Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:21])[CH:3]=1.[Si]([C:26]#[N:27])(C)(C)C.O>CCN(CC)CC.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>[Cl:21][C:4]1[CH:3]=[C:2]([CH:20]=[CH:19][C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]1=[O:18])[C:26]#[N:27]
Reactant: C[Si](C)(C)C#N
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Yield: 98.2 %

Procedure:
Dissolve 3-(4-bromo-2-chlorobenzyl)-1-cyclohexylpyrrolidin-2-one (Example 55) (0.50 g, 1.35 mmol) in Et3N (20 mL) under N2. Add Pd(PPh3)4 (0.32 g, 0.27 mmol), TMSCN (0.40 g, 4.05 mmol) with stirring. Heat the reaction mixture for 24 hours until LC-MS shows the starting material has gone. Cool the reaction to room temperature and add water (20 mL). Extract the aqueous with EtOAc (3×50 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 30-60% of EtOAc-Hexane) to give 0.42 g (98%) of the title compound as white solid: MS (APCI-pos mode) m/z (rel intensity) 317.2 (100), 319.2 (30).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([OH:24])=[O:23])[C:13]1=[O:25].S(=O)(=O)(O)O.[CH3:31][CH:32](O)[CH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15](=[O:20])[N:14]([CH2:21][C:22]([O:24][CH:32]([CH3:33])[CH3:31])=[O:23])[C:13]1=[O:25]
Reactant: Cn1c(=O)n(CC(=O)O)c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Temperature: 25 °C

Procedure:
A solution of 3-(2-chloro-4-fluoro-5-nitrophenyl)tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetic acid (43.6 g, 0.105 mol) and concentrated sulfuric acid (25 mL) in 2-propanol (300 mL) is refluxed for 12 hours, cooled to room temperature and filtered to obtain a solid. The solid is dried to give the title product as an off-white solid which is identified by NMR spectral analyses. The filtrate is partially concentrated in vacuo and poured over ice. The resultant aqueous mixture is extracted with ethyl acetate and the organic extract is dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an orange oil. Flash column chromatography of the oil using silica gel and 2.5% to 5% ether in methylene chloride solutions gives additional title product as a yellow foam.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:40][CH3:41])=[C:24]([CH:39]=1)[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32].O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:40][CH3:41])=[C:24]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])[CH:39]=2)[N:7]=1)[CH3:4]
Reactant: COc1ccc(CCl)cc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OC)c(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 4-(5-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (516 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (647 mg, yield: 83%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 109–110° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].[C:20]1(=[O:31])[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[CH2:21]1.O1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:31])[CH2:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([OH:26])=[O:25])[CH:16]=[CH:17][CH:18]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: CCOC(=O)c1csc(/C=C/c2cccc(N)c2)n1
Solvent: C1CCOCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc(/C=C/c2cccc(NC(=O)Cc3ccccc3C(=O)O)c2)n1
Yield: 100.6 %

Procedure:
A solution of 0.5 g of (E)-2-[2-(3-aminophenyl)ethenyl]-4-thiazolecarboxylic acid ethyl ester, 0.3 g of homophthalic anhydride, 15 ml of toluene and 5 ml of tetrahydropyran was heated to reflux for 0.5 hr. Upon cooling, a solid formed which was filtered to yield 0.8 g of (E)-2-[2-[3-[2-[4-(ethoxycarbonyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 221°-223° C. from ethanol.
Reaction SMILES: O.O.[Sn](Cl)Cl.Cl.C1(C2C=CC(C([N:19]3[C:25]4[CH:26]=[C:27]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=[CH:29][C:24]=4[CH2:23][N:22]4[C:34](C(N5CCN(C)CC5)=O)=[CH:35][CH:36]=[C:21]4[CH2:20]3)=O)=CC=2)CCCCC1.CO>Cl>[CH3:33][O:32][C:30]([C:27]1[CH:28]=[CH:29][C:24]2[CH2:23][N:22]3[CH:34]=[CH:35][CH:36]=[C:21]3[CH2:20][NH:19][C:25]=2[CH:26]=1)=[O:31]
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)c1ccc(C3CCCCC3)cc1)Cc1ccc(C(=O)N3CCN(C)CC3)n1C2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2c(c1)NCc1cccn1C2
Temperature: 40 °C
Reaction time: 2 h
Yield: 500.2 %

