Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH:18]=[O:19])[C:10]([CH3:17])([CH3:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1.N12CCCC1=NCCC2>C1COCC1.C(O)C.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2[CH:18]=[O:19])=[CH:6][CH:7]=1
Reactant: CC1(C)C=C(c2ccc(F)cc2)C(C=O)C(C)(C)C1
Agent: C1CN=C2CCCN2C1
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)CC(c2ccc(F)cc2)=C(C=O)C(C)(C)C1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
The aldehyde obtained in Step 5 (130 g, 50 mmoles) was dissolved in a solution of 50 ml of THF and 50 ml of ethanol. To this solution was added 0.62 ml (5 mmoles) of 1,5-diazabicyclo-[4,3,0]-non-5-ene and the reaction mixture stirred at room temperature for 50 hours. The reaction mixture then was diluted with ether and extracted with dilute HCl, saturated NaHCO3, and brine. The solvents were evaporated in vacuo and the residue purified by flash chromatography on silica gel.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@@H:9]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:41][Si:42]([CH3:49])([CH3:48])[CH2:43][CH2:44][O:45][CH2:46]Cl.[Na+].[Cl-]>C(Cl)Cl>[CH3:41][Si:42]([CH3:49])([CH3:48])[CH2:43][CH2:44][O:45][CH2:46][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C@@H:9]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(OCOCC[Si](C)(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of thioglycoside 78 (1.40 g, 3.10 mmol) in 15 mL of methylene chloride is added N,N-diisopropylethylamine (0.64 mL, 3.70 mmol), followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.60 mL, 3.40 mmol). The mixture is stirred at room temperature for 2 h, poured into saturated NaCl (50 mL) and extracted with CH2Cl2 (2×50 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (40% EtOAc/hexane) to give 1.60 g (89%) of 1-deoxy-1-{4-[2(trimethylsilyl)ethoxymethoxy]phenylthio}-2,3,4,6-tetra-O-acetyl-β-D-galactopyranose 79 as a colorless oil: Rf 0.4 (33% EtOAc/hexane); 1H NMR (CDCl3, 270 MHz) δ 7.46 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 5.40 (d, J=3.3 Hz, 1H, H-4), 5.22 (s, 2H, SEM), 5.20 (dd, J=9.9, 9.9 Hz, 1H, H-2), 5.02 (dd, J=3.3, 9.9 Hz, 1H, H-3), 4.58 (d, J=9.9 Hz, 1H, H-1), 4.18 (dd, J=6.6, 11.2 Hz, 1H), 4.10 (dd, J=6.6, 11.2 Hz, 1H), 3.89 (dd, J=6.6, 6.6 Hz, 1H, H-5), 3.75 (t, J=8.4 Hz, 2H, SEM), 2.11 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.04 (s, 3H, OAc), 1.98 (s, 3H, OAc), 0.94 (t, J=8.4 Hz, 2H, CH2 --TMS), 0.01 (s, 9H, SiMe3).
