charged and heated at 120° to 130° C. for 8 hours with agitation. After the completion of the reaction, propionic acid was evaporated off under reduced pressure. The residue was extracted with toluene (60 ml) and water (40 ml) and treated as in Example 1 to obtain 2-allyl-4-propionyloxy-3-methyl-2-cyclopentenone (19.7 g). Yield, 94.7%. B.P., 115°-120° C./0.1-0.2 mmHg.
Reaction SMILES: N#N.Cl.[F:4][C@H:5]1[CH2:9][CH2:8][NH:7][CH2:6]1.Cl[CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])[CH2:6]1
Reactant: OCCOCCCl
Reactant: F[C@H]1CCNC1
Agent: Cl
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: OCCOCCN1CC[C@H](F)C1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of (5)-3-fluoropyrrolidine hydrochloride (250 mg, 1.99 mmol) and 2-(2-chloroethoxy)ethanol (0.21 mL, 1.99 mmol) in dry toluene (7 mL) was added K2CO3 (1.51 g, 10.95 mmol) at rt followed by KI (33 mg, 0.20 mmol). The reaction mixture was stirred at reflux for 15 h. The mixture was filtered and the filtrate concentrated under reduced pressure to give crude (S)-2-(2-(3-fluoropyrrolidin-1-yl)ethoxy)ethanol as a yellow oil. TLC:rf (90:10:0.5 CH2Cl2-MeOH—NH4OH)=0.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=[N:11]1.Br[CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:21][CH2:22][Cl:23])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=[N:11]1
Reactant: ClCCBr
Reactant: O=c1n(-c2cc(O)c(Cl)cc2Cl)nc2n1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=c1n(-c2cc(OCCCl)c(Cl)cc2Cl)nc2n1CCCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3.0 Parts of 2-(2,4-dichloro-5-hydroxyphenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-A]pyridin-3(2H)-one prepared as described above in Example 3, 1.4 parts of 1-bromo-2-chloroethane, 1.5 parts of anhydrous potassium carbonate and 20 parts of dry acetonitrile were combined and refluxed for 6 hours followed by stirring for 72 hours at room temperature. The reaction mixture was poured into 200 parts of water. The aqueous suspension of the product was extracted three times with 200 parts of methylene chloride. The organic extracts of the product were dried with anhydrous sodium sulfate. The solvent was stripped from the product at reduced pressure on a rotary evaporator. The resulting dark oil was crystallized from ether yielding 0.2 parts of a light brown solid with m.p. 148°-150°.
Reaction SMILES: C(OC(N[C@H](C1C=CC(OCCOC2CCCCO2)=CC=1)C(O)=O)=O)(C)(C)C.C(OC(N[C@H](C1C=CC(OCC(OC)OCC)=CC=1)C(O)=O)=O)(C)(C)C.[O:55]=[C:56]1[NH:60][C@H:59]([C:61]2[CH:66]=[CH:65][C:64]([O:67][CH:68]([CH2:75][O:76][Si](C)(C)C)[CH2:69][O:70][Si](C)(C)C)=[CH:63][CH:62]=2)[C:58](=[O:81])[N:57]1[C@@H:82]([C@H:94]([C:96]1[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=1)[CH3:95])[C:83]([NH:85][C:86]1[CH:91]=[CH:90][C:89]([I:92])=[CH:88][C:87]=1[F:93])=[O:84]>N[C@H](C1C=CC(OC(CO)CO)=CC=1)C(N[C@@H]([C@H](C1C=CC=CC=1)C)C(NC1C=CC(I)=CC=1F)=O)=O>[F:93][C:87]1[CH:88]=[C:89]([I:92])[CH:90]=[CH:91][C:86]=1[NH:85][C:83](=[O:84])[C@@H:82]([N:57]1[C:58](=[O:81])[C@@H:59]([C:61]2[CH:62]=[CH:63][C:64]([O:67][CH:68]([CH2:69][OH:70])[CH2:75][OH:76])=[CH:65][CH:66]=2)[NH:60][C:56]1=[O:55])[C@H:94]([C:96]1[CH:97]=[CH:98][CH:99]=[CH:100][CH:101]=1)[CH3:95]
Reactant: C[C@@H](c1ccccc1)[C@@H](C(=O)Nc1ccc(I)cc1F)N1C(=O)N[C@H](c2ccc(OC(CO[Si](C)(C)C)CO[Si](C)(C)C)cc2)C1=O
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCOC2CCCCO2)cc1
Agent: CCOC(COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)OC
Agent: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC(CO)CO)cc1)C(=O)Nc1ccc(I)cc1F
Product: C[C@@H](c1ccccc1)[C@@H](C(=O)Nc1ccc(I)cc1F)N1C(=O)N[C@H](c2ccc(OC(CO)CO)cc2)C1=O

Procedure:
