Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2F)[CH:4]=1.[CH3:25][C:26]1([CH3:33])[O:30][C@H:29]([CH2:31][OH:32])[CH2:28][O:27]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:25][C:26]1([CH3:33])[O:30][C@H:29]([CH2:31][O:32][CH2:2][C:3]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[N:5]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:4]=2)[CH2:28][O:27]1
Reactant: COC(=O)c1cc2c(CCl)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CC1(C)OC[C@@H](CO)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(COC[C@@H]3COC(C)(C)O3)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 40 °C
Reaction time: 24 h
Yield: 82.9 %

Procedure:
To a solution of methyl 3-(chloromethyl)-1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (7.43 mL, 0.197M in CH2Cl2, 1.4645 mmol)) [prepared as described in step 2 of example 40] in anhydrous DMF (10 mL) was added (R)-(−)-2,2-Dimethyl-1,3-dioxolane-4-methanol (7.32 mmol, 0.91 mL, 5 eq.) followed by i-Pr2NEt (5.86 mmol, 1.02 mL, 4 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 40° C. After stirring for 24 hours (40° C.) the reaction was judged to be complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. The crude material was diluted with EtOAc (40 mL) and washed with water (4×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the target compound, which was purified by chromatography on a column of silica gel (40 mm OD, 150 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2-EtOAc-MeOH 70:30:2 v/v, 2.0 L, 25 mL fractions) using the flash technique. Fractions were combined to afford 0.520 g (83%) of methyl 3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}methyl)-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, ESI, +mode): RT-2.98 min, m/e=429.1 (M+H+, base). 1H-NMR (300 MHz, CDCl3): o=1.38 (s, 3H), 1.42 (s, 3H), 3.53 (m, 2H), 3.72 (m, 1H), 4.04 (m, 4H), 4.27 (m, 1H), 4.78 (q, 2H), 5.38 (s, 2H), 7.05 (t, 2H), 7.17 (m, 2H), 7.32 (s, 1H), 8.56 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Yield: 78 %

Procedure:
In another preparation, 100 g (0.634 mole) of ethyl isonipecotate and 130.4 g (0.74 mole) of benzenesulfonyl chloride were reacted by the above procedure for 4.5 hr to give the title product in 78% yield.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)[CH:8]=1.[C:26]([C:28]1[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[F:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:34])=[N:30][CH:31]=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)[CH:8]=1
Reactant: ON=C(Cl)Cc1ccc(COc2cc(F)ccn2)cc1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3cc(F)ccn3)cc2)no1
Temperature: 50 °C
Reaction time: 4 h
Yield: 35.8 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-(4-fluoro-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (200 mg, 0.679 mmol) described in Manufacturing Example 59-1-5 and 3-ethynyl-pyridin-2-ylamine (50 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (237 μL, 1.7 mmol) at room temperature, which was stirred for 4 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1-1:1) to obtain the title compound (57 mg, 22%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1
Reactant: C[O-]
Reactant: ClCc1cn2ccccc2n1
Agent: [Na+]
Solvent: CO
Product: COCc1cn2ccccc2n1

Procedure:
To a solution of 3.0 g of 2-chloromethylimidazo [1,2-a]pyridine in 50 ml of methanol is added 1.1 g of sodium methoxide, followed by heating under reflux for 3 hours. Methanol is distilled off under reduced pressure and chloroform is added to the residue. The resulting insoluble substance is filtered off, and the filtrate is washed with water and dried over anhydrous sodium sulfate. After distilling chloroform off, 2.9 g of the title compound is obtained as crystals.
Reaction SMILES: C([Li])CCC.[CH:6]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:8][CH2:7]1.[C:24](=[O:26])=[O:25]>C1COCC1>[CH:6]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:24]([OH:26])=[O:25])=[C:18]([F:22])[C:17]=2[F:23])[CH2:8][CH2:7]1
Reactant: Fc1cccc(OCCCCCCC2CC2)c1F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCCCCCC2CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
30 ml of butyllithium (1.6M in hexane) were added dropwise at -60° C. to a solution of 11.7 g of 6-cyclopropylhexyloxy-2,3-difluorobenzene in 70 ml of THF. After 5 hours at -60° C., CO2 was passed in until saturation was complete. The solution was warmed to RT, the solvent was removed by distillation, 400 ml of H2O were added, and the mixture was acidified to pH 3 using acetic acid. The precipitate was filtered off with suction. 12.3 g of 4-(6-cyclopropylhexyloxy)-2,3-difluorobenzoic acid were obtained. Melting point 100°-108° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[C:7]([O:6][C:4](=[O:5])[C@H:3]([NH:2][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCCN[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 50 °C
Yield: 73.7 %

