Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[CH:22](O)=O>ClCCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[CH:22]=[N:16][CH:15]=[C:11]2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: NCc1cc(OCc2ccccc2)ccn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: c1ccc(COc2ccn3cncc3c2)cc1

Procedure:
0.7 g (3.27 mmol) of 1-[4-(benzyloxy)pyridin-2-yl]methanamine (described in stage B) in 16 ml of formic acid is heated at reflux for 5 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 7 ml of 1,2-dichloroethane. 0.6 ml (6.54 mmol) of phosphoryl chloride dissolved in 7 ml of 1,2-dichloroethane is added. After heating at reflux for 4 hours, the reaction medium is concentrated under reduced pressure and the residue is then taken up in dichloromethane. The organic phase is washed with a saturated aqueous sodium hydrogencarbonate solution, dried over sodium sulfate and concentrated under reduced pressure. 0.97 g of a brown oil is collected.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.N1C=CC=CC=1.O>C1C=CC=CC=1>[Cl:3][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1
Reactant: OCc1nc(-c2ccccc2)cs1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: ClCc1nc(-c2ccccc2)cs1
Reaction time: 1 h

Procedure:
Thionyl chloride (6.25 g, 0.052 mole) was added dropwise to a stirred solution of 2-hydroxymethyl-4-phenylthiazole (9.55 g; 0.05 mole) and dry pyridine (4.0 g; 0.051 mole) in dry benzene (60 ml) held at room temperature. The mixture was stirred and heated to boiling for 1 hour. The cooled reaction mixture was then shaken with 2 × 70 ml H2O and dried over anhydrous MgSO4. The solvent was removed under vacuum and the remaining red oil extracted with 40°-60° C. petroleum ether (100 ml), discarding a small tarry residue. The extract was treated with decolourising charcoal, filtered and evaporated, leaving a yellow-red oil that crystallised on refrigeration.
Reaction SMILES: [OH-].[Na+:2].[NH2:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][C:6]([OH:8])=[O:7]>O.CC(C)=O>[NH2:3][C@H:4]([C:9]([O-:11])=[O:10])[CH2:5][C:6]([O-:8])=[O:7].[Na+:2].[Na+:2]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]

Procedure:
Sodium hydroxide 8 g was added to a suspension of 13.3 g L-aspartic acid in 72 ml water and 48 ml acetone to form a solution of disodium L-aspartate. This solution was held at 0°C, and the solution of palmitic acid-sulfuric acid mixed acid anhydride and a solution of 12 g sodium hydroxide in 30 ml water was added dropwise simultaneously with stirring. This solution was stirred for 1 hour at 0°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([NH2:19])[N:18]=3)[N:15]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33].[N-:34]=[C:35]=[O:36]>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([NH:19][C:35]([NH:34][C:22]4[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=[CH:26][C:21]=4[F:20])=[O:36])[N:18]=3)[N:15]=2)=[CH:4][CH:3]=1)=[O:33]
Reactant: [N-]=C=O
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(C#Cc2ccc3nc(N)cn3n2)cc1
Product: O=C(Nc1ccc(C#Cc2ccc3nc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cn3n2)cc1)Nc1cc(C(F)(F)F)ccc1F

Procedure:
The compound of Example 10 was made by preparing 6-[(4-aminophenyl)ethynyl]imidazo[1,2-b]pyridazin-2-amine as in Example 20, followed by a procedure similar to Example 3 using 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene as the isocyanate (see also Schemes 1, 2, and 9).
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[C:23]=2[F:25])[N:18]=[CH:17][C:16]=1[Cl:28])(=O)OCC)C.[C:29]([O:33][C:34](=[O:45])[NH:35][C@@H:36]1[CH2:41][CH2:40][C@@H:39]([CH2:42][CH:43]=O)[O:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30].CCCCCC>O1CCCC1.C(OCC)(=O)C>[C:29]([O:33][C:34](=[O:45])[NH:35][C@@H:36]1[CH2:41][CH2:40][C@@H:39]([CH2:42][CH:43]=[CH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[C:23]=3[F:25])[N:18]=[CH:17][C:16]=2[Cl:28])[O:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOP(=O)(Cc1c(Cl)cnc2ccc(OC)c(F)c12)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CC=O)OC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2ncc(Cl)c(C=CC[C@@H]3CC[C@@H](NC(=O)OC(C)(C)C)CO3)c2c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A solution of n-butyllithium (1.6 M in n-hexane, 4.72 mL, 7.55 mmol, 1.5 eq) is added dropwise at 0° C. to a stirred solution of (3-chloro-5-fluoro-6-methoxy-quinolin-4-ylmethyl)-phosphonic acid diethyl ester (1.82 g, 5.03 mmol, 1.0 eq) in tetrahydrofuran (130 mL). After 2 hours stirring at 0° C., a solution of (3R,6S)-[6-(2-oxo-ethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester (1.22 g, 5.03 mmol, 1.0 eq) in tetrahydrofuran (30 mL) is added dropwise within 2 minutes. After 10 minutes stirring at 0° C., the reaction mixture is quenched with water (10 mL). Then solvent is evaporated and the residue is extracted with ethyl acetate (3×150 mL) and water (100 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: n-hexane:ethyl acetate, 10:1 to 1:1, v/v) to afford (3R,6S)-{6-[3-(3-chloro-5-fluoro-6-methoxy-quinolin-4-yl)-allyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester as a light red solid (1.82 g, 80% yield).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([C:27]([N:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH:30]2[CH2:42][O:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:28])=[CH:24][CH:23]=1>CO>[ClH:15].[ClH:1].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH:30]2[CH2:42][O:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:28])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccccc3Cl)s2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2ccccc2Cl)s1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 40 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(5-(2-chlorophenyl)thiophene-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (75.9 mg, 0.121 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 23.8 mg (40%) of the desired product as a white solid. LC-MS: RT=5.27 min, [M+H]+=414.1.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3](O)[CH2:2]1.C(O)C>CN(C)C=O>[CH3:16][C:15]1[C:13](=[O:14])[N:12]=[C:10]2[N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([O:11]2)[CH2:2]3)[CH:17]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Temperature: 70 °C
Yield: 60.3 %