Prepared by the same method as described in example 1 except that (i) 2-fluoro-4-iodoaniline was used in place of 4-bromoaniline in step 2, (ii) (R)-tert-butoxycarbonylamino-[4-(2-hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-acetic acid (prepared as described in example 160) was used in place of (R)-tert-butoxycarbonylamino-(4-methoxy-phenyl)-acetic acid in step 4, (iii) the diol functionality contained in (2S,3S)-2-{(R)-2-amino-2-[4-(2-hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-acetylamino}-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide was temporarily protected as the bis-trimethylsilyl ether (performed as described in example 114) prior to performing step 6, and (iv) acid catalyzed hydrolysis of (2S,3S)-2-{(R)-2,5-dioxo-4-[4-(2-trimethylsilanyloxy-1-trimethylsilanyloxymethyl-ethoxy)-phenyl]-imidazolidin-1-yl}-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide was performed as described in example 114 prior to purification and isolation of (2S,3S)—N-(2-fluoro-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide in step 6.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:31])[CH:23]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[NH2:41][C@@H:42]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=1)[CH2:43][OH:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])[CH2:10][CH2:9]2)=[N:4][C:3]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](=[O:28])[NH:41][C@@H:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=2)[CH2:43][OH:44])=[C:24]([F:31])[CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)n2)CC1
Reactant: N[C@H](CO)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(c2cnc(N)c(-c3ccc(C(=O)N[C@H](CO)c4cccc(Cl)c4)c(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To 4-(3-amino-6-(4-((tert-butoxycarbonyl)amino)cyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (222 mg, 0.516 mmol) was added DMSO (4 mL), Hünig's base (0.450 mL, 2.58 mmol), (S)-2-amino-2-(3-chlorophenyl)ethanol (133 mg, 0.774 mmol) and then HATU (392 mg, 1.031 mmol). The reaction was stirred for 1 h at room temperature. To the reaction was added 50 mL of ethyl acetate, washed with water twice, saturated salt solution, dried over sodium sulfate, filtered and concentrated to residue. The crude was purified by flash chromatography using 12 gram column (solid load) eluting with 10-95% ethyl acetate in heptane. The desired fractions were concentrated to constant mass to give 252 mg of product (which is 2:1 trans to cis ratio), used as is (83% over two steps). LCMS (m/z): 584.3 (MH+), 0.91 min for both.
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[N:6]=[C:7](N)[S:8][C:4]=2[CH:3]=1.C(ON=O)(C)(C)C>CN(C=O)C>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1
Reactant: Nc1nc2cc(F)c(Br)cc2s1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: Fc1cc2ncsc2cc1Br
Temperature: 50 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
To a solution of 6-bromo-5-fluoro-benzothiazol-2-ylamine (2.73 g, 11.05 mmol) in DMF (60 mL) was added tert-butylnitrite (1.58 mL, 13.26 mmol) dropwise. The reaction mixture was stirred at 50° C. for 3 h, then it was concentrated in vacuo. The residue was stirred in 1 N aqueous KOH for 10 min, then ethyl acetate was added and the mixture was stirred overnight. The insolubles were filtered, washed with water then ethyl acetate. The resulting filtrate was separated, and the organic layer was washed with brine and directly adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-30% ethyl acetate/hexane afforded 1.33 g of 6-bromo-5-fluoro-benzothiazole as a light yellow solid (52% yield): 1H NMR (DMSO-d6) δ 8.13 (d, 1H), 8.63 (d, 1H), 9.50 (s, 1H); MS (m/z) 232, 234 [M+H+]+.
