Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[OH:19][C:20]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=1[CH:22]=O.C(O)(=O)C>O1CCCC1>[OH:19][C:20]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:21]=1/[CH:22]=[CH:11]/[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)/C=C/c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
Sodium hydride (content: 62%, 3.3g) was suspended in tetrahydrofuran (30 ml). The suspension was ice-cooled in an atmosphere of argon gas. A solution of t-butyl diethylphosphonoacetate (20.9 g) in tetrahydrofuran (20 ml) was added to the suspension. The mixture was stirred for 15 min. at room temperature. A solution of 2-hydroxy-5-nitrobenzaldehyde (6.6 g) in tetrahydrofuran (20 ml) was gradually added to the mixture often with ice-cooling. The mixture was stirred for 10 min. at room temperature. Acetic acid was gradually added to the mixture until pH of the mixture was down to 5.0. The reaction mixture was gel-filtered with using YMC gel. Moreover the gel was washed with ethyl acetate. A mixture of the filtrate and washings was evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→3:2) to give the title compound (10.0 g) having the following physical data.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([O:21][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:20])=[CH:14][CH:15]=1
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCC(=O)c1ccc(Br)cc1)OCc1ccccc1
Reaction time: 18 h
Yield: 79 %

Procedure:
Benzyl bromide (9.98 g, 58.3 mmol) was added to a solution of 4-(4-bromophenyl)-4-oxobutanoic acid (15.0 g, 58.3 mmol) and K2CO3 (3.5 g, 58.3 mmol) in DMF (300 mL) and stirred for 18 hours. The reaction mixture was partitioned between water (200 mL) and ethyl acetate (500 mL). Sat'd NaHCO3 soln (20 mL) was added and the aqueous layer extracted with ethyl acetate (2×) and the combined organic layers were washed with brine and dried and filtered. Concentration gave Example J5, benzyl 4-(4-bromophenyl)-4-oxobutanoate 16 g (79%) which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.35-7.34 (m, 5H), 5.14 (s, 2H), 3.27 (t, J=6.7 Hz, 2H), 2.81 (t, J=6.7 Hz, 2H). HRMS: Anal. C17H16BrNO3 Calcd. 347.0277. found: 347.0283 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[C:12]([NH:14][C@H:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[CH3:16])=[O:13].O[Li:31].O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[C:12]([NH:14][C@H:15]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O-:23])=[O:22])=[CH:25][CH:26]=1)[CH3:16])=[O:13].[Li+:31]
Reactant: [Li]O
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(C)c2)cc1
Solvent: O
Product: Cc1cccc(CN2CCCC[C@@H]2C(=O)N[C@@H](C)c2ccc(C(=O)[O-])cc2)c1
Product: [Li+]

Procedure:
The title compound (E7) (28 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((S)-1-((R)-1-(3-methylbenzyl)piperidine-2-carboxamido)ethyl)benzoate (D24) (48 mg). (LiOH H2O: 3 eq; reaction time: 3 hrs)
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[C:17]2[CH:25]=[C:24]([Cl:26])[N:23]=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1.C(N(CC)CC)C.CNC>CC(O)C>[Cl:26][C:24]1[N:23]=[CH:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH:12][C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:14][CH:13]=3)[C:17]=2[CH:25]=1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CNC
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Clc1cc2c(Nc3ccc(Oc4ccccc4)cc3)ncnc2cn1

