Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].C=O.[C:17]([O-])(=[O:19])C.[Na+]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH2:17][OH:19])[C:6]1=[O:14]
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1n(CO)c2ccccc2n1CCCCl
Yield: 90.7 %

Procedure:
1-(3-Chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.30 g, 1.42 mmol), paraformaldehyde (0.0853 g, 2.84 mmol), and sodium acetate (0.117 g, 1.42 mmol) in acetic acid (3 mL) were heated at 65° C. for 20 hours. The mixture was evaporated to dryness, dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (50% ethyl acetate/hexanes) to give product as a white solid (0.31 g, 90%); NMR (DMSO-d6); 82.06-2.13 (m, 2H); 3.66 (t, J=6.4 Hz, 2H); 3.96 (t, J=6.8 Hz, 2H); 5.22 (d, J=7.2 Hz, 2H); 6.38 (t, J=7.2 Hz, 1H); 7.07 (m, 2H); 7.20-7.22 (m, 1H); 7.23-7.25 (m, 1H); MS for C11H13ClN2O2 m/z 241 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@@H:37]([CH2:40][CH2:41][CH3:42])[NH:36]1)[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@@H:37]([CH2:40][CH2:41][CH3:42])[N:36]1[C:11](=[O:13])[CH2:10][C:9]1[C:8]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=2[O:6][C:5]=1[C:3](=[O:4])[C:2]([CH3:20])([CH3:1])[CH3:21])[CH2:33][CH3:34]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Reactant: CCC[C@@H]1CC[C@H](CCC)N1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCC[C@@H]1CC[C@H](CCC)N1C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 13.7 mg cis-2,5-dipropylpyrrolidine from the Step A above followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 70-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.59 min. (m/Z=428.3, 344.2, 450.3).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(=O)C.CCO>[CH:12](=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(NN=Cc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.5 g, 0.0033 mol) in abs. EtOH (10 mL) and benzaldehyde (0.35 g, 0.0033 mol) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.68 g, in 86% yield, mp: 226.4° C. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.83 (d, 4H), 7.42 (d, 3H), 6.88 (d, 2H). 13C NMR (CDCl3) δ 167.5, 162.9, 149.8, 135.7, 131.4, 130.9, 129.8, 128.7, 124.9, 116.3. Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 69.82; H, 5.34; N, 11.60.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:20]=[C:11]3[C:12]4[C:17]([CH2:18][CH2:19][N:10]3[N:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1.[O-][CH2:22][CH3:23].[Na+].C(I)C>C(O)C>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:20]=[C:11]3[C:12]4[C:17]([CH2:18][CH2:19][N:10]3[N:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1)[CH3:23]
Reactant: Oc1cccc(-c2nc3n(n2)CCc2ccccc2-3)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCI
Solvent: CCO
Product: CCOc1cccc(-c2nc3n(n2)CCc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Hydroxyphenyl)-5,6-dihydro-s-triazolo-[5,1-a]isoquinoline (3.95 g.) is added to 60 ml. of ethanol containing one equivalent proportion of sodium ethoxide. To this mixture is added 1.57 ml. of ethyl iodide in 15 ml. of ethanol. After stirring for one hour at room temperature, a further 1.57 ml. of ethyl iodide is added and the mixture is refluxed for 18 hours. The solvent is distilled off and the residue is washed with water and extracted with dichloromethane. Evaporation of the solvent and crystallization of the residue from ethanol gives 3.87 g. of the title product; m.p. 102°-3° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: CN1CCNCC1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C)CC3)nn12
Temperature: 170 °C
Reaction time: 2 h

Procedure:
(rac)-6-[1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 69 mg, 0.20 mmol), KF (58 mg, 1.0 mmol) and N-methyl-piperazine (60 mg, 0.60 mmol) were suspended in NMP (1.0 mL). The RM was stirred at 170° C. for 2 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a yellow foam (tR 2.83 min (conditions 1), MH+=409.1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20]>>[C:50]([O:49][C:46]1[CH:45]=[CH:44][C:43]([CH2:42][C@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:16])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:48][CH:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid (Compound VI-10) 67 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:13][CH2:12][CH2:11][N:10]1[CH2:9][CH2:8][CH2:7]2)=[O:5])C.[ClH:14]>[OH-].[Na+].C(O)C>[ClH:14].[CH2:13]1[C:6]2([C:4]([OH:5])=[O:3])[N:10]([CH2:9][CH2:8][CH2:7]2)[CH2:11][CH2:12]1
Reactant: CCOC(=O)C12CCCN1CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C12CCCN1CCC2
Reaction time: 2.5 h
Yield: 92.4 %

