Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Si:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.C1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[O:33][C:32]=2[C:31](C2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:8][C:6]1[CH:5]=[C:4]([Si:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=[C:2]([C:7]2[CH:2]=[CH:3][CH:4]=[C:36]([C:35]3[C:34]4[O:33][C:32]5[CH:12]=[CH:11][CH:10]=[CH:15][C:31]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)[CH:6]=2)[CH:7]=1
Reactant: CC1(C)OB(c2cccc(-c3cccc4c3oc3ccccc34)c2)OC1(C)C
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A solution of (3,5-Dibromophenyl)triphenylsilane (4.27 g, 8.64 mmol), 2-(3-(dibenzo[b,d]furan-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 4.32 mmol), Pd(PPh3)4 (0.100 g, 0.086 mmol) and K2CO3 (1.792 g, 12.96 mmol) in toluene (100 mL) and water (10 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated, and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (4/1 to 3/1, v/v) as eluent to yield (5-Bromo-3′-(dibenzo[b,d]furan-4-yl)[1,1′-biphenyl]-3-yl)triphenylsilane (1.3 g, 45%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](O)=[O:14])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:27]>C1(C)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([Cl:27])=[O:14])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)O)sc2-c2ccc(F)cc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(C(=O)Cl)sc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.8 %

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylic acid (7.1 g) and phosphorus pentachloride (4.1 g) in toluene (100 ml) and tetrahydrofuran (25 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated to dryness to give pale yellow crystals of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonyl chloride (8.1 g).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH:8]1([C:14]([C:16]2[CH:22]=[CH:21]C(O)=C[C:17]=2[OH:23])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[O:31]1CC[CH2:33][CH2:32]1>>[C:5]([O:4][C:1]1[CH:21]=[CH:22][C:16]([C:14]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:15])=[C:17]([O:23][C:32](=[O:31])[CH3:33])[CH:2]=1)(=[O:7])[CH3:6]
Reactant: O=C(c1ccc(O)cc1O)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C(=O)C2CCCCC2)c(OC(C)=O)c1
Reaction time: 4 h

Procedure:
Acetic anhydride (1.58 ml, 16.7 mmol) was added to a solution of 4-cyclohexylcarbonyl resorcinol (1.47 g, 6.68 mmol) in tetrahydrofuran (15 ml) at room temperature, followed by triethylamine (2.80 ml, 20.0 mmol) and the solution stirred for 4 h. At this time, TLC showed the clean formation of a single product (Rf 0.71) and no starting material (Rf 0.40) (Note 5). The solvent was removed under reduced pressure to give 4-cyclohexylcarbonyl resorcinol diacetate as a light-yellow oil (3.0 g) and used without further purification for the next synthetic step (Note 6).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[C:10](=[O:11])[N:9]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][C:18]3[S:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=3)=[CH:15][C:8]2=[N:7][C:6]=1[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[CH2:32]([Zn]CC)C.CCCCCC.IC.[Cl-].[NH4+]>ClCCl>[OH:1][CH2:2][CH:3]1[CH2:32][CH:4]1[C:5]1[C:10](=[O:11])[N:9]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][C:18]3[S:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=3)=[CH:15][C:8]2=[N:7][C:6]=1[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/CO)c(N4CCOCC4)nc3c2)n1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CI
Solvent: ClCCl
Product: CC(C)c1csc(CCc2ccn3c(=O)c(C4CC4CO)c(N4CCOCC4)nc3c2)n1
Reaction time: 2 h
Yield: 73 %

Procedure:
3-[(E)-3-Hydroxy-1-propenyl]-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (81 mg, 0.18 mmol) was added with dichloromethane (3 ml) and a solution of diethyl zinc in hexane (1.02 M, 270 μl, 0.275 mmol) and subsequently added dropwise with iodomethane (30 μl, 0.366 mmol) at room temperature. After the reaction solution was stirred for 2 hours, the reaction was stopped with saturated aqueous ammonium chloride, and the reaction solution was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform:methanol=15:1) to obtain 61 mg (73%) of the title compound.
Reaction SMILES: C(C1C=NC(C2C=CC(O[CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]([O:31][C:32]([F:49])([F:48])[C:33]([F:47])([F:46])[O:34][C:35]([F:45])([F:44])[C:36]([F:43])([F:42])[O:37][C:38]([F:41])([F:40])[F:39])([F:30])[F:29])=CC=2)=NC=1)CCCCCCC.[CH2:50]([O:57][C:58]1[CH:59]=[N:60][C:61]([C:64]2[CH:69]=[CH:68][C:67]([OH:70])=[CH:66][CH:65]=2)=[N:62][CH:63]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]>>[CH2:50]([O:57][C:58]1[CH:63]=[N:62][C:61]([C:64]2[CH:65]=[CH:66][C:67]([O:70][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]([O:31][C:32]([F:48])([F:49])[C:33]([F:46])([F:47])[O:34][C:35]([F:44])([F:45])[C:36]([F:42])([F:43])[O:37][C:38]([F:40])([F:41])[F:39])([F:30])[F:29])=[CH:68][CH:69]=2)=[N:60][CH:59]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Product: CCCCCCCOc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 4-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy) 1-bromobutane (6.1 g, 15.0 mmol, Example 25) with 5-heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 10.5 mmol). The resulting crude product was further purified by recrysallization from ethanol and subsequent Kugelrohr distillation (b.p. 200°-210° C. at 0.3 torr; yield of 5.2 g).
Reaction SMILES: C[CH:2]1[CH2:6][S:5][CH:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C:3]1=[O:13].[ClH:14].NO.C(=O)([O-])[O-].[Ba+2]>C(O)(C)C>[Cl:14][CH:2]1[CH2:6][S:5][CH:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C:3]1=[O:13]
Reactant: Cl
Reactant: CC(C)OC(=O)C1SCC(C)C1=O
Agent: NO
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CC(C)O
Product: CC(C)OC(=O)C1SCC(Cl)C1=O