Procedure:
6-Chloro-4-(4-phenoxyanilino)pyrido[3,4-d]pyrimidine was prepared by the reaction of 4-phenoxyaniline and 4,6-dichloropyrido[3,4-d]pyrimidine in 2-propanol according to Procedure A, with triethylamine present to give the free base of the product directly. Reaction of this product with dimethylamine (33% aqueous solution) according to Procedure C gave the title compound: δH (CDCl3) 9.00 (1H,s), 8.54 (1H,s), 7.70 (2H, d), 7.00-7.44 (5H,m), 7.13 (2H,d), 6.38 (1H,s), 3.22 (6H,s); m/z (M+1)+358.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][CH2:35][CH:36]([OH:49])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:48])[CH3:47])=[CH:41][CH:40]=1>>[C:46]([NH:45][C:42]1[CH:43]=[CH:44][C:39]([O:38][CH2:37][CH:36]([OH:49])[CH2:35][NH:34][C:16]([C@@H:9]2[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]2[C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])=[O:18])=[CH:40][CH:41]=1)(=[O:48])[CH3:47]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Nc1ccc(OCC(O)CN)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccc(NC(C)=O)cc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and N-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl)acetamide, the title compound was obtained in 79% purity by HPLC. MS(ESI+): m/z=545.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:3]=12.[H-].[Na+].[C:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1)#[N:17].CC(O)=O>CN(C=O)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:27]3[CH:26]=[CH:25][C:24]([C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[C:16]#[N:17])=[CH:29][CH:28]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: CCCc1nc2nccc(C)c2[nH]1
Reactant: N#Cc1cnccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccncc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 7-methyl-2-propylimidazo[4,5-b]pyridine (170 mg, 1.0 mmol) from Step B in DMF at rt was added NaH (1.0 mmol). After 20 min, 3-cyano-4-(4-bromomethylphenyl)pyridine (1 mL of a 2M solution in CH2Cl2, 2 mmol) was added and the mixture was stirred at rt for 3 h. HOAc (100 μL) was added, the excess DMF was removed in vacuo then the crude product was isolated by extraction with EtOAc from brine. Purification by flash chromatography (100% EtOAc) gave the above titled compound as a glassy solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[CH2:16]=[CH:17][CH:18]=[CH2:19]>C(O)C>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[C:7]1[CH2:16][CH2:17][CH2:18][CH2:19][C:8]=1[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: C=CC=C
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CCO
Product: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 72.9 %

Procedure:
24.8 g of crude 5-nitronaphthoquinone (comprised of 82 wt% of 5-nitronaphthoquinone and 10 wt% of 6-nitronaphthoquinone), 12.1 g of 1,3-butadiene, and 124 g of ethanol were introduced into an autoclave. The autoclave was hermetically sealed and the reaction was effected at about 80°C for 2.5 hours. The resultant reaction solution was cooled to 25°-30°C to crystalize 5-nitrotetrahydroanthraquinone, and filtered. The cake was washed with 40 g of ethanol and dried to obtain 22.9 g of 5-nitrotetrahydroanthraquinone. The yield was 89.0%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[O:11]1[CH2:15]CC[CH2:12]1.CN(C)C=O.COCCl>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:12][O:11][CH3:15])=[CH:8][N:9]=1
Reactant: C1CCOC1
Reactant: Oc1ccc(Cl)nc1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Cl)nc1
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
Sodium hydride, 60% dispension in mineral oil (3:2, Sodium hydride:Mineral Oil, 2.32 g) was added portion wise to a solution of 6-Chloro-pyridin-3-ol (5.00 g, 38.6 mmol) in a mixture of Tetrahydrofuran (10.0 mL, 123 mmol) and N,N-Dimethylformamide (20.0 mL, 258 mmol). The mixture formed was stirred for 15 min and Chloromethyl Methyl Ether (3.66 mL, 48.2 mmol) was added dropwise. The above mixture was stirred for 6 hours (monitored by LCMS), poured into water and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated in vacuum. Purified on 40 g silica column eluting with 10-40% ethyl acetate in heptane to give 6.33 g of 2-chloro-5-(methoxymethoxy)pyridine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:24])=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(OC)c(OC)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3,4-dimethoxybenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (19.3 mg) with purity >90%. LCMS (pos) m/z 387.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][C:26](O)=[O:27])([OH:24])[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.CCN(C(C)C)C(C)C>CC#N.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][C:26]([NH:31][CH3:30])=[O:27])([OH:24])[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)C[C@@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C[C@@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 60 °C