Procedure:
A mixture of pyrrolizidine-7a-carboxylic acid ethylester (35.4 g, 0.193 mol) in 360 ml of 10% aqueous sodium hydroxide solution and 360 ml of ethanol was stirred at 10° to 15° C. for 2.5 hours. The reaction mixture was acidified with concentrated hydrochloric acid and then evaporated in vacuo to dryness. After addition of ethanol to the remaining residue, undissolved sodium chloride was filtered-off and the filtrate was evaporated in vacuo to dryness. The purifying operation described above was repeated twice. To the remaining residue, acetone was added to form crystals. The crystals were obtained through filtration and washed with small amount of acetone to give 34.2 g (92.4%) of the desired compound.
Reaction SMILES: [F:1]C1C=CC(OC)=C2C=1N[C@@H](C)CC2.[Br:15][C:16]1[CH:25]=[CH:24][C:23]2[N:22]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@@H:21]([CH3:31])[CH2:20][CH2:19][C:18]=2[C:17]=1[OH:32]>>[Br:15][C:16]1[C:17]([OH:32])=[C:18]2[C:23](=[C:24]([F:1])[CH:25]=1)[N:22]([C:26]([CH:28]1[CH2:30][CH2:29]1)=[O:27])[C@@H:21]([CH3:31])[CH2:20][CH2:19]2
Reactant: COc1ccc(F)c2c1CC[C@H](C)N2
Reactant: C[C@H]1CCc2c(ccc(Br)c2O)N1C(=O)C1CC1
Product: C[C@H]1CCc2c(O)c(Br)cc(F)c2N1C(=O)C1CC1

Procedure:
(S)-(6-Bromo-8-fluoro-5-hydroxy-2-methyl-3,4-dihydroquinolin-1 (2H)-yl)(cyclopropyl)methanone was synthesized from (S)-8-fluoro-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline according to the procedures described above for (2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol (Intermediate 2, Steps 1a, 2a, and 3). MS (ESI, pos. ion) m/z 328, 330 [M+H]+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:13]=[C:12]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[CH3:31])=[C:21]([CH2:32][O:33][CH3:34])[CH:20]=3)[O:16][N:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].Cl>CO.O>[F:3][C:4]1[CH:13]=[C:12]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[CH3:31])=[C:21]([CH2:32][O:33][CH3:34])[CH:20]=3)[O:16][N:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1N1CCCCC1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1cc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)ccc1N1CCCCC1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 5N aqueous solution of NaOH (0.52 mL, 2.62 mmol) was added to a suspension of methyl 2-fluoro-4-{5-[3-(methoxymethyl)-4-(2-methylpiperidin-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}benzoate (230 mg, 0.52 mmol, obtained in Example 113) in MeOH (5 mL). The resulting mixture was stirred at RT for 30 minutes. The reaction mixture was acidified with a 1N aqueous solution of HCl until pH=4 and diluted with water. The precipitate was filtered off, washed with water (3×) and dried under reduced pressure to give the title compound as a white powder. HPLC (Method A), Rt: 3.79 min (purity: 99.5%). LC/MS, M+(ESI): 426.2, M−(ESI): 424.3.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:8][CH2:7]1)#[N:2]>CO.N.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:8][CH2:7]1
Reactant: N#CCCCN1CCN(c2ccccc2F)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCCN1CCN(c2ccccc2F)CC1
Reaction time: 12 h
Yield: 99 %

Procedure:
1-(3-Cyanopropyl)-4-(2-fluoro phenyl)piperazine (2 g) was dissolved in a mixture of methanol and aqueous ammonia 28% (1-1, 20 ml) and the mixture is introduced in a Parr bottle. Then, Raney nickel (500 mg) is added as catalyst, and the mixture is hydrogenated in a Parr apparatus for 12 h under 60 psi. The catalyst is filtered of. The filtrate is evaporated in vacuo and the residue is taken of with AcOEt, the organic layer is washed three times with H2O, dried over anhydrous Na2SO4 and evaporated. The residue is taken with EtOH and concentrated HCl (15 mL 37%) is added. The mixture is evaporated and the hydrochloride is crystallized in a mixture of EtOH-Et2O (1-1) to yield the title compound B3 (99%). 1H NMR (200 MHz, CDCl3) δ: 1.44-1.61 (m, 4H), 1.88 (s, 2H), 2.37-2.45 (t, 2H), 2.60-2.65 (t, 4H), 2.65-2.72 (t, 2 H), 3.09-3.14 (t, 4H), 6.90-7.08 (m, 4H). RMN 13C (50 MHz, CDCl3): δ 24.2, 31.6, 42.0, 50.4, 53.2, 58.4, 115.7, 118.8, 122.3, 124.4, 142.8, 158.1.
Reaction SMILES: B.O1CCCC1.[CH2:7]([N:14]1[CH2:32][CH2:31][C:17]2[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:16]=2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:33]>C(O)(=O)C>[ClH:33].[CH2:7]([N:14]1[CH2:32][CH2:31][C@H:17]2[N:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C@@H:16]2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(CN2CCc3c(c4ccccc4n3-c3ccccc3)C2)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc(CN2CC[C@@H]3[C@@H](C2)c2ccccc2N3c2ccccc2)cc1