Reaction SMILES: O[C:2]1(CNC(C)C)COC2C=CC(O)=CC=2OC1.[CH:19]([N:22]1[CH2:26][C:25]2([CH2:32][O:31][C:30]3[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:29]=3[O:28][CH2:27]2)[O:24][C:23]1=[O:38])([CH3:21])[CH3:20]>>[CH:19]([N:22]1[CH2:26][C:25]2([CH2:32][O:31][C:30]3[CH:33]=[CH:34][C:35]([O:37][CH3:2])=[CH:36][C:29]=3[O:28][CH2:27]2)[O:24][C:23]1=[O:38])([CH3:21])[CH3:20]
Reactant: CC(C)N1CC2(COc3ccc(O)cc3OC2)OC1=O
Reactant: CC(C)NCC1(O)COc2ccc(O)cc2OC1
Product: COc1ccc2c(c1)OCC1(CO2)CN(C(C)C)C(=O)O1

Procedure:
This compound is prepared by employing the same reactants, reaction conditions and procedure outlined in Example 90 except the 3,7-dihydroxy-3-isopropylaminomethyl-3,4-dihydro-2H-1,5-benzodioxepin is replaced by an equivalent quantity of 3'-isopropyl-7-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one from Example 94, Step A.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](C)[C:3]=1N1CCCC2C(=O)N(C)NC1=2.[CH3:21][N:22]([CH3:41])[C:23]1[N:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][C:31]3[C:35](=[O:39])[N:36]([CH3:38])[NH:37][C:30]2=3)=[C:25]([CH3:40])[CH:24]=1>>[CH3:21][N:22]([CH3:41])[C:23]1[CH:24]=[C:25]([CH3:40])[C:26]([N:29]2[CH2:34][CH2:33][CH2:32][C:31]3=[C:35]([O:39][CH:2]([CH2:7][CH2:6][CH3:8])[CH2:3][CH2:4][CH3:5])[N:36]([CH3:38])[N:37]=[C:30]23)=[CH:27][N:28]=1
Reactant: Cc1cc(N(C)C)ncc1N1CCCc2c1[nH]n(C)c2=O
Reactant: Cc1cc(C)c(N2CCCc3c2[nH]n(C)c3=O)c(Cl)c1
Product: CCCC(CCC)Oc1c2c(nn1C)N(c1cnc(N(C)C)cc1C)CCC2

Procedure:
Example 12c was prepared according to the procedure described in Example 12a, except that 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one was replaced by 7-(6-dimethylamino-4-methylpyridin-3-yl)-2-methyl-1,2,4,5,6,7-hexahydropyrazolo[3,4-b]pyridin-3-one.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH:12]([C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[O:11]
Reactant: N#Cc1ccc(CO)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C=O)cn1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
1.04 g (8.2 mmol) oxalylchloride are dissolved in 8 ml dichloromethane. At −78° C., 1.28 g (16.4 mmol) dimethylsulfoxide are added dropwise. The solution is stirred at −78° C. for 20 minutes, then 1 g (7.46 mmol) of the compound of Example 2A, dissolved in 7 ml dichloromethane, is added, and stirring at −78° C. is continued for another 2 hours. 3.4 g (33.6 mmol) triethylamine are then added dropwise, and after warming up to room temperature, the mixture is purified by column chromatography (silica, eluent: cyclohexane to cyclohexane/ethyl acetate 2:1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[N:21][C:22]([N:29]2[CH2:32][CH:31](OS(C)(=O)=O)[CH2:30]2)=[C:23]([CH:28]=1)[C:24]([O:26]C)=[O:25].O.[OH-].[Li+]>C(#N)C>[Cl:18][C:19]1[CH:20]=[N:21][C:22]([N:29]2[CH2:32][CH:31]([NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[CH2:30]2)=[C:23]([CH:28]=1)[C:24]([OH:26])=[O:25]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cc(Cl)cnc1N1CC(Nc2cccc(C(F)(F)F)c2)C1
Temperature: 160 °C
Yield: 36 %

Procedure:
To a solution of 3-(Trifluoromethyl)aniline (0.047 ml, 0.374 mmol) in acetonitrile (0.5 ml), potassium carbonate (67.21 mg, 0.486 mmol) was added followed by the addition of methyl 5-chloro-2-(3-((methylsulfonyl)oxy)azetidin-1-yl)nicotinate (D63)(120 mg, 0.374 mmol). The reaction mixture was heated at 160° C. under microwave irradiation for 25 min. Lithium hydroxide monohydrate (23.54 mg, 0.561 mmol) was added and the resulting reaction mixture was heated at 150° C. under microwave irradiation for 5 min. Solvents were evaporated in vacuo and the residue was diluted with water (5 ml) and HCl 1M (15 ml) and extracted with ethyl acetate (3×20 ml). Collected organics, after solvent evaporation, afforded the title compound (D115) (50 mg)
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[CH:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[C:27](O)=[O:28].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[C:27]([N:8]1[CH2:9][CH2:10][C:5]2[CH:4]=[CH:3][O:2][C:6]=2[CH2:7]1)=[O:28]