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.C(N(CC)CC)C.Cl[S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>ClCCl>[O:2]1[C:10]2[CH2:9][CH2:8][N:7]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=3)(=[O:21])=[O:20])[CH2:6][C:5]=2[CH:4]=[CH:3]1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.900 g (18.169 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride and 12.7 ml (90.8 mmol) of triethylamine in 100 ml of dichloromethane, 4.81 g (21.8 mmol) of 4-chlorosulfonylbenzoic acid was added under ice-cooling, followed by overnight stirring at room temperature. After the solvent was distilled off under reduced pressure, 1 N hydrochloric acid was added; the resulting precipitate was filtered, washed with 1 N hydrochloric acid and dried to yield the desired product.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([O:17][CH3:18])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[CH2:6]([O:5][C:3]([CH2:2][O:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[C:8]([O:17][CH3:18])=[O:16])=[O:4])[CH3:7]
Reactant: CCOC(=O)CCl
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1C(=O)OC
Yield: 110.4 %

Procedure:
8020 g (65.44 mol) of ethyl chloroacetate are added to a mixture of 62 l of acetonitrile, 9490 g (62.38 mol) of methyl salicylate, 8610 g (62.38 mol) of potassium carbonate and 620 g of potassium iodide at 20° C., and the mixture is stirred and heated under reflux for 9 hours and stirred overnight without further heat being supplied. The mixture is filtered over Celite and the filtrate is concentrated under reduced pressure. 16.4 kg of methyl 2-ethoxycarbonylmethoxybenzoate are obtained (HPLC: logP=2.1)
Reaction SMILES: C(O[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([OH:19])[CH:6]=1)C.[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28]O)[CH:22]=1.[CH3:31][O:32][C:33]([C:35]1([NH2:44])[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36]1)=[O:34]>>[CH3:31][O:32][C:33]([C:35]1([NH:44][C:4](=[O:20])[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:7]([O:19][CH2:28][CH2:27][C:23]3[CH:22]=[C:21]([CH3:30])[CH:26]=[CH:25][CH:24]=3)[CH:6]=2)[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36]1)=[O:34]
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)c(O)c1
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cccc(CCO)c1
Product: COC(=O)C1(NC(=O)c2ccc(OCc3ccccc3)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1

Procedure:
The compound of step 2 was reacted with 2-m-tolyl-ethanol in analogy to step 1 of example 1, and the obtained ester was hydrolyzed in analogy to example 2. The obtained carboxylic acid was reacted with 2-amino-indane-2-carboxylic acid methyl ester in analogy to step 2 of example 13.
Reaction SMILES: C(N1C2C(=CC=C3C=2NC(=O)C3=O)CC1)(=[O:3])C.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]3[CH2:30][CH2:29][CH2:28][CH2:27][C:25]3=2)[C:20](=O)[C:19]1=[O:32].C([O:36][CH2:37][C:38](=O)[CH2:39][C:40]1[C:41]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:42]=2[S:43][CH:44]=1)(=O)C.C([NH+](CC)CC)C>>[Cl:49][C:47]1[CH:46]=[CH:45][C:42]2[S:43][CH:44]=[C:40]([CH2:39][C:38]3[C:37]([OH:36])=[C:20]([C:19]([OH:32])=[O:3])[C:21]4[C:26](=[C:25]5[CH2:27][CH2:28][CH2:29][CH2:30][C:24]5=[CH:23][CH:22]=4)[N:18]=3)[C:41]=2[CH:48]=1
Reactant: CC(=O)N1CCc2ccc3c(c21)NC(=O)C3=O
Reactant: CC(=O)OCC(=O)Cc1csc2ccc(Cl)cc12
Reactant: O=C1Nc2c(ccc3c2CCCC3)C1=O
Agent: CC[NH+](CC)CC
Product: O=C(O)c1c(O)c(Cc2csc3ccc(Cl)cc23)nc2c3c(ccc12)CCCC3
Yield: 21 %

Procedure:
The procedure described above for the synthesis and purification of compound 7 was followed, reacting 6,7,8,9-tetrahydrobenzo[g]indoline-2,3-dione (0.200 g, 0.994 mmol) with 3-(5-chlorobenzo[b]thiophen-3-yl)-2-oxopropyl acetate (0.365 g, 1.29 mmol). It was not possible to convert the triethylammonium salt obtained by preparative HPLC (basic modifier) back to the free acid by the usual method. Thus, the final product, a sunflower-yellow powder, was a triethylammonium salt with 6:5 acid:base stoichiometry (108 mg, 21% yield): 1H NMR (400 MHz, DMSO-d6) δ 1.17 (t, J=7.2 Hz, 7.5H) 1.72-1.87 (m, 4H) 2.77 (t, J=5.9 Hz, 2H) 3.10 (dq, 5H) 3.18 (t, J=5.7 Hz, 2H) 4.46 (s, 2H) 7.08 (d, J=8.8 Hz, 1H) 7.35 (dd, J=8.7, 2.2 Hz, 1H) 7.59 (s, 1H) 7.96 (d, J=8.3 Hz, 1H) 8.41 (d, J=2.1 Hz, 1H) 8.94 (d, J=8.8 Hz, 1H); HRMS (ESI+) calcd for C23H19ClNO3S (MH+) 424.0769, found 424.0770. Anal. Calcd for [C23H19ClNO3S]6[C6H15N]5[H2O]: C, 65.60; H, 5.78; N, 4.72. Found: C, 64.75; H, 6.01; N, 4.56.
