Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.FC1C(O)=C(F)C(F)=C(F)C=1F.C(O)=O.[NH2:31][CH2:32][C:33]1[CH:34]=[C:35]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:36]=[CH:37][C:38]=1[O:39][C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][CH2:46][S:45][C:44]=2[CH:49]=1.B.C1COCC1.C1COCC1.Cl>CCOCC.C(Cl)Cl.CCOC(C)=O>[O:48]1[C:43]2[CH:42]=[CH:41][C:40]([O:39][C:38]3[CH:37]=[CH:36][C:35]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])=[CH:34][C:33]=3[CH2:32][NH:31][CH3:1])=[CH:49][C:44]=2[S:45][CH2:46][CH2:47]1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)SCCO3)c(CN)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: B
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CNCc1cc(NS(C)(=O)=O)ccc1Oc1ccc2c(c1)SCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
Dicyclohexylcarbodiimide (460 mg, 2.23 mmol) was added to a solution of pentafluorophenol (413 mg, 2.24 mmol) in ether (10 mL) followed by formic acid (95 μL, 2.5 mmol). The mixture was stirred for 2 h and then filtered, washing the residue with ether. The filtrate was concentrated to ˜5 mL and a solution of the primary amine of Example 105 (411 mg, 1.1 mmol) in DCM (10 mL) was added. The mixture was stirred for 16 h then concentrated to an oily residue. This crude oil was taken up in a solution of BH3.THF in THF (1M, 20 mL, 20 mmol) and heated at reflux for 1.5 h under N2. After cooling to room temperature the reaction was quenched by the cautious addition of MeOH (10 mL) and then concentrated in vacuo. The oily residue was treated with 6M HCl and heated at reflux for 30 min. After cooling to room temperature the mixture was basified with aq K2CO3 and extracted with DCM (3×). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified by column chromatography [SiO2; 90:10:1 (DCM/MeOH/880 NH3)] to give a colourless oil which was taken up in EtOAc (20 mL) and treated with 1M ethereal HCl (2 mL). After stirring for 1.5 h the solid was collected by filtration to give the title product (282 mg, 60%); δH (CD3OD, 400 MHz) 2.78 (3H, s), 2.98 (3H, s), 3.18 (2H, m), 4.29 (2H, s), 4.39 (2H, m), 6.74 (1H, d), 6.80-6.90 (3H, m), 7.22 (1H, d), 7.44 (1H, s); MS m/z (TS+) 381 (MH+).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([C:9]3[CH:14]=[C:13]([CH2:15][O:16][CH3:17])[CH:12]=[CH:11][C:10]=3[N:18]3[CH:22]=[N:21][CH:20]=[N:19]3)=[N:8][C:4]=2[CH:3]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=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>[C:23]([N:6]1[C:5]2[CH:27]=[CH:28][C:2]([C:33]3[CH:32]=[N:31][C:30]([NH2:29])=[N:35][CH:34]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[C:13]([CH2:15][O:16][CH3:17])[CH:12]=[CH:11][C:10]=1[N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)([CH3:25])([CH3:26])[CH3:24]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: COCc1ccc(-n2cncn2)c(-c2nc3cc(Br)ccc3n2C(C)(C)C)c1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 110 °C
Yield: 79.8 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-(5-methoxymethyl-2-[1,2,4]triazol-1-yl-phenyl)-1H-benzoimidazole (34 mg, 0.08 mmol) in DMF (1.5 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (20 mg, 0.09 mmol), tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol) and 2M aqueous Na2CO3 (0.15 mL). The reaction mixture is heated under argon at 110° C. for 2 hours. The residue is diluted with EtOAc (20 mL), washed with brine (10 mL), dried under anhydrous Na2SO4 (500 mg). The mixture is filtered and concentrated. The residue is purified by silica gel flash chromatography with 0-4% 2M NH3 in MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (29 mg, 83%). LCMS (ESMS): m/z 455.44 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1)=O.C(OC(=O)C)(=O)C.C(N(C(C)C)CC)(C)C.Cl>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH:12][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: COC(=O)/C=C/c1ccc(C=O)cc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1ccc(C=C(C(=O)O)c2ccc(F)cc2)cc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A mixture of 4-fluorophenylacetic acid (2.5 g, 13.2 mmol) and methyl (E)-3-(4-formylphenyl)acrylate (2.03 g, 13.2 mmol) were dissolved under stirring with acetic anhydride (8 mL). To this mixture, diisopropylethylamine (DIPEA) (3.4 mL, 19.7 mmol) was added and stirred at 30° C. for 2 hours. Upon completion (as monitored by TLC using 100% ethyl acetate as eluent), the reaction mixture was poured into water and the pH adjusted to 1 using dilute HCl (1:1). The aqueous layer was extracted with ethyl acetate (2×150 mL). The combined ethyl acetate layer was washed with water till the washings were neutral and dried over anhydrous Na2SO4. The ethyl acetate layer was evaporated to dryness to obtain a sticky compound and further triturated with cold dichloromethane (DCM) to furnish a white solid. The solid obtained was filtered and dried under vacuum to afford the title compound (2 g, 47% yield).