Procedure:
A mixture of (R)-tert-butyl 2-amino-2-phenylacetate hydrochloride (0.5 g, 2.051 mmol), ethyl 4-bromobutanoate (0.44 g, 2.26 mmol), and K2CO3 (1.13 g, 8.21 mmol) in CH3CN (10 mL) was heated to 50° C. for 40 hours. The mixture was diluted with EtOAc and then washed with H2O and brine. The organic was then dried (MgSO4), filtered and concentrated. Purification by chromatography (silica gel, 40% EtOAc in Hexanes) afforded 486 mg (74%) of the title compound. MS (ESI) m/z 322 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[S:30][C:7]3[N:8]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:16]=4[F:29])[C:9](=[O:13])[NH:10][C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:34].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH:1]1([C:4]2[S:30][C:7]3[N:8]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:16]=4[F:29])[C:9](=[O:13])[N:10]([CH2:32][C:33]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)=[O:34])[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(C4CC4)sc32)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Cn2c(=O)c3cc(C4CC4)sc3n(Cc3ccc(-c4ccccc4C#N)cc3F)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a mixture of 4′-[(6-cyclopropyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.99 g) and N,N-dimethylformamide (40 mL) was added 60% sodium hydride (0.17 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.95 g, 47%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([CH3:16])[CH3:15].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH3:15][C:8]1([CH3:16])[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([O:4][CH2:3][CH2:2][N:31]3[CH2:32][CH2:33][N:28]([CH2:27][C:18]4[CH:19]=[CH:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:17]=4)[CH2:29][CH2:30]3)[CH:6]=2)[NH:10][C:9]1=[O:14]
Reactant: CC1(C)C(=O)Nc2ccc(OCCCl)cc21
Reactant: c1ccc2nc(CN3CCNCC3)ccc2c1
Solvent: ClC(Cl)Cl
Product: CC1(C)C(=O)Nc2ccc(OCCN3CCN(Cc4ccc5ccccc5n4)CC3)cc21
Temperature: 150 °C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
5-(2-Chloroethoxy)-3,3-dimethyl-2,3-dihydroindol-2-one (182 mg, 3.0 mmol) and N--(2-quinolylmethyl)piperazine (690 mg, 3.0 mmol) were mixed, followed by stirring at 150° C. for 3 hours under an argon gas stream. The resulting mixture was allowed to cool down, and was then dissolved in chloroform. The thus-obtained solution was washed with water and then dried over anhydrous sodium sulfate. After the solution was concentrated under reduced pressure, the residue was purified by chromatography on a silica gel column while using chloroform-methanol (10:1) as an eluent. Fractions containing the target compound were collected and then concentrated under reduced pressure. The concentrate was crystallized from n-hexane and was then recrystallized from ethyl acetate-ethyl ether, whereby 240 mg of the title compound were obtained as pale yellow powder (yield: 73%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:9]1)=O)(C)(C)C.[ClH:20]>>[ClH:20].[N:15]1([C@H:10]2[C@H:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](N2CCCC2)C1
Agent: Cl
Product: O[C@@H]1CCNC[C@H]1N1CCCC1

Procedure:
The titled product was prepared by deprotection of (trans)-4-hydroxy-3-pyrrolidin-1-yl-piperidine-1-carboxylic acid tert-butyl ester (described in Heterocycles 1994, 39, 1, 163) with hydrochloric acid analogously to intermediate 30. MS: 171.0 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][OH:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][O:20][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.9 %