Procedure:
To a stirred solution of tin(II) chloride dihydrate (23 g, 3.5 equiv.) in 2 N hydrochloric acid (106 mL) was added the [4-(2-formyl-1H-pyrrole-1-yl)methyl]-3-nitro]-benzoic acid methyl ester of Step A (8 g). Methanol (200 mL) was then added and the reaction mixture was stirred at 40° C. for 2 hours. The reaction was then cooled to room temperature, quenched by the addition of saturated aqueous sodium carbonate (20 mL) and filtered through Celite. The filter pad was washed with methanol and hot ethyl acetate. The filtrate and washings were combined, concentrated in vacuo to a volume of 300 mL and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a volume of 200 mL. Acetic acid (1 g) and 10% palladium on charcoal (1.5 g) were added and the mixture was hydrogenated overnight at atmospheric pressure. The reaction was then filtered through Celite and the solvent removed in vacuo to give a dark brown crystalline solid (16.4 g). This was dissolved in dichloromethane and filtered through a silica gel pad eluting with dichloromethane to provide the title compound which was recrystallized from 1,2-dichloroethane to yield a yellow crystalline solid (5.7 g), m.p. 198–200° C.
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([N:2]4[CH2:3][CH2:4][CH2:5][S:1]4(=[O:7])=[O:6])=[CH:14][N:13]=3)=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 37.1 %

Procedure:
Using isothiazolidine 1,1-dioxide (121 mg) and (5-bromopyridin-2-yl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 134 and by the reaction and treatment in the same manner as in Example 1, the title compound (154 mg) was obtained.
Reaction SMILES: [NH:1]([S:8]([C:11]1[CH:19]=[CH:18][C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3].[NH:20]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:21]([C:23]([NH:25][C@H:26]([C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34]O)=[O:29])[CH3:27])=[O:24])[CH3:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl.CO>[NH:20]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[C@H:21]([C:23]([NH:25][C@H:26]([C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:1]([S:8]([C:11]1[CH:19]=[CH:18][C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=1)(=[O:9])=[O:10])[C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3])=[O:29])[CH3:27])=[O:24])[CH3:22]
Reactant: COC(=O)[C@H](C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)N(CCCCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 10 h

Procedure:
To a cold (−15° C.) vigorously stirring solution of Ns-Ala-OMe (50 mg, 0.17 mmol), Boc-Ala-Ala-NH—(CH2)4—OH (57 mg, 0.17 mmol) and PPh3 (68 mg, 0.26 mmol) in dry THF (1.5 mL) was added DIAD (53 mg, 0.26 mmol) slowly dropwise. After 7 h another portion of PPh3 (68 mg, 0.26 mmol) and DIAD (52 mg, 0.26 mmol) was added and stirred for further 10 h, when TLC (MeOH:DCM) indicated complete consumption of the starting material. The mixture was concentrated under vacuum and the resulting residue was diluted with EtOAc (15 mL), washed with water (2 mL), dried over Na2SO4 and concentrated under vacuum to give a crude residue which was purified by silica gel flash column chromatography (EtOAc:Hexanes—3:1) to give the desired product as a viscous oil in good yields (71 mg, 76%). TLC (MeOH:DCM—1:9—Rf=0.5).
Reaction SMILES: ClC1C=CC=CC=1C([NH:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:10]=[C:9]([CH3:21])[C:8]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])=O.Br.O>C(O)(=O)C>[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=2[Cl:20])[N:10]=[C:9]([CH3:21])[C:8]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29]
Reactant: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(NC(=O)c2ccccc2Cl)c1C(=O)c1ccccc1Cl
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(=O)c1ccccc1Cl

Procedure:
A solution of 1.94 g (3.50 mmol of the product of Step B in 20 mL of glacial acetic acid was treated with 20 mL of 48% hydrogen bromide and stirred at reflux for 8 hours. The cooled reaction mixture was treated with water to crystallize the product which was separated by filtration, washed with water and air dried to give the title product, 1.45 g (100%), m.p. softens about 210° C. and melts at 220° C. Anal. Calcd. for C17H11ON3Cl4 : 412.9656. Found: 412.9722.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[C:19](O)(=[O:21])[CH3:20]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: CC(=O)O
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: CC(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OCC2(F)F)c1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and acetic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=302.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:12][CH2:13][C:14]([OH:16])=[O:15].[OH-].[Na+].C([O-])([O-])=O.[K+].[K+].Cl>CC(N(C)C)=O.O.C(=O)([O-])[O-].[Cu+2]>[C:14]([CH:13]=[N:12][C:2]1[C:3](=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:4]([OH:6])=[O:5])([OH:16])=[O:15]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NCC(=O)O
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Temperature: 80 °C
Yield: 76 %