Reaction SMILES: N#N.C(O)C.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1B(O)O.[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[C:24]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH2:6])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: Nc1ccccc1B(O)O
Agent: [Pd]
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)Cc1cccc(-c2ccccc2N)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 106.8 %

Procedure:
(The following reaction is done in an oxygenfree N2 atmosphere.) Add ethanol (0.8 mL), Tetrakis-(triphenylphosphine)-palladium(0) (30 mg, 2.2 mol %) and Na2CO3 decahydrate (944 mg, 3.30 mmol; presolved in 1.2 mL H2O) subsequently to dissolved 2-Amino-benzeneboronic acid (70) (201 mg, 1.30 mmol) in toluene (6.0 mL). Degas the reaction mixture for 5 times and flood with N2 again. Add (3-Bromo-phenyl)-acetic acid methyl ester (69) (270 mg, 1.18 mmol) in toluene (6.0 mL), degas again (5 times) and stir the reaction solution overnight at 100° C. Partition the reaction solution between EtOAc and brine (1+1) and extract the separated aqueous layer 3 times with EtOAc. Wash combined organic layer with brine and dry with Na2SO4. Remove solvent under reduced pressure and purify the crude product by preparative radial chromatography (silica gel 60 PF, CyH/EtOAc 3+1) to obtain (2′-Amino-biphenyl-3-yl)-acetic acid methyl ester (71) as an orange oil (304 mg, 81%). 1H NMR (400 MHz, CDCl3): 3.66 (s, 2H); 3.69 (s, 3H); 3.62-3.86 (br.s, 2H); 6.75 (d, 1H, J=8.1 Hz); 6.80 (t, 1H, J=7.3 Hz); 7.11 (d, 1 H, J=7.3 Hz); 7.15 (d, 1H, J=8.1 Hz); 7.22-7.26 (br.m, 1H); 7.32-7.42 (m, 3H).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:29])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH3:28].[F:30][C:31]([F:54])([C:50]([F:53])([F:52])[F:51])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]COS(C1C=CC(C)=CC=1)(=O)=O.[C:55](=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:29])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:55])[CH2:28][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:31]([F:30])([F:54])[C:50]([F:51])([F:52])[F:53]
Reactant: O=C([O-])O
Reactant: CNCCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCC(F)(F)C(F)(F)F)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCCCCCC(F)(F)C(F)(F)F)CCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F

Procedure:
A solution of 381 mg of 11β-fluoro-3-hydroxy-7α-[6-(methyl-amino)-hexyl]-estra-1,3,5(10)-trien-17-one in 5 ml of dimethylformamide is stirred with 200 mg of 8,8,9,9,9-pentafluorononyltosylate for 2 hours at a bath temperature of 100° C. Then, it is added to semi-saturated sodium bicarbonate solution, extracted three times with methylene chloride, dried on magnesium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 90 mg of 11β-fluoro-3-hydroxy-7α-{6-[methyl-(8,8,9,9,9-pentafluoro-nonyl)-amino]-hexyl}-estra-1,3,5(10)-trien-17-one is obtained as a foam.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)Nc1ccccc1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (4.6 g, 0.037 mole) was added dropwise (slowly) to a stirred and chilled (10°-15°° C.) solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (10.0 g, 0.035 mole) in anhydrous dimethylformamide (100 ml). The reaction mixture was heated at 55°-60° C. for 5 hours, cooled to room temperature, and added dropwise to a stirred and chilled (10°-15° C.) solution of aniline (3.5 g, 0.038 mole) and triethylamine (7.6 g, 0.076 mole) in anhydrous dimethylformamide (75 ml). The reactionwas stirred dat room temperature overnight, poured into water (500 ml), allowed to precipitate, and diltered. The filter cake was twice suspended in position bicarbonate solution (250 ml) and filtered. The filter cake was washed with water, air dried, and recrystallized from ethanol, giving 4.74 g (37%) of off-white needles, mp 211°-212° C.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.C(S)C.[Al+3].[Cl-].[Cl-].[Cl-].C([O-])(O)=[O:31].[Na+]>C(Cl)Cl>[OH:31][C:7]1[CH:8]=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:9][C@H:10]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C[C@H](Cc1ccc(OC)cc1)c1cccnc1