Procedure:
To a solution of 0.140 moles of borane in 150 ml. of tetrahydrofuran stirred at 0° C. in a three-necked round bottom flask fitted with magnetic stirrer, thermometer, condenser and addition funnel, and maintained under a nitrogen atmosphere, was added a solution of 23.9 g. (0.071 mole) of 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido[4,3-b]indole in 460 ml. of dry tetrahydrofuran. The addition was carried out at such a rate as to maintain the reaction temperature below 9° C. When the addition was completed the resulting mixture was heated to reflux and maintained at this temperature for one hour. The solvent was then evaporated in vacuo to afford a white solid mass which was suspended in 40 ml. of dry tetrahydrofuran and heated, slowly at first, with 180 ml. of a 1:1 by volume mixture of acetic acid and 5 N hydrochloric acid. The resulting suspension was heated at reflux for one hour, then cooled. Evaporation of tetrahydrofuran and part of the acetic acid resulted in precipitation of a white solid which was separated by filtration and washed with water. The solid was resuspended in tetrahydrofuran, filtered, washed with ethyl ether and air dried to afford 16.7 g. (63%) of the desired trans-isomer. M.P. 256°-260° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13](/[CH:14]=[CH:21]/[N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(COc2ccc(F)cn2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(COc2ccc(F)cn2)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 90.4 %

Procedure:
A mixture of 4-(5-fluoro-pyridin-2-yloxymethyl)benzaldehyde (2.71 g, 11.7 mmol) described in Manufacturing Example 56-1-2, nitromethane (1.26 mL, 23.4 mmol), ammonium acetate (1.35 g, 17.6 mmol) and acetic acid (30 mL) was stirred for 10 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (2.9 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:13](=[O:16])[CH2:14][CH3:15])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.C(O)(=O)C.[BrH:21].Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[CH3:1][NH:2][C:3]1[S:4][C:5]([C:13](=[O:16])[CH:14]([Br:21])[CH3:15])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1
Reactant: Br
Reactant: CCOC(=O)c1nc(NC)sc1C(=O)CC
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(NC)sc1C(=O)C(C)Br

Procedure:
To a solution of ethyl 2-methylamino-5-propionyl-4-thiazolecarboxylate (7.4 g) and 30% hydrogen bromide acetic acid (10 ml) in acetic acid (50 ml) was added pyridinium hydrobromide perbromide (13.0 g) at ambient temperature and the mixture was stirred for an hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a crystalline residue, which was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give ethyl 2-methylamino-5-(2-bromopropionyl)-4-thiazolecarboxylate (7.4 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=2[OH:14])[CH2:3][CH2:2]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:14][C:7]1[CH:8]=[C:9]([CH:10]=[O:11])[CH:12]=[CH:13][C:6]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1ccc(OCC2CC2)c(O)c1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1cc(C=O)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 4-(cyclopropylmethoxy)-3-hydroxybenzaldehyde (0.440 g, 2.289 mmol) in DCM (20 m), TEA (0.479 ml, 3.43 mmol) was added followed by methanesulfonyl chloride (0.196 ml, 2.52 mmol), and the mixture was stirred at RT overnight. A second portion of TEA (0.096 ml, 0.687 mmol) and methanesulfonyl chloride (0.054 ml, 0.687 mmol) was added, and the reaction was stirred at RT for additional 3 hours. The mixture was washed with HCl 1N and twice with K2CO3 1N. The organic layer was dried over Na2SO4, and the solvent was removed under vacuum affording 2-(cyclopropylmethoxy)-5-formylphenyl methanesulfonate (0.565 g, 2.090 mmol, 91% yield, MS/ESI+ 270.9 [MH]+). This crude was used for the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:28]=[CH:27][C:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[CH2:31]([O:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:28]=[CH:27][C:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19][C:13]=3[CH:12]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(S(=O)(=O)c3cccc(O)c3)cc2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(S(=O)(=O)c3cccc(OCc4ccccc4)c3)cc2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A solution of D3 (270 mg, 0.67 mmol) in dimethylformamide (5 mL) was treated with 60% sodium hydride (40 mg) at 0° C., then allowed to warm to room temperature. Benzyl bromide (137 mg, 0.8 mmol) in dimethylformamide (2 mL) was added, and the solution stirred overnight. The mixture was then poured onto water and extracted with ethyl acetate. The combined organic layers were washed with brine dried and evaporated. Chromatography on silica, eluting with 40% ethyl acetate in hexane afforded the product (200 mg). MH+ 494.
Reaction SMILES: [CH2:1]([C:3]1([CH2:33][CH3:34])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([NH:16][CH3:17])[CH3:15])=[CH:10][CH:9]=2)[N:5]([C:18]([NH:20][C@H:21]([CH2:29][CH2:30][CH3:31])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:19])[C:4]1=[O:32])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>C(Cl)Cl>[CH2:33]([C:3]1([CH2:1][CH3:2])[C@H:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]([CH3:17])[C:47](=[O:48])[CH2:46][O:45][CH3:44])[CH3:15])=[CH:12][CH:13]=2)[N:5]([C:18]([NH:20][C@H:21]([CH2:29][CH2:30][CH3:31])[C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)=[O:19])[C:4]1=[O:32])[CH3:34]
Reactant: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc([C@H](C)NC)cc1)c1ccc(C)cc1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc([C@H](C)N(C)C(=O)COC)cc1)c1ccc(C)cc1
Reaction time: 0.25 h
Yield: 97 %