Procedure:
A mixture of 505 g (2.5 mol) of i-propyl 4-methyl-3-oxo-tetrahydrothiophene-2-carboxylate, 497 g (7.2 mol) of hydroxylamine hydrochloride, 753 g (3.8 mol) of barium carbonate and 2.5 litres of isopropanol is heated under reflux for about 12 hours. The mixture is subsequently filtered off with suction, the filter cake is washed with hot isopropanol and the filtrate is concentrated using water pump vacuum. The residue is taken up in 2 litres of diethyl ether, washed twice with water, dried over magnesium sulphate and filtered. The solvent is carefully distilled off from the filtrate using water pump vacuum.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:13]=[CH:12][C:11]([S:14]CCC(OC)=O)=[CH:10][C:9]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:5][CH:6]=1.[Cl:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1>>[ClH:28].[CH3:37][O:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][S:14][C:11]1[CH:10]=[C:9]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]([NH:7][C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)=[N:13][CH:12]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(CSc2cnc(Nc3nc(C)cs3)c(Oc3ccccc3)c2)c1
Product: Cl

Procedure:
Prepared according to the method of Example 16, using methyl 3-(6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate and 1-(chloromethyl)-3-methoxybenzene. 1H NMR (d6-DMSO) δ 8.09 (d, 1H), 7.42 (t, 2H), 7.18 (m, 3H), 6.98 (d, 2H), 6.76 (m, 4H), 4.09 (s, 2E), 3.68 (s, 3H), 2.26 (s, 3H); Mass spectrum (esi) m/z=436.2 (M+H-1HCl).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]2[C:12]([CH2:13][C:14]3[C:18]([C:19]4[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=4)=[N:17][NH:16][C:15]=32)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:27]=[C:26]2[C:12]([CH2:13][C:14]3[C:18]([C:19]4[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=4)=[N:17][N:16]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:15]=32)=[CH:11][C:10]=1[O:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc2c(cc1OCc1ccccc1)-c1[nH]nc(-c3ccc(Br)cc3)c1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCc1ccccc1)-c1c(c(-c3ccc(Br)cc3)nn1COCC[Si](C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a mixture of Example 267D (11.66 g, 26.1 mmol) and DMF (500 mL) in ice bath was added 95% NaH (0.69 g, 27.41 mmol). The mixture was stirred at room temperature for 0.5 hour and then cooled at 0° C. 2-(trimethylsilyl)ethoxymethyl chloride (4.85 mL, 27.41 mmol) was added to the mixture. After 0.5 hour, the ice bath was removed. The reaction was run at room temperature for another hour, and then poured into water. Ethyl acetate (200 mL×3) was used to extract the product. The organic solution was dried with MgSO4, concentrated, and purified by flash chromatography to give the desired product (10.84 g 72%). MS (DCI/NH3) m/z 577 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[O:40]=[S:41]1(=[O:53])[CH2:46][CH2:45][CH:44]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:50]3[CH2:51][CH2:52][N:47]([CH:44]4[CH2:43][CH2:42][S:41](=[O:40])(=[O:53])[CH2:46][CH2:45]4)[CH2:48][CH2:49]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine dihydrochloride (example 22) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C38H47N4O5SCl2 [(M+H)+] 741.2639, observed 741.2637.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([F:13])[CH:6]=1.C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH:4]([Br:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([F:13])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OC)c(F)c1
Temperature: 25 °C