Procedure:
47.8 g(0.25 mol) of 2,4-dichlorobenzoic acid are dissolved in 500 g of dimethylacetamide, 26.3 g (0.35 mol) of glycine and 1.7 g (7.5 mmol) of basic copper carbonate are added and the mixture is heated to 80° C. After addition of 24 g (0.6 mol) of NaOH and 22.5 g (0.16 mol) of K2CO3, the mixture is heated at 140° C. for 5 h. It is cooled to room temperature, diluted with 200 ml of water and adjusted to pH 2 with hydrochloric acid, and the crystalline product is filtered off. 43.9 g (0.19 mol, 77%) of N-carboxymethylene-4-chloroanthranilic acid are obtained.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]3[CH:15]=[CH:16][C:17](=[O:20])[NH:18][N:19]=3)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Br.Cl[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24]>>[CH2:1]([N:4]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]3[CH:15]=[CH:16][C:17](=[O:20])[NH:18][N:19]=3)[CH:11]=2)[CH2:6]1)[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[CH2:2][CH3:3]
Reactant: CCCNC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: CC(C)COC(=O)Cl
Agent: Br
Product: CCCN(C(=O)OCC(C)C)C1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1

Procedure:
2-Propylamino-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide and isobutyl chloroformate were treated in the same manner as in Example 51 to obtain 2-(N-propyl-N-isobutoxycarbonylamino)-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [NH:1]1[CH:6]([CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:9][OH:10].I[CH2:12][C:13]#[N:14].CCN(CC)CC>CN(C=O)C>[OH:10][CH2:9][CH:2]1[CH2:3][CH2:4][CH2:5][CH:6]([CH2:7][OH:8])[N:1]1[CH2:12][C:13]#[N:14]
Reactant: OCC1CCCC(CO)N1
Reactant: N#CCI
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCN1C(CO)CCCC1CO
Yield: 51.8 %

Procedure:
The method follows that of S5. 2,6-piperidinedimethanol (3.80 g, 26.21 mmol), iodoacetonitrile (5.24 g, 31.45 mmol), Et3N (4.38 mL, 31.45 mmol) and dry DMF (20 mL). Purification by flash chromatography using CH2Cl2/CH3OH (9:1) as eluent afforded the title compound as a straw-coloured oil (2.5 g, 53%). FAB MS, m/z(M+H)+ 185.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][Si](C)(C)C)=[CH:9][N:8]([C@@H:17]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]3[OH:19])[C:4]=2[N:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[CH:12])=[CH:9][N:8]([C@@H:17]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]3[OH:19])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ncnc(N)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A mixture of the compound 3 from Step 1 (686 mg, 1.89 mmol) and K2CO3 (130 mg, 0.94 mmol) in MeOH (15 ml) was stirred at RT for 1 h, followed by the co-evaporation with silica. Column chromatography on silica (5% MeOH in CHCl3) provided title compound 2o as white crystalline solid (528 mg, 96%). Compound was recrystallized from MeOH/water as long ochry needles. Mp 215-217° C. [α]D −88.3 (c 0.524, DMSO). 1H NMR (500.0 MHz, DMSO-d6): 3.53 (ddd, 1H, Jgem=12.0, J5′b,OH=6.2, J5′b,4′=3.8, H-5′b); 3.63 (dd, 1H, Jgem=12.0, J5′a,OH=5.0, J5′a,4′=3.8, H-5′a); 3.89 (td, 1H, J4′,5′=3.8, J4′,3′=3.2, H-4′); 4.07 (ddd, 1H, J3′,2′=5.0, J3,OH=4.8, J3′,4′=3.2, H-3′); 4.29 (s, 1H, HC≡C—); 4.37 (ddd, 1H, J2′,OH=6.3, J2′,1′6.1, J2′,3′5.0, H-2′); 5.16 (d, 1H, JOH,3′=4.8, OH-3′); 5.23 (dd, 1H, JOH,5′=6.2, J2′,3′5.0, OH-5′); 5.38 (d, 1H, JOH,2′=6.3, OH-5′); 6.01 (d, 1H, J1′,2′=6.1, H-1′); 6.70 (bs, 2H, NH2); 7.83 (s, 1H, H-6); 8.12 (s, 1H, H-2). 13C NMR (125.7 MHz, DMSO-d6): δ1.73 (CH2-5′); 70.74 (CH-3′); 74.21 (CH-2′); 77.52 (—CCH); 83.37 (—CCH); 85.51 (CH-4′); 87.42 (CH-1′); 94.17 (C-5); 102.65 (C-4a); 127.74 (CH-6); 149.73 (C-7a); 153.04 (CH-2); 157.78 (C-4). MS (ESI) m/z 291 (M+H), 313 (M+Na). HRMS (ESI) for C13H15N4O4 [M+H] calcd: 291.1088. found: 291.1088. Anal. Calcd for C13H14N4O4: C, 53.79; H, 4.86; N, 18.91. Found: C, 53.34; H, 4.95; N, 18.97.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]([F:34])([F:33])[CH:30]1[O:32][CH2:31]1>>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[CH:17]=2)[CH2:31][CH:30]([OH:32])[C:29]([F:34])([F:33])[F:28])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)COc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Reactant: FC(F)(F)C1CO1
Product: OC(CN(Cc1cccc(OCC(F)(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Yield: 20.4 %