Procedure:
To a solution of 2-((1R,3S)-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoic acid, 60d, (0.032 g, 0.076 mmol) in MeCN (1.6 mL) and DMF (1.6 mL) was added HATU (0.058 g, 0.152 mmol), Methanamine (0.154 mL of 2 M solution, 0.305 mmol) and iPr2NEt (0.053 mL, 0.305 mmol). The reaction was heated to 60° C. overnight then concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Water/HCl:MeOH). Pure fractions were combined and concentrated in vacuo to give 29 mg of 751 as the HCl salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.C[N+]1([O-])CC[O:30]CC1.[OH2:34].CC(C)=O>[Os](=O)(=O)(=O)=O>[O:34]=[S:11]1(=[O:30])[CH2:12][CH2:13][N:8]([C:7]2[C:2]([F:1])=[CH:3][C:4]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:5][C:6]=2[F:14])[CH2:9][CH2:10]1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCSCC3)c(F)c2)C(=O)O1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
N-({(5S)-3-[3,5-difluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (13.36 g, 35.97 mmol) is dissolved in a solution of 25% water/acetone and then treated sequentially with 4-Methylmorpholine N-oxide (3 eq, 12.64 g, 107.91 mmol) and a catalytic amount of osmium tetroxide (2.8 mL). The reaction is stirred overnight at room temperature under nitrogen. In the morning, another 2 mL of osmium tetroxide is added. Another 2 eq of 4-Methylmorpholine N-oxide and 2.5 mL of osmium tetroxide are added a few hours later. The reaction is stirred overnight again under nitrogen. The following morning, the reaction is complete. The reaction mixture is quenched with a solution of sodium hydrosulfite and then extracted with methylene chloride three times. The organic layer is washed with sodium hydrosulfite and brine, dried with sodium sulfate, filtered, and concentrated. The crude product is then chomatographed on silica gel, eluting with methylene chloride and then 2% and 5% methanol/methylene chloride solutions. Appropriate fractions are combined and concentrated to yield 11.99 g (83%) of the title compound as a white solid, mp: 187-189.5° C.
Reaction SMILES: S1C=CC=C1CC([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([Cl:17])[CH2:15][S:16][C@H:11]12)=O.C(Cl)Cl.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(O)C(C)C>[ClH:17].[NH2:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[O:19])=[C:14]([Cl:17])[CH2:15][S:16][C@H:11]12
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(C)CO
Solvent: ClCCl
Product: Cl
Product: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 500 mg. of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate in 6 ml. of methylene chloride was added 95 mg. of dry pyridine and 237 mg. of phosphorus pentachloride. The reaction mixture was stirred at room temperature for 1.5 hours, was thereafter cooled in an ice-water bath to about 5° C. and 0.6 ml. of iso-butyl alcohol were added. On continued cooling and stirring the reaction product, p-nitrobenzyl 7-amino-'-chloro-3-cephem-4-carboxylate hydrochloride, crystallized from the reaction mixture. The product was filtered, washed with cold methylene chloride and dried to yield 200 mg. of the crystalline product melting with decomposition at about 168° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1.[F:22][C:23]([F:28])([F:27])C([O-])=O.[Na+].C(OCC)C.O>CN1CCCC1=O>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([NH:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:23]([F:28])([F:27])[F:22])[N:7]=1)=[O:21]
Reactant: Cc1ccc(NC(=O)C(C)(C)C)c(-c2cncc(Br)n2)c1
Reactant: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(NC(=O)C(C)(C)C)c(-c2cncc(C(F)(F)F)n2)c1
Temperature: 25 °C
Yield: 18 %