Reactant: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)C[C@H](Cc1ccccc1O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of ethyl (S)-4-(4-methoxyphenyl)-3-(pyridin-3-yl)butanoate (9.25 g, 31 mmole) in CH2Cl2 (150 mL) was cooled to 0° C. Ethanethiol (11.5 mL, 155 mmole) was added, then AlCl3 (20.7 g, 155 mmole) was added portionwise. After 2 hr, the mixture was poured over ice, allowed to warm to RT, and neutralized with NaHCO3. The resulting suspension was filtered through celite® and the filter pad was washed with CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated. Flash chromatography on silica gel (1:1 EtOAc/hexanes) afforded the title compound (6.435 g, 73%) 1H NMR (400 MHz, CDCl3) δ 8.72, 8.41 (dd, J=4.9, 1.5 Hz, 1 H), 8.24 (narrow m, 1 H), 7.26 (dd, J=7.8, 4.9 Hz, 1 H). 6.78 (d, J=8.5 Hz, 2 H), 6.64 (d, J=8.5 Hz, 2 H), 4.03 (q, J=7.1 Hz, 2 H), 3.34-3.48 (m, 1 H), 2.92 (dd, J=13.7, 6.1 Hz, 1 H). 2.69-2.81 (m, 2 H), 2.64 (dd, J=15.6, 8.7 Hz, 1 H), 1.13 (t, J=7.1 Hz, 3 H); MS (ES) m/e 286 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]([OH:26])[CH2:23][CH:24]=C)=[N:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.[OH2:35].C(Cl)Cl>O1CCOCC1.O>[C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]([OH:26])[CH2:23][CH:24]=[O:35])=[N:18]3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCC(O)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Reactant: O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Product: O=CCC(O)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of compound 17 (330 mg, 0.760 mmol) in dioxane-water (3:1, 8 mL) were added 2,6-lutidine (0.177 mL, 1.73 mmol), K2OsO4·2 H2O (6 mg, 0.016 mmol), and NalO4 (655 mg, 3.06 mmol). The reaction was stirred at 25° C. and monitored by TLC. After the reaction was complete, water (10 mL) and CH2Cl2 (20 mL) were added. The organic layer was separated, and the aqueous layer was extracted by DCM (10 mL) three times. The organic layers were pooled, washed with brine, and dried over Na2SO4. The solvent was removed, and the product was purified with SiO2 column chromatography (hexanes/EtOAc=2/3) to afford aldehyde 18 (250 mg, 0.573 mmol, 75%) as a colorless oil. MS-ESI (m/z): [M+H]+ calculated for C18H15BrNO5S, 435.99 (79Br) and 437.98 (81Br); found 436.04 (79Br) and 437.97 (81Br).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]=[CH:6][N:5]([CH2:8][C:9]([OH:11])=O)[N:4]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[CH2:28][CH2:27][CH2:26][NH:25][C:24]=3[CH:23]=[N:22]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[CH2:28][CH2:27][CH2:26][N:25]([C:9](=[O:11])[CH2:8][N:5]4[CH:6]=[N:7][C:3]([C:2]([F:1])([F:13])[F:12])=[N:4]4)[C:24]=3[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cn1cnc(C(F)(F)F)n1
Product: O=C(Cn1cnc(C(F)(F)F)n1)N1CCCc2c1cnn2-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)acetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2× brine. The reaction slurry was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide 33 mg of the title compound as a white solid. 1H NMR (400 MHz, CD3OD, mixture of rotamers) δ 8.41 (s, 1H), 8.35 (s, 0.75H), 7.60 (s, 0.25H), 7.43-7.50 (m, 2H), 7.15-7.23 (m, 2H), 5.41 (s, 0.5H), 5.30 (s, 1.5H), 3.94 (m, 0.5H), 3.84 (m, 1.5H), 2.89 (m, 2H), 2.15 (m, 1.5H), 2.07 (m, 0.5H); MS: (ES) m/z calculated for C17H15F4N6O [M+H]+ 395.1, found 395.1.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([S:10]SCC)[CH3:9]>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].C1(C)C(C)=CC=CC=1>[CH2:8]([S:10][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH3:9]
Reactant: Oc1ccccc1
Reactant: CCSSCC
Agent: [Zr+4]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: CCSc1ccccc1O
Temperature: 150 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