Procedure:
The N-(3-phenoxyphenyl )[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amine (0.50 g, 1.35 mmol) product from EX-659B and 1,1,1-trifluoro-2,3-epoxy-propane (1.0 ml, 11 mmol) were heated to 90° C. in a sealed container under argon for 2 d. The resulting mixture was eluted from silica gel with 4% ethyl acetate in hexane, and fractions were pooled based on TLC analysis to give 134 mg (21%) of the desired 3-[(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a clear, colorless oil. 1H NMR (C6D6) δ6.80-7.08 (m, 7H), 6.64 (d, 1H), 6.53 (bt, 1H), 6.49 (t, 1H), 6.44 (dd, 1H), 6.34 (dt, 2H), 4.23 (s, 2H), 3.84 (m, 1H). 3.61 (m. 2H), 3.53 (dd, 1H), 3.20 (m, 1H), 2.03 (d, 1H). 19F NMR (C6D6) δ−74.20 (t, 3F), −78.95 (d, 3F). HRMS calcd. for C24H21F6NO3: 486.1504 [M+H]+, found: 486.1498.
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1>CO>[CH3:1][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]=[O:5])=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1ccc(CO)cc1
Solvent: CO
Product: COC(=O)Cc1ccc(C=O)cc1
Reaction time: 18 h

Procedure:
Acetyl chloride (5 mL) was added cautiously to solution of (4-hydroxymethylphenyl)acetic acid (5.78 g) in methanol (200 mL), stirred for 18 hours and evaporated. The residue was dissolved in dichloromethane (100 mL) and treated with manganese (IV) oxide (29.47 g), stirred for 18 hours and filtered through Celite. The filter pad was washed with dichloromethane and the combined filtrates evaporated. Purification on silica, eluting with 20% diethyl ether in iso-hexane, afforded the subtitle compound as a white solid (3.60 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[C:19]([C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1)#[N:20]
Reactant: Ic1cccc(-c2nc(-c3ccccn3)cs2)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2nc(-c3ccccn3)cs2)c1
Temperature: 80 °C
Yield: 30 %

Procedure:
A mixture of 2-(3-iodophenyl)-4-(pyridin-2-yl)-1,3-thiazole (1–30 mg, 0.36 mmol), zinc cyanide (117 mg, 1.0 mmol) and Pd(PPh3)4 (10 mg, 0.009 mmol) in N,N-dimethylformamide (2 mL) was heated overnight at 80° C. The mixture was cooled and diluted with toluene (5 mL). The organic solution was washed with 2N NH4OH (2×10 mL). The mixture was then extracted with ethyl acetate and the organic extract was washed with brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography afforded 28 mg (30%) of 2-(3-cyanophenyl)-4-(pyridin-2-yl)-1,3-thiazole: 1H-NMR (CDCl3), ppm: 8.65. (d, 1H), 8.38 (s, 1H), 8.25 (m, 2H), 8.15 (s, 1H), 7.85 (m, 1H), 7.72 (m, 1H), 7.6 (t, 1H), 7.28 (m, 1H). GC/EI-MS gave m/z 263 (M+).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:37])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:37])[C:5]([C:3]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(-c2cc3c(O)c(C(=O)NCCC(=O)O)nc(-c4cccnc4)c3n(Cc3ccccc3)c2=O)cc1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(4-methoxy-phenyl)-2-oxo-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (44 mg, 0.089 mmol), β-alanine (636 mg, 7.1 mmol) and NaOMe solution (10.7 mL, 5.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 34 mg of the title compound as a yellow solid. MS: (+) m/z 551.39 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH2:13]1[O:12][C:9]2[CH:10]=[CH:11][C:6]([N:5]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3](=[O:4])[CH2:2][NH:1][C:31]([NH:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=3)=[O:32])=[CH:7][C:8]=2[O:14]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccc2c(c1)OCO2
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccc3c(c2)OCO3)c1
Yield: 49.8 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(3,4-methylenedioxyphenyl)acetamido]acetate (2.4 g) and 3-methylphenyl isocyanate (1 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{N-(3,4-methylenedioxyphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (1.65 g), m.p. 142° C., is obtained.