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)c2cc(C(=O)N3CCc4ccoc4C3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.302 g (1.2 mmol) of anthraquinone-2-carboxylic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1); the resulting solid was washed with ethyl acetate to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]=[C:7](Cl)[C:8]([F:11])([F:10])[F:9].Cl[C:18](=[CH2:21])[C:19]#[N:20].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[CH:21][C:18]=2[C:19]#[N:20])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: FC(F)(F)C(Cl)=NCc1ccc(Cl)c(Cl)c1
Reactant: C=C(Cl)C#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A solution of N-(3,4-dichlorobenzyl)-2,2,2-trifluoroacetimidoyl chloride (20.0 g, 0.069 mol) and 2-chloroacrylonitrile (7.2 g, 0.082 mol) in N,N-dimethylformamide is cooled to 5° C. and treated with a solution of triethylamine (22 mL, 0.16 mol) in N,N-dimethylformamide (38 mL). When the addition is half complete, the cooling bath is removed and the reaction mixture is treated with the remaining triethylamine solution, stirred for two hours and diluted with water. The aqueous mixture is filtered to obtain the title product as a tan solid (18.38 g, mp 230°-232° C.).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:13]([O:15]C)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.OC1C=C2C(C=CC(C(O)=O)=C2)=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:13]([OH:15])=[O:14])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCc2ccc(OC)cc2C1
Agent: O=C(O)c1ccc2ccc(O)cc2c1
Product: O=C(O)C1CCc2ccc(O)cc2C1

Procedure:
7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid was prepared from methyl 7-methoxy-1,2,3,4tetrahydronaphthalene-2-carboxylate in a manner similar to that described for 7-hydroxy-2-naphthoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.Br[C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[C:28]1([C:54]3[C:45](=[CH:46][C:47]4[O:52][CH2:51][CH2:50][O:49][C:48]=4[CH:53]=3)[O:44][CH2:43]1)[C:29](=[O:42])[N:30]2[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.BrC1C=CC=C2C=1C1(C3C(=CC4OCCOC=4C=3)OC1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[C:28]2([C:54]4=[CH:53][C:48]5[O:49][CH2:50][CH2:51][O:52][C:47]=5[CH:46]=[C:45]4[O:44][CH2:43]2)[C:29](=[O:42])[N:30]3[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[CH:5][CH:4]=1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Agent: OB(O)c1cnc2ccccc2c1
Product: COc1ccc(-c2cccc3c2C2(COc4cc5c(cc42)OCCO5)C(=O)N3Cc2ccccn2)cc1

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 4-methoxyphenyl boronic acid to replace quinolin-3-ylboronic acid, and 4′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 4′-(4-methoxyphenyl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one was obtained (68%) as a colorless solid: mp 205-206° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 8.59 (d, J=4.7 Hz, 1H), 7.65-7.68 (m, 1H), 7.32-7.17 (m, 3H), 6.91-6.84 (m, 2H), 6.78-6.61 (m, 4H), 6.41 (s, 1H), 6.25 (s, 1H), 5.26 (d, J=15.8 Hz, 1H), 4.92 (d, J=15.8 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.36 (d, J=9.0 Hz, 1H), 4.27-4.08 (m, 4H), 3.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.3, 158.9, 155.6, 155.5, 149.5, 144.6, 142.6, 140.0, 137.9, 137.1, 130.9, 129.8, 129.0, 128.7, 125.7, 122.9, 122.8, 121.7, 113.2, 111.1, 108.5, 99.4, 64.6, 64.0, 58.5, 55.3, 46.2; MS (ES+) m/z 493.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N+:8]([O-])[NH:7][C:6]=2[C:14]#[N:15])([O-:3])=[O:2].P(Cl)(Cl)Cl.[N+](C1C=CC=C2C=1C(C(O)=O)=NN2)([O-])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(#N)C>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([C:14]([NH2:15])=[O:21])=[N:7][NH:8]2)([O-:3])=[O:2]
Reactant: N#Cc1[nH][n+]([O-])c2cccc([N+](=O)[O-])c12
Reactant: O=C(O)c1n[nH]c2cccc([N+](=O)[O-])c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClP(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NC(=O)c1n[nH]c2cccc([N+](=O)[O-])c12

Procedure:
The arylaldehyde was nitrated using a mixture of fuming nitric acid and sulfuric acid to give a mixture of mono-, di- and tri-nitrated products. The mono-nitrohaloarylaldehyde was separated by conventional separation techniques (e.g. column chromatography) and again subjected to the nitrating conditions described above to give the corresponding dinitroarylhaloarylaldehyde. The dinitroarylhaoloaldehyde was reacted with a suitably substituted boronic acid or boronic acid derivative in the presence of a suitable catalyst (e.g. tetrakistriphenylphosphinepalladium(0)) and a suitable base (e.g. sodium carbonate) in a suitable solvent (e.g. toluene) as described by Miyaura and. Suzuki (see Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866-867) to give the corresponding dinitroaldehyde. The dinitroaldehyde was then reacted with a primary aryl- or alkyamine (e.g. 4-bromoaniline) in the presence of a cyanide source (e.g. sodium cyanide) and acetic acid and acetic anhydride to give the corresponding nitrocyanoindazole-N-oxide. The nitrocyanoindazole-N-oxide can be converted to the corresponding nitrocyanoindazole by treatment with a reagent such as phosphorus (III) trichloride. The cyano group of the nitrocyanoindazole can then be hydrolysed to the corresponding nitroindazole carboxylic acid (e.g. using sodium hydroxide in aqueous ethanol), which can then be coupled to an amine using standard peptide coupling conditions (e.g. HATU/DIPEA/acetonitrile) to give the a nitroindazoleamide. The nitroindazoleamide can then be reduced to the corresponding nitroindazoleamine using standard conditions normally associated with the reduction of an arylnitro-group to an aniline (e.g iron in the presence of an aqueous alcoholic solvent).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22](NC(C3C=CC=CC=3C)CCO)=[O:23])[N:9]=2)=[CH:4][CH:3]=1.[F:36][C:37]([F:48])([F:47])[CH2:38][CH:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH2:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:17])([F:16])[F:18])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:40][CH:39]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:38][C:37]([F:47])([F:48])[F:36])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(CC(F)(F)F)c1ccccc1
Reactant: Cc1ccccc1C(CCO)NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)NC(CC(F)(F)F)c1ccccc1

Procedure:
In the same way as for the compound from Example 86, 50 mg (0.14 mmol) of the compound from Example 8A and 28 mg (0.15 mmol) of 3,3,3-trifluoro-1-phenylpropan-1-amine were reacted. This gave 44 mg (59% of theory) of the target compound.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[C:4]2[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[NH4+].[OH-]>CO>[OH:2][C:3]1[C:4]2[CH:11]=[C:10]([CH2:12][CH2:13][NH:14][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(C)(C)OC(=O)NCCc1cc2c(OC(=O)OC(C)(C)C)ncnc2s1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1cc2c(O)ncnc2s1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a 25-mL round-bottom flask containing a solution of 6-(2-[[(tert-butoxy)carbonyl]amino]ethyl)thieno[2,3-d]pyrimidin-4-yl tert-butyl carbonate (370 mg, 0.94 mmol, 1.00 equiv) in 10 mL of methanol was added NH4OH (2.1 mL) at room temperature and the resulting solution was stirred for 2 hours under N2. After completion, the resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to afford 252 mg (91%) of the desired tert-butyl N-(2-[4-hydroxythieno[2,3-d]pyrimidin-6-yl]ethyl)carbamate as a white solid. MS (ES): m/z 296 (M+H)+.
Reaction SMILES: [Li+].[OH-].[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]2)=[CH:7][CH:6]=1.Cl>O.O1CCOCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:20]([F:21])([F:22])[F:23])=[N:11]2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cc(C(=O)O)c(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
Add a solution of LiOH (122 mg, 5.03 mmol) in H2O (3 mL) to a stirred solution of ethyl 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (550 mg, 1.68 mmol) in 1,4-dioxane (10 mL). Stir overnight at ambient temperature. Acidify to pH 5 with 1 N HCl and extract with CH2Cl2 and 2× with 20% iPrOH in CHCl3. Dry the combined organic layers with MgSO4, filter and concentrate under reduced pressure to obtain 140 mg of the title compound as a white solid. Acidify the aqueous layer to pH 2-3 with 1 N HCl, and extract twice with 20% iPrOH in CHCl3. Dry the combined organics over MgSO4, filter, and add the solution to the initially obtained 140 mg white solids. Concentrate to afford the title compound as a white solid (426 mg, 85%). ES/MS m/z 299.0 (M−1).