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:49][N:48]=[C:47]([C:50]([F:53])([F:52])[F:51])[N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[O:49][N:48]=[C:47]([C:50]([F:53])([F:52])[F:51])[N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1noc(CCl)n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3nc(C(F)(F)F)no3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole and isolated as brown gum. MS (m/e): 433.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16](O)=O)[CH2:12][CH2:11]1.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:16]([CH:13]3[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]3)=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Brc1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 190 °C
Yield: 46.7 %

Procedure:
4-bromobenzene-1,2-diamine (1.43 g, 7.64 mmol) and piperidine-4-carboxylic acid (0.99 g, 7.64 mmol) were dissolved in polyphosphoric acid (20 g). This mixture was heated at 190° C. for three and half hours. Reaction mixture cooled to rt and diluted with water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 14. Solid was filtered, washed with methanol and dried to obtain the title compound (1 g) as a dark brown solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.Cl.[CH3:16][NH:17][O:18][CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([N:17]([O:18][CH3:19])[CH3:16])=[O:14]
Reactant: O=C(O)c1ccc2ccccc2c1Br
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
To a mixture of 1-bromo-2-naphthoic acid (1.04 g, 4.14 mmol, TCI America) and N,O-dimethylhydroxylamine hydrochloride (0.465 g, 4.76 mmol) in N,N-dimethylformamide (10 mL,) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.11 g, 4.76 mmol). After stirred at room temperature for 10 minutes, N,N-diisopropylethylamine (2.16 mL, 12.4 mmol) was added to the resulting mixture. The reaction was stirred at room temperature for 2 h, quenched with water, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was concentrated and the residue was purified on silica gel, eluting with 0% to 50% ethyl acetate in hexane, to give the desired product (1.08 g, 88%). LCMS calculated for C13H13BrNO2(M+H)+: m/z=294.0; found: 294.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7]2)([O-])=O.C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1-c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2n1-c1ccccc1

Procedure:
300 mg (0.97 mmol) of ethyl 5-nitro-1-phenyl-1H-indole-2-carboxylate from Example LVI are initially charged in 40 ml of ethyl acetate and 40 ml of ethanol. 365 mg (5.80 mmol) of ammonium formate and 102 mg of palladium on activated carbon (10%) are added. The mixture is heated to reflux, and at 50° C. gas evolves. After 4 hours at reflux, the mixture is cooled and filtered off through kieselguhr, which is washed with 500 ml of ethanol. The solvent is removed under reduced pressure and the residue is dried.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3([NH:38]C(=O)OC(C)(C)C)[CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[ClH:46].O1CCOCC1>C(Cl)Cl>[ClH:46].[ClH:46].[ClH:46].[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:29]=[CH:30][C:31]([C:34]3([NH2:38])[CH2:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4cccc([N+](=O)[O-])c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4cccc([N+](=O)[O-])c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
tert-Butyl (1-{4-[2-(3-nitrophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (30.0 mg, 0.0499 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 18 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (21.7 mg, 71.3%) as pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.69 (br s, 2H), 8.64 (s, 1H), 8.23 (t, J=1.8 Hz, 1H), 8.14-8.08 (m, 2H), 8.00 (dd, J=8.0, 1.8 Hz, 1H), 7.93-7.88 (m, 1H), 7.64-7.57 (m, 3H), 7.44-7.36 (m, 3H), 7.34-7.29 (m, 1H), 7.18-7.12 (m, 1H), 6.98 (dd, J=8.0, 1.8 Hz, 1H), 6.75 (dd, J=8.0, 4.8 Hz, 1H), 2.65-2.46 (m, 4H), 2.26-2.12 (m, 1H), 1.93-1.78 (m, 1H); LCMS: 501 [M+H].