Procedure:
A solution of 82.0 g (0.31 mol) of 1-benzyl-3-(R)-hydroxymethyl-4-(S)-phenyl pyrrolidine (from Step C) and 46.5 g (0.36 mol) of N,N-diisopropylethylamine in 1 L of CH2Cl2 was treated with 54.2 g (0.36 mol) of t-butyldimethylsilyl chloride and the resulting mixture was stirred at rt for 20 h. The reaction was quenched with 750 mL of sat'd NaHCO3 and the layers were separated. The organic layer was combined with 150 g of silica gel and aged for 45 min. The mixture was filtered and the filtrate was concentrated to afford 117 g (100%) of the title compound.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:5]=1[CH:6]=[O:7].O>C(Cl)(Cl)Cl>[Br:1][C:10]1[C:9]([O:12][CH3:13])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:3])[CH:11]=1
Reactant: COc1ccc(F)c(C=O)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Bromine (15 ml, 300 mmol) was added slowly to a solution of 2-Fluoro-5-methoxy-benzaldehyde (23.12 g, 150 mmol) in chloroform (500 ml), and the mixture was stirred at room temperature for 5 days. The mixture was poured into water (200 ml) and extracted with chloroform (2×200 mL). The organics were washed with water (200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (2–16% EtOAc in hexanes) to give the product. Yield: 20.7 g, 60%. 1H NMR (CDCl3) δ: 3.93 (s, 3H), 7.08–7.13 (m, 1H), 7.29 (d, J=12.4 Hz, 1H).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:55][CH:54]=[CH:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[C:50]1=[O:63]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:11])[NH:48][C@H:49]1[CH2:55][CH:54]=[CH:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[C:50]1=[O:63])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: Cc1ccccc1N1CC=CC[C@H](N)C1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC=CCN(c4ccccc4C)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S,Z)-2-oxo-1-o-tolyl-2,3,4,7-tetrahydro-1H-azepin-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (29 mg, 0.051 mmol) and Intermediate 68 (17 mg, 0.051 mmol) to give a white solid (24 mg, 61% yield). Anal. Calcd. for C44H52N4O6S m/z 764.7. found: 765.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.45-6.98 (m, 12H), 6.98-6.84 (m, 2H), 5.89-5.70 (m, 2H), 5.39-5.21 (m, 2H), 5.11 (d, J=5.4 Hz, 1H), 5.04-4.91 (m, 1H), 4.81 (t, J=19.2 Hz, 1H), 4.45 (s, 2H), 3.98 (s, 1H), 3.67 (d, J=3.2 Hz, 3H), 3.63-3.43 (m, 1H), 3.09 (dd, J=25.8, 13.3 Hz, 1H), 2.95-2.62 (m, 5H), 2.54-2.21 (m, 4H), 2.16 and 2.12 (2s, 3H), 2.07-1.89 (m, 3H), 1.87-1.40 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:19]([F:20])=[CH:18][C:14]([C:15]([OH:17])=O)=[C:13]([CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[N:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:30]1[CH:34]=[CH:33][N:32]=[C:31]1[NH2:35].N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CCCCCC.C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:19]([F:20])=[CH:18][C:14]([C:15]([NH:35][C:31]3[S:30][CH:34]=[CH:33][N:32]=3)=[O:17])=[C:13]([CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[N:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: O=C(O)c1cc(F)c(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN1CCOCC1
Product: O=C(Nc1nccs1)c1cc(F)c(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.9 %

Procedure:
To a dichloromethane (2 ml) solution were added 6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoronicotinic acid (100 mg, 0.23 mmol) were added thiazol-2-ylamine (25 mg, 0.25 mmol), benzotriazol-1-ol (34 mg, 0.25 mmol), 4-methylmorpholine (0.027 ml, 0.25 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (48 mg, 0.25 mmol) at room temperature. The resulting mixture was stirred at room temperature for 14 hours. To the reaction mixture was added ethyl acetate. The resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure. The residue was washed with ethanol and collected by filtration to give the title compound (72 mg, 0.14 mmol, 60%) as a white solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[N:9]=[C:8]([C:10](=[O:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:6][CH:5]=1.Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[N:9]=[C:8]([CH:10]([OH:31])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1cccc(F)n1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (4.19 g, 30.7 mmol) in diethyl ether (100 ml) was added sodium borohydride (2.33 g, 61.4 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off, and a solution of ethyl 3-(6-fluoropyridin-2-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (6.41 g, 15.4 mmol) in diethyl ether (50 ml) was added to the filtrate at −78° C. The mixture was stirred for 30 min. 1N Hydrochloric acid was added to the reaction solution to quench the reaction. Then, water (100 ml) was added and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(6-fluoropyridin-2-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate((2RS,3RS) form: (2RS,3SR) form=6:1, 5.70 g, 88%) as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[C:13]2[N:14]=[CH:15][NH:16][C:12]=2[CH:11]=[CH:10][N:9]=1.[C:17]([CH:21]([C:37]1[CH:42]=[CH:41][C:40]2[O:43][CH2:44][O:45][C:39]=2[CH:38]=1)[O:22][C:23]1[C:30]([CH2:31][CH2:32][CH3:33])=[CH:29][C:26]([CH2:27]Br)=[CH:25][C:24]=1[CH2:34][CH2:35][CH3:36])([O:19][CH3:20])=[O:18]>CN(C=O)C>[C:17]([CH:21]([C:37]1[CH:42]=[CH:41][C:40]2[O:43][CH2:44][O:45][C:39]=2[CH:38]=1)[O:22][C:23]1[C:30]([CH2:31][CH2:32][CH3:33])=[CH:29][C:26]([CH2:27][N:14]2[C:13]3[C:8]([Cl:7])=[N:9][CH:10]=[CH:11][C:12]=3[N:16]=[CH:15]2)=[CH:25][C:24]=1[CH2:34][CH2:35][CH3:36])([O:19][CH3:20])=[O:18]
Reactant: Clc1nccc2[nH]cnc12
Reactant: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2cnc3ccnc(Cl)c32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 25.9 %