A mixture of phenol (87.5 g, 0.93 moles), xylene (100 ml), and zirconium tetrachloride (6.0 g, 0.026 moles) was heated to reflux under a slow nitrogen stream. The xylene was distilled through a 10 inch Vigreux column. The distillation was continued over a 2 hour period until the reaction mixture reached 177° C. Approximately 10 g of phenol was distilled with the xylene. The reaction mass was cooled to 150° C., and ethyl disulfide (62.0 g, 0.50 moles) was added. The reaction mixture was heated to 152° C., then heated slowly over a 5 hour period to 180° C., and finally held at 180° C. for an additional 10 hours. Ethyl mercaptan was removed continuously by distillation. The reaction mixture was cooled to 100° C., then vacuum distilled at 100 mm mercury until the pot temperature reached 200° C. to give 70.8 g of distillate. GC analysis indicated the distillate contained 34.0 g of ortho-(ethylthio)phenol (44% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=[N:55][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCCC1>CN(C=O)C>[CH:50]1([NH:55][C:30](=[O:31])[C:29]2[CH:33]=[C:34]([F:37])[C:35]([CH3:36])=[C:27]([C:10]3[C:11]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[C:12]=4[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:38][CH3:39])[N:9]=3)[CH:28]=2)[CH2:51][CH2:52][CH2:53][CH2:54]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC3CCCC3)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and cyclopentanamine (8.15 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18.2 mg, 56%). LC-MS m/z 607 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C[CH2:15][N:16]=[C:17]=NCCCN(C)C.Cl.CNC.C1COCC1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:16]([CH3:17])[CH3:15])=[O:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1n[nH]c2cc(Br)ccc12
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1n[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-bromo-1H-indazole-3-carboxylic acid (1 g, 4.15 mmol) and EDC.HCl (1.2 g, 6.2 mmol) in DMF (5 mL) was added 2 M dimethylamine in THF (3.45 mL, 10.3 mmol). Mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo to remove the volatiles, then diluted with EtOAc (30 mL) and washed with water. The aqueous layer was extracted with more EtOAc (20 mL). The combined organics were washed with water (30 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white solid: 1H NMR (250 MHz, DMSO) delta 3.06 (3H, s), 7.34 (1H, dd, J=8.68, 1.52 Hz), 7.84 (1H, d, J=1.07 Hz), 7.92 (1H, d, J=8.68 Hz), 13.62 (1H, br. s.); LC-MS: m/z=+269.75 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][CH:9](O)[CH3:10].C([N:14](CC)CC)C.ClC(OCC)=O.O.N>C(OCC)(=O)C>[CH:9]([O:6][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([NH2:14])=[O:7])([CH3:10])[CH3:8]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)OC(=O)/C=C\C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
196 g (2.00 mol) of maleic anhydride was dissolved in 123 g (2.05 mol) of 2-propanol and 800 mL of ethyl acetate. Thereafter, 300 mL (2.15 mol) of triethylamine was added dropwise to the solution at an internal temperature of 10° C. or lower over 1.5 hours, and the obtained mixture was then stirred for 1 hour. Thereafter, 193 mL (2.03 mol) of ethyl chloroformate was added dropwise to the reaction mixture at an internal temperature of −5° C. or lower over 2 hours. After the mixture had been stirred for 30 minutes, the obtained reaction mixture was added dropwise to an aqueous solution containing 300 mL (2.16 mol) of 28% ammonia water and 250 g of ice. The obtained reaction mixture was left at room temperature overnight. Thereafter, 400 mL of ethyl acetate was added to reaction product, followed by stirring. Thereafter a liquid separation operation was performed on the reaction solution, so as to remove an aqueous layer. This operation was repeated three times. The obtained organic layers were gathered and were then concentrated. Recrystallized from hexane/ethyl acetate was performed, so as to obtain 50.5 g of isopropyl-(Z)-4-amino-4-oxo-2-butenoate in the form of a white solid. Yield: 16.1%.