Procedure:
Thymidine (85.4 g; 0.353 mol) was dissolved in 500 mL dry DMF (dimethyl formamide) and added to N-(2-chloro-1,1,2-trifluoroethyl)dielthylamine (100.3 g; 0.529 mol) [prepared according to the method of D. E. Ayer, J. Med. Chem. 6, 608 (1963)]. This solution was heated at 70° C. for 30 minutes then poured into 950 mL ethanol with vigorous stirring. The product precipitated from this solution and was filtered. The ethaol supernatant was refrigerated then filtered to yield a total of 47.75 g (0.213 mol; 60.3%) of 2,3'-anhydrothymidine mp=228°-230° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[O:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[N:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[C:31]([F:32])=[CH:30][C:29]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:28][C:27]=2[F:37])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[CH:14]1([C:11]2[O:10][C:9]([CH2:8][C:4]3[N:3]=[C:2]([NH:17][C:18]4[S:19][C:20]([C:26]5[C:27]([F:37])=[CH:28][C:29]([C:33]([OH:36])([CH3:34])[CH3:35])=[CH:30][C:31]=5[F:32])=[CH:21][C:22]=4[C:23]([NH2:25])=[O:24])[CH:7]=[CH:6][CH:5]=3)=[N:13][N:12]=2)[CH2:16][CH2:15]1
Reactant: Brc1cccc(Cc2nnc(C3CC3)o2)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(Cc4nnc(C5CC5)o4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 2-bromo-6-[(5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl]pyridine (94 mg, 0.34 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (110 mg, 0.35 mmol) according to the general procedure in Example 1.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:25][CH2:24][C@:7]2([O:11][CH2:10][C:9]([C:12]3[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=3[O:20][CH:21]([CH3:23])[CH3:22])=[CH:8]2)[C@@H:6]1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:4].CO.[OH-].[Na+].Cl>C1COCC1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C@@H:6]2[C@@H:5]([C:3]([OH:4])=[O:2])[CH2:25][CH2:24][C@@:7]32[O:11][CH2:10][C:9]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=2[O:20][CH:21]([CH3:23])[CH3:22])=[CH:8]3)=[CH:31][CH:30]=1
Reactant: COC(=O)[C@H]1CC[C@@]2(C=C(c3cc(C#N)ccc3OC(C)C)CO2)[C@@H]1c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C#N)cc1C1=C[C@@]2(CC[C@H](C(=O)O)[C@H]2c2ccc(F)cc2)OC1

Procedure:
(5R,6S,7S)-6-(4-Fluorophenyl)-3-(5-cyano-2-isopropoxyphenyl)-1-oxaspiro[4.4]non-3-ene-7-carboxylic acid methyl ester(128 mg, 0.294 mmol) was taken up in THF(2 mL) and methanol (2 mL) and treated with 2.5N NaOH (0.4 mL, 1.0 mmol) for 6 hours at room temperature. 2N Hydrochloric acid (5 mL) was then added, and the product extracted with ethyl acetate (2×30 mL). The combined extracts were washed with saturated brine solution, dried (MgSO4), and evaporated to afford the title compound; yield 124 mg.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S-:10][C:11]#[N:12].[NH4+].[Cl:14][C:15]1[CH:36]=[CH:35][C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH2:28][CH2:29][NH:30]3)=[CH:17][CH:16]=1>CC(C)=O>[Cl:14][C:15]1[CH:36]=[CH:35][C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH2:28][CH2:29][N:30]3[C:11]([NH:12][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:10])=[CH:17][CH:16]=1
Reactant: Clc1ccc(OCCCCCOc2cccc3c2CCN3)cc1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=C(NC(=S)N1CCc2c(OCCCCCOc3ccc(Cl)cc3)cccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a stirred solution of benzoyl chloride (42 mg, 0.3 mmol) in acetone (3.0 mL) was added ammonium thiocyanate (