Procedure:
The (3-fluoro-4-methoxyphenyl)acetic acid methyl ester (5.16 g, 26.0 mmol) is dissolved in carbon tetrachloride (300 mL) along with NBS (5.56 g, 31.3 mmol) and benzoyl peroxide (0.63 g, 2.60 mmol) and refluxed for 2 h. The solution is then allowed to cool to room temperature and is filtered. The filtrate is evaporated and the residue purified via flash column chromatography (EtOAc/hexanes 5:95→EtOAc/hexanes 2:8) to give bromo-(3-fluoro-4-methoxyphenyl)acetic acid methyl ester as a yellow oil. 1H NMR (CDCl3) δ 7.37 (d, J=12 Hz, 1H), 7.26-7.23 (m, 1H), 6.93 (t, J=8 Hz, 1H), 5.31 (s, 1H), 3.91 (s, 3H), 3.81 s, 3H).
Reaction SMILES: [C:1]([NH2:4])(=O)[CH3:2].O=P(Cl)(Cl)Cl.[BH4-].[Na+].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:18]1[C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:1][NH:4]1
Reactant: Cc1ccccc1
Reactant: CC(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: c1ccc2c(c1)CCNC2
Yield: 51 %

Procedure:
Primary amine from example 1 (200 mg) was reacted with acetyl chloride (1.3 eq.) in dry ethylamine (3 eq.) and dry dichloromethane (5 ml) at 0° C. for 1 hour, then 25° C. for 14 hours and gave the acetamide in 88% yield. The acetamide (103 mg, 0.263 mmol) was refluxed for 3 hours with POCl3 (7.5 eq.) in dry toluene (10 ml) at 110° C. for 14 hours followed by NaBH4 reduction (11 eq.) in dry ethanol gave the corresponding 1,2,3,4-tetrahydroisoquinoline (50 mg, 51%). Demethylation as in example 1 gave the expected product as the hydrobromide salt (50 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[NH:14][NH2:15].[C:16]([CH2:19][C:20](=O)[CH3:21])(=O)[CH3:17].C(O)C.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:11])=[O:12])=[CH:4][C:3]=1[N:14]1[C:20]([CH3:21])=[CH:19][C:16]([CH3:17])=[N:15]1
Reactant: CC(=O)CC(C)=O
Reactant: CS(=O)(=O)Oc1cc(NN)c(F)cc1Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(C)n(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)n1
Yield: 92 %

Procedure:
A mixture of 2-fluoro-4-chloro-5-methylsulfonyloxyphenylhydrazine (25.5 g), acetylacetone (10.0 g), ethanol (100 ml) and water (100 ml) was refluxed for 2 hours. After cooling, toluene was added to the reaction mixture to separate layers. The toluene layer as separated was washed with water and then subjected to distillation under a reduced pressure to remove the toluene, yielding the titled compound (29.3 g) as pale yellow crystals. Recrystallization from a mixture of hexane/ethyl acetate gave colorless crystals with melting point 77.5°-79° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([C:16]4(O)[CH2:18][C:17]4=C=O)[C:12]=3[O:14][CH3:15])[C:7](=[O:23])[C:6]([C:24]([O:26]CC)=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[OH-:29].[Na+].Cl.[CH2:32]([OH:34])C>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([C:16]4([C:32]([OH:34])=[O:29])[CH2:17][CH2:18]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(C3(O)CC3=C=O)c(F)cc2c1=O
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: COc1c(C2(C(=O)O)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.2 %

Procedure:
180 mg of ethyl 1-cyclopropyl-6-fluoro-7-(1-hydroxy-carbonylcyclopropyl)-8-methoxy-1,4-dihydro-4-oxo-3-quino-linecarboxylate was suspended in 2 ml of ethanol. After adding 1 ml of 2N NaOH, the mixture was stirred at room temperature for 15 hours. Then 2N HCl was added to the reaction mixture and the organic layer was collected, successively washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the residue was crystallized from diisopropyl ether and the crystals were collected by filtration. Thus 144 mg of 1-cyclopropyl-6-fluoro-7-(1-hydroxycarbonylcyclopropyl)-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was obtained (yield: 86.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH2:16]O.P(Br)(Br)[Br:19]>C1COCC1>[Br:19][CH2:16][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[CH3:15]
Reactant: COc1c(C)c(CO)c(OC)c(OC)c1OC
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: COc1c(C)c(CBr)c(OC)c(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 161.9 %