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.C([O:18][C:19]([C:21]1[C:22]([O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH:39]([NH2:43])[C:40]([OH:42])=[O:41])=[CH:34][CH:33]=2)=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])C.[OH-].[Na+]>CS(C)=O>[C:40]([CH:39]([NH:43][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][C:22]2[C:21]([C:19]([OH:20])=[O:18])=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:33][CH:34]=1)([OH:42])=[O:41]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: CCOC(=O)c1cc2ccccc2nc1Oc1ccc(CC(N)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Oc2nc3ccccc3cc2C(=O)O)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-[4-(2-amino-2-carboxy-ethyl)-phenoxy]-quinoline-3-carboxylic acid ethyl ester in DMSO to provide, after hydrolysis with aqueous NaOH, the title compound in good yield.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-])=O)=[CH:9][CH:10]=2)[CH:5]=1)([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([NH2:14])[CH:7]=2)[CH:12]=[CH:13][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc2ccc([N+](=O)[O-])cc2c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2ccc(N)cc2c1

Procedure:
To 1.39 g (6.37 mmol) of 2,7-dinitronaphthalene (124) was added 25 mL of concentrated HCA and 15 mL of ethanol. Then, 9.6 g (50.9 mmol) of tin (II) chloride was added and the reaction was heated at 78 C for 24 hours. The reaction was made basic with NaOH and extracted with ethyl acetate. The ethyl acetate layer was dried (MgSO4), filtered, and the volatiles removed by rotary evaporation. The product was purified by silica gel column chromatography eluting with 1% methanol in dichloromethane. This provided 0.965 g of compound 125.
Reaction SMILES: [C:1]([O:5][CH:6]([O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12])[CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][CH3:3]>C(O)C.[Pd]>[C:1]([O:5][CH:6]([O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12])[CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][CH3:3]
Reactant: CCCC(OC(=O)CC)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCCC(OC(=O)CC)OC(=O)NCC1(CC(=O)O)CCCCC1
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A suspension of (135) (2.5 g, 5.77 mmol) and 10% Pd/C (250 mg) in ethanol (100 mL) was stirred under an atmosphere of hydrogen (balloon) for 30 minutes then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the crude product, which was purified by preparative LC-MS to give 1.21 g of the desired acid (131). (CDCl3, 400 MHz): 0.97 (t, J=7.2 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H), 1.50-1.38 (m, 12H), 1.72 (m, 2H), 2.32 (m, 4H), 3.18 (dd, J=6.4, 4.4 Hz, 2H), 5.27 (t, J=6.4 Hz, 1H), 6.72 (t, J=5.6 Hz, 1H). MS (ESI) m/z 344.39 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[CH2:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)[C:17]([CH3:18])=[O:19]
Reactant: O=C1CCC(c2ccc(O)cc2)=NN1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
A mixture of 4,5-dihydro-6-(p-hydroxyphenyl)-3(2H)pyridazinone (0.55 g), chloroacetone (0.32 g) and potassium carbonate (0.4 g), with a catalytic amount of potassium iodide, was stirred and heated under reflux in acetone (60 ml) for 16 hr. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was dried (MgSO4) and evaporated to a gum which was purified by chromatography on Silica gel. Elution with methanol-chloroform (4:96) gave 4,5-dihydro-6-(4-acetonyloxyphenyl)-3(2H)-pyridazinone as a pale yellow solid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13](OC)(=[O:17])[CH:14]([CH3:16])[CH3:15].C(O)(=O)C>C1COCC1.O>[CH3:15][CH:14]([CH3:16])[C:13](=[O:17])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)C(C)C)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Dimethyl methylphosphonate (8.8 g, 0.071 mol) was dissolved in anhydrous THF (100 ml) under argon atmosphere. To the solution stirred at -78° C. was added dropwise n-butyl lithium (1.58N, 45 ml, 0.071 mol) over 30 minutes and then a solution of methyl isobutyrate (2.9 g, 0.0284 mol) in anhydrous THF (5 ml) was added dropwise over 30 minutes. The reaction mixture was warmed to room temperature. After 30 minutes, acetic acid (4.3 ml) and water (10 ml) were added with ice cooling. After concentration, water (20 ml) was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The ethyl acetate layers were washed with water (20 ml×1) and with brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. Distillation of the residue gave dimethyl 3-methyl-2-oxo-butylphosphonate (4.8 g, 0.025 mol, yield 88%, b.p.