Procedure:
The residue from Step B was taken up in methylene chloride (150 mL) and cooled in an ice bath and diisopropylethylamine (7.0 mL, 40 mmol) was added. A solution of methoxyacetyl chloride (3.5 gm, 32 mmol) in methylene chloride (20 mL) was added over 10 min. The reaction was stirred another 15 min before it was quenched into a mixture of ice water, 2N hydrochloric acid (40 mL) and methylene chloride. The layers were separated and the aqueous layer was extracted with another portion of methylene chloride. The methylene chloride layers were each washed with brine, combined, dried over sodium sulfate and evaporated. The residue was purified by preparative chromatography with 5% methanol/25% ethyl acetate/70% hexanes to give 28 gm (97%) of the title compound.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[CH:8])=[CH:3][CH:2]=1.CO>Cl[Cu].N1C=CC=CC=1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:8]#[C:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=2)=[CH:3][CH:2]=1
Reactant: C#Cc1ccc(C)cc1
Agent: Cl[Cu]
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc(C#CC#Cc2ccc(C)cc2)cc1
Yield: 69 %

Procedure:
In a 100 mL round bottom flask equipped with a gas inlet tube, was placed a Teflon covered magnetic stirring bar, p-tolylacetylene (5.0 g, 43 mmol), methanol 5 mL, pyridine 1.25 mL, and CuCl (0.2 g, 2 mmol). The reaction mixture was vigorously stirred while air was bubbled through it (A. Vogel, Vogel's Textbook of Practical Organic Chemistry, 4th Ed. Longman, London, England, 1978, p 351) Concentrated HCl (2 mL) and saturated sodium chloride (10 mL) was added. The precipitate was isolated by filtration. It was washed with water, dried, and recrystallized from toluene to give 3.45 g, 69% yield, mp 181-183° C. (Lit, 183° C. (Kunckell, Chem. Zentralblatt, 1913, I,1768)). 1H NMR δ: 7.40(d, 4H, J=8.25 Hz), 7.12(d, 4K J=8.25 Hz), 2.35(s, 6H)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([C:16]1[CH:33]=[CH:32][C:19]([CH2:20][NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:12]([C:16]1[CH:33]=[CH:32][C:19]([CH2:20][N:21]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[C:4](=[O:6])[C:3]2[CH:7]=[C:8]([Cl:11])[CH:9]=[N:10][C:2]=2[Cl:1])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)c(Cl)c2)C(=O)c2cc(Cl)cnc2Cl)cc1
Yield: 95.6 %

Procedure:
A solution of 2,5-dichloronicotinic acid (300 mg, 1.56 mmol), (4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine (578 mg, 1.72 mmol), 4-methylmorpholine (474 mg, 7.81 mmol), and HBTU (889 mg, 2.34 mmol) in DMF (9 mL) was stirred at RT for 16 h, then partitioned between heptane, ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (761 mg, 95%). White foam, MS (ISP) 509.0 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([N:4]1[C:5]2[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=2)[C:2]([I:1])=[N:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
3-Iodo-4-nitro-1H-indazole (0.50 g; 1.73 mmol) was dissolved with stirring in dimethylformamide (15 mL) under an atmosphere of nitrogen. Potassium carbonate (0.478 g; 3.46 mmol) was added followed by benzyl bromide (0.325 g; 1.90 mmol). The mixture was stirred for 16 hours at 25° C. The mixture was added to water (50 mL) and ethyl acetate (50 mL) with stirring. The mixture was transferred to a reparatory funnel and the phases were separated. The ethyl acetate phase was dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography, eluting with hexane/ethyl acetate (5:1). The fractions containing product were concentrated under vacuum to give the 1-benzyl-3-iodo-4-nitro-1H-indazole as a yellow oil (456 mg).