Procedure:
Cesium carbonate (117.3 mg, 0.36 mmol) was added to 4-chloroimidazo[4,5-c]pyridine (25 mg, 0.18 mmol) in DMF (2 mL) at room temperature under nitrogen. After stirring for 15 min, a solution of 4-(1-carbomethoxy- 1-(3,4-methylenedioxyphenyl)methoxy)-3,5-dipropylbenzyl bromide (106.5 mg, 0.23 mmol) in DMF (2 mL) was added and the mixture stirred at room temperature for 12 h. The mixture was poured onto ice/water and the crude product that precipitated was collected by filtration. The crude material was pre-adsorbed on silica gel and chromatographed (0 to 50% hexane/ethyl acetate) to afford the title compound (25 mg).
Reaction SMILES: [O:1]=[C:2]([C:6]1[C:11]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)C(O)=O.C1C=CC2N(O)N=[N:27]C=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:13]2[O:14][C:10]3[C:11](=[C:6]([C:2]([NH2:27])=[O:1])[CH:7]=[CH:8][CH:9]=3)[N:12]=2)[CH:16]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C(=O)c1cccc2oc(-c3cccnc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2oc(-c3cccnc3)nc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 18.7 %

Procedure:
To a solution of 2-oxo-2-(2-(pyridin-3-yl)benzo[d]oxazol-4-yl)acetic acid (135 mg, 0.56 mmol) in DMF (15 mL) was added HOBt (148 mg, 1.1 mmol), NH4Cl (54 mg, 1.0 mmol), DIPEA (387 mg, 3.0 mmol) and EDCI (211 mg, 1.1 mmol). The mixture was stirred at 25° C. for 10 hr. To the resulting mixture, water (10 mL) and 1N aqueous hydrochloric acid was added to pH=3, then extracted with ethyl acetate (100 mL×4). The organic phase was washed with saturated sodium bicarbonate solution and brine, concentrated, and dried in vacuum. The crude product was purified by preparative HPLC to obtain 2-(pyridin-3-yl)benzo[d]oxazole-4-carboxamide as a solid (25 mg, yield 18%). 1H-NMR (400 MHz, DMSO-d6) δ 7.52-7.56 (t, J=8 Hz, 1H), 7.88-7.95 (m, 3H), 8.03-8.05 (d, J=8 Hz, 1H), 8.21-8.22 (d, J=4 Hz, 2H), 8.86 (d, J=4 Hz, 2H); LC-MS (ESI) m/z 240 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](C(F)(F)F)=[CH:6][CH:5]=1)=[O:3].C(C(O)=O)=O.Cl>>[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=CC(=O)O
Product: CC(=O)c1ccccc1

Procedure:
This procedure required close temperature control to avoid tar formation. To avoid this, the method was modified to a two-step process wherein the intermediate alpha-hydroxy acid was isolated and pyrolyzed separately. 4-Trifluoromethylacetophenone (75.2 g, 0.4 mole) and OHCCO2H.H 2 O (75.2 g) were heated neat at 79°-80° for 8 hr. The hot mixture was poured into diluted aqueous HCl (7.5 ml of concd HCl and 800 ml of H2O) with stirring. The aqueous mixture was extracted with Et2O (2 × 250 ml), and the aqueous phase was discarded. The extract was washed with H2O (2 × 100 ml), and dried (Na2SO4), and Et2O was removed (aspirator). The resulting residue was digested with hot CHCl3 (100 ml) and the mixture was concentrated to a volume of 80-85 ml. Petroleum ether (30°-60°, 250 ml), was added with stirring. The resulting precipitate was collected and washed with petroleum ether (100 ml). (Removal of petroleum ether from the combined washes and filtrate yielded unreacted acetophenone, 39.3 g, 52.3%, suitable for recycling.) The solid was digested again with CHCl3 (150 ml), filtered, and air-dried to yield 2-hydroxy-3-(4-trifluoromethylbenzoyl)propionic acid (31.2 g, 62%), mp 118°-120°. anal. (C11H9F3O4) C, H. The alpha-hydroxy acid was heated neat under vacuum (1-2 mm) in an oil bath until the internal temperature reached 155°. The temperature was increased to 160° over 40 minutes to complete the elimination of H2O. The flask was allowed to cool and crystallization of the title acrylic acid usually began at around 138°. The product was sufficiently pure for conversion to isonicotinic acid.