Procedure:
The product obtained from Step B (0.8 g, 2.3 mmol) was dissolved in N-methylpyrrolidinone (16 mL). Cuprous iodide (1.7 g, 9.2 mmol) and sodium trifluoroacetate (2.5 g, 18.4 mmol) were then added and the resultant mixture heated at 180° C. for 6 h. After cooling to room temperature, diethyl ether (200 mL) and water (100 mL) were added. The two-phase mixture was filtered through a pad of Celite and the filter cake subsequently washed with three 50 mL-portions of ether. The layers of the filtrate were separated and the ether layer dried (MgSO4). The ethereal solution was evaporated and the residue chromatographed on silica gel eluting with 15% ethyl acetate/hexane. In this manner, 0.14 g (18%) of the title compound was obtained as a yellow semisolid. 1H NMR (300 MHz,CDCl3) δ 10.25 (br s,1H), 9.18 (s,1H), 8.93 (s,1H), 8.33-8.35 (m,1H), 7.41 (s, 1H), 7.33-7.35 (m,1H), 2.41 (s,3H), 1.25 (s,9H). 19F NMR (282 MHz, CDCl3) δ 67.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5]O.S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][Cl:13]
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: ClCc1cc(Cl)cc(Cl)c1

Procedure:
A mixture of 3,5-dichlorobenzyl alcohol (Aldrich, 25 g), thionyl chloride (100 ml) and DMF (0.5 ml) was stirred and refluxed for 4 hours. After cooling the mixture was concentrated in vacuo, the residue was taken up in ether, washed with saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to give 3,5-dichlorobenzyl chloride as a light yellow solid, which was used without further purification, 28 g, mp. 32°-36° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[C:5]#[C:6][C:7](=[N:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](F)(F)[F:9])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[C:38]([F:44])[C:37]=1[O:45][CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:8]([F:9])=[C:7]([NH:12][C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:32][CH2:33][CH3:34])[N:43]=2)=[C:38]([F:44])[C:37]=1[O:45][CH3:46]
Reactant: CCOC(C#CC(=NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F)OCC
Reactant: COc1c(Cl)ccc(CN)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 80 °C

Procedure:
In a typical reaction, N-(5,5-diethoxy-1,1,1-trifluoropent-3-yn-2-ylidene)-1,1,1-triphenylmethanamine is mixed with about a 2.5 to 3 fold excess of (4-chloro-2-fluoro-3-methoxyphenyl)methyl amine and about a 2.5 to 3 fold excess of cesium carbonate in anhydrous terahydrofuran. The mixture is heated at about 80° C. until the reaction is complete. After cooling, an extraction solvent like a halogenated hydrocarbon is added to the mixture along with water. The organic layer is recovered, washed with brine and dried. The solvent is evaporated to provide crude 2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine.
Reaction SMILES: [CH:1]1([C:7]([NH:9][CH2:10][CH2:11][C:12]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=3[S:14][CH:13]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:26])=O>>[CH:1]1([C:7]([NH:9][CH2:10][CH2:11][C:12]2[C:16]3[CH:17]=[C:18]([C:21]([Cl:26])=[O:23])[CH:19]=[CH:20][C:15]=3[S:14][CH:13]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Reaction time: 1 h

Procedure:
5 mmol of the product obtained in Step F are dissolved in 40 ml of thionyl chloride. After stirring under an inert atmosphere for 1 hour, the thionyl chloride is removed by evaporation under reduced pressure to yield the title product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:27][N:28]([CH:34]1[C:43]2[N:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH2:37][CH2:36][CH2:35]1)[CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:27][N:28]([CH:34]1[C:43]2[N:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH2:37][CH2:36][CH2:35]1)[CH2:29][CH2:30][CH2:31][CH:32]=[O:33])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)n1c(CN(CCCCO)C2CCCc3cccnc32)nc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)n1c(CN(CCCC=O)C2CCCc3cccnc32)nc2ccccc21
Reaction time: 0.33 h
Yield: 34.3 %