Procedure:
To a solution of 2,3,4,5-tetramethoxy-6-methylphenylmethanol (44.4 g) in THF (200 ml) was dropwise added phosphorus tribromide (29.8 g) with cooling with ice. After being stirred for 1 hr, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (54.4 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][N:9]2[C:13]([CH:14]=[CH:15][C:16](OCC)=[O:17])=[C:12]([Cl:21])[N:11]=[C:10]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].C([Al+]C(C)C)(C)C>C1COCC1.CCOCC>[N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][N:9]2[C:13]([CH2:14][CH:15]=[CH:16][OH:17])=[C:12]([Cl:21])[N:11]=[C:10]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(C=CC(=O)OCC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.5 g of 3-[1-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl]propenoic acid, ethyl ester, E isomer in 20 mL of THF was cooled with an ice bath, 1.7 mL of 1.5M diisopropylaluminum hydride (in toluene) was added slowly. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then quenched with 3 mL of conc. NH4Cl solution and the mixture was stirred for an additional 30 minutes. During this period an extensive gel-like material formed. The reaction mixture was further diluted with ether and filtered through celite. The filtrate was concentrated and the crude product was purified by flash column chromatography on silica gel (Hexane: EtOAc=1:1 elution). The desired compound was obtained as a thick liquid; NMR (200 MHz, CDCl3): δ 6.5-6.15 (m, 2H); 5.21 (s, 2H); 4.25 (d, 2H, J=4.5 Hz); 2.35 (t, 3H, J=7.4 Hz); 1.68 (m, 2H); 1.34 (m, 2H); 0.86 (t, 3H, J=7.4 Hz).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].N1C=CC=CC=1.C(Cl)Cl.[O:16](S(C(F)(F)F)(=O)=O)[S:17]([C:20]([F:23])([F:22])[F:21])(=O)=[O:18]>O>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:18])=[O:16]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCC(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reaction time: 0.25 h

Procedure:
Combine 2,2,2-trifluoro-ethanol (6.2 mL), pyridine (6.8 mL) and CH2Cl2 (20 mL) cooled in an ice bath. Add Tf2O (25 g) over about 45 minutes. After 15 minutes, add water, separate the layers and extract with water. The organic layer was dried over Na2SO4 and concentrated through a short path distillation apparatus (8 g, 54%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:11]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:12][CH:13]=[C:14]([O:17][CH3:18])[C:15]=2[N:16]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:35][O:36][CH:37]1[CH2:40][NH:39][CH2:38]1>>[CH3:35][O:36][CH:37]1[CH2:40][N:39]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:11]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:12][CH:13]=[C:14]([O:17][CH3:18])[C:15]=3[N:16]=2)=[O:6])[CH2:38]1
Reactant: COC1CNC1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CC(OC)C4)c3)nc12

Procedure:
From 2-bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)isonicotinamide with cesium carbonate and 3-methoxy-azetidine hydrochloride. ES-MS m/e (%): 457 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:6][C:3]=1[CH2:4][OH:5].C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29]Cl.O>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])=[CH:6][C:3]=1[CH2:4][O:5][CH2:27][O:28][CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CO)c1
Reactant: COCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 2-bromo-5-tert-butyldimethylsiloxybenzylalcohol (36.9 g, 116 mmol) and diisopropylethylamine (26.0 mL, 150 mmol) in dichloromethane (300 mL) was added chloromethyl methyl ether (11.0 mL, 145 mmol), and the mixture was stirred at room temperature for overnight. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (96:4 hexane/ethyl acetate) to give 1-bromo-4-tert-butyldimethylsiloxy-2-methoxymethoxymethylbenzene (39.3 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.O.CCOC(C)=O.CCCCCC.C(Cl)[Cl:30]>>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]=1[Cl:30]
Reactant: CC(C)OC(=O)c1cc(N)c(F)c(Cl)n1
Reactant: ClCCl
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1nc(Cl)c(F)c(N)c1Cl
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Propan-2-yl 4-amino-6-chloro-5-fluoropicolinate (1.191 g, 5.12 mmol) was almost completely dissolved in CH2Cl2 (40 mL). Water (40 mL) was added. Chlorine was bubbled through the solution for 5 min. After 30 min, an aliquot of the reaction mixture was analyzed by GC, showing desired product and only 1.7% starting material. The aqueous layer was separated and extracted with CH2Cl2 (50 mL). The combined organic extracts were washed with satd aq NaHCO3 solution and then brine. The extracts were dried (MgSO4) and concentrated under reduced pressure to yield an orange oil. Flash chromatography (120 g silica column; 0-50% EtOAc-hexane gradient) afforded a bright yellow crystalline solid (394 mg, 28%): 1H NMR (400 MHz, CDCl3) δ 5.29 (septet, J=6.3 Hz, 1H, CHMe2), 5.19 (br s, 2H, NH2), 1.40 (d, J=6.3 Hz, 6H, CHMe2); 13C{1H} NMR (101 MHz, CDCl3) δ 163.2 (CO2R), 143.3 (d, JF-C=5 Hz, C2), 142.8 (d, JF-C=270 Hz, C5), 141.0 (d, JF-C=26 Hz, C4), 135.3 (d, JF-C=17 Hz, C6), 114.9 (s, C3), 70.6 (CHMe2), 21.6 (s, Me); 19F NMR (376 MHz, CDCl3) δ −136.5.