= 82°-84° C./0.31 mmHg). The structure was identified by the following data.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[F:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=2)[N:3]=1
Reactant: CCCCCCCCC1CCc2cc(-c3ccc(O)cc3)nc(F)c2C1=O
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(-c2cc3c(c(F)n2)C(=O)C(CCCCCCCC)CC3)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1-fluoro-3-(4-hydroxyphenyl)-7-octyl-6,7-dihydro-5H-isoquinolin-8-one are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1-fluoro-3-[4-(octyloxy)phenyl]-7-octyl-6,7-dihydro-5H-isoquinolin-8-one.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[Cl:32][C:33]1[C:34]([F:42])=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[C:34]=3[F:42])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: OB(O)c1cccc(Cl)c1F
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3cccc(Cl)c3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-chloro-2-fluorophenyl)boronic acid gave 248. 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.59 (s, 1H), 8.30-8.21 (m, 1H), 7.86-7.77 (m, 2H), 7.52-7.43 (m, 1H), 5.05-4.77 (m, 2H), 4.16 (ddd, J=24.7, 13.6, 4.7 Hz, 1H), 3.99 (ddd, J=17.9, 13.5, 4.8 Hz, 1H), 3.77 (s, 3H), 3.27-3.22 (m, 1H), 2.18-2.09 (m, 1H), 1.88-1.78 (m, 2H), 1.71-1.60 (m, 3H). LCMS (ES+) m/z 468 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=2)[CH:7]=1
Reactant: COc1cccc(N)c1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc(OC)c2)c1
Yield: 82.8 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)-acrylic acid methyl ester (3) (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 3-methoxyphenylamine (0.189 g, 1.53 mmol) in dioxane (1 ml) and NaHCO3 (0.25 g, 3.06 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (2:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.44 g, 82%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.60 (3H, s), 3.71 (3H, s); 6.52–6.74 (3H, m); 6.63 (1H, d, J=16.0 Hz); 7.07 (1H, m); 7.43–8.05 (5H, m); 10.27 ppm (1H, br s).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(CC)CC.Cl[C:20]([O:22][CH3:23])=[O:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:20](=[O:21])[O:22][CH3:23])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(Br)n1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1ccc([N+](=O)[O-])c(Br)n1
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a solution of 6-bromo-5-nitropyridin-2-amine (1.4 g, 10 mmol), Et3N (2.0 g, 20 mol) and DMAP (70 mg) in CH2Cl2 (20 mL) was added ClCO2Me (1.3 g, 10 mmol) drop-wise at 0° C. The mixture was stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give methyl 6-bromo-5-nitropyridin-2-ylcarbamate (1.4 g, 82%). 1H NMR (400 MHz, DMSO) δ 10.78 (brs, 1H), 8.56 (d, J=9.2 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 3.70 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1Br.[C:15]1([NH:21][C:22](=O)[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:22]([CH3:23])=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:14]
Reactant: CC(=O)Nc1ccccc1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Product: COC(=O)c1cccc2nc(C)n(-c3ccccc3)c12
Yield: 30 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 2-Bromo-3-nitrobenzoic acid methyl ester and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as viscous oil (40 mg, 30%). 1H NMR (DMSO) δ 2.41 (s, 3 H), 3.08 (s, 3 H), 7.39-7.63 (m, 7 H), 7.96 (br s, 1 H); 13C NMR δ 14.1, 51.8, 117.2, 121.1, 123.0, 124.9, 137.0, 139.3, 139.6, 137.0, 140.2, 155.2, 165.7.