Procedure:
To a stirred solution of oxalyl chloride (4.5 mL, 9.0 mmol) in CH2Cl2 (40 mL) at −78° C. was added DMSO (0.86 mL, 12.1 mmol). After 30 minutes [1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-(4-hydroxy-but-1-yl)-amine (3.66 g, 8.13 mmol) was added as a solution in CH2Cl2 (7.5 mL). After a further 20 minutes, triethylamine (70 mL, 71.7 mmol) was added and the ice bath was removed. The reaction was stirred for a further 75 minutes then concentrated under reduced pressure. The residue was taken up in ethyl acetate and filtered through celite to give a crude yellow oil (3.88 g). Purification of this oil by column chromatography on silica gel (solvent=35:1:1 CH2Cl2: CH3OH: NH4OH) afforded the desired pure aldehyde (1.25 g, 39%). 1H NMR (CDCl3) δ 1.52-1.72 (m, 13H), 1.74-1.88 (m, 1H), 1.90-2.00 (m, 1H), 2.06-2.17 (m, 1H), 2.36 (t, 2H, J=6.6 Hz), 2.53-2.74 (m, 2H), 2.79-2.88 (m, 1H), 4.22 (dd, 1H, J=9.7, 6.3 Hz), 4.48 (d, 1H, J=15.4 Hz), 4.66 (d, 11H, J=15.2 Hz), 6.93 (dd, 1H, J=7.6, 4.7 Hz), 7.19-7.28 (m, 4H), 7.65-7.70 (m, 1H), 7.73-7.82 (m, 1H),8.33 (d, 1H, J=3.6 Hz), 9.56 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][OH:12])[CH:4]=[CH:3]1.C([Li])CCC.[C:18](=[O:20])=[O:19].O>C(OCC)C.CCCCCC>[OH:12][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[C:3]([C:18]([OH:20])=[O:19])=[CH:4]2
Reactant: O=C=O
Reactant: Cn1ccc2cccc(CO)c21
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: Cn1c(C(=O)O)cc2cccc(CO)c21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon a solution of 4 g (1-methyl-1H-indol-7-yl)-methanol in 80 ml diethyl ether is added dropwise to 76 ml of a 1.6 M solution of n-butyllithium in hexane at 0° C., while the temperature does not exceed 35° C. Then the mixture is stirred for another 12 hours at ambient temperature and the solution thus obtained is poured onto 30 g of crushed dry ice in 100 ml diethyl ether. The mixture is stirred until all the dry ice has dissolved and the reaction is then stopped by the addition of 40 ml of water. The phases are separated and the organic phase is extracted twice with 20 ml of water. The combined aqueous phases are suction filtered and the filtrate is adjusted to pH 2 with concentrated hydrochloric acid. The solid precipitated is suction filtered and dried in vacuo.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:20][O:21][CH:22]2[CH2:24][CH2:23]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1.C(OC(C)C)(C)C>C(O)=O>[CH:22]1([O:21][N:20]=[C:14]([C:12]2[N:13]=[C:9]([NH:8][CH:1]=[O:3])[S:10][CH:11]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:24][CH2:23]1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=NOC1CC1)c1csc(N)n1
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C(=NOC1CC1)c1csc(NC=O)n1
Temperature: 45 °C

Procedure:
A mixture of formic acid (13.1 ml) and acetic anhydride (32.6 ml) was warmed at 45° C. for 45 minutes. After the mixture was cooled until ambient temperature, ethyl 2-(2-aminothiazol-4-yl)-2-cyclopropyloxyiminoacetate (syn isomer)(22 g) was added thereto. The suspension was turned to a clear solution and soon a precipitate was appeared. To the suspension was added diisopropyl ether (50 ml) and the mixture was stirred at ambient temperature for additional an hour. The mixture was cooled in ice-bath and the precipitate was collected and washed with diisopropyl ether to give ethyl 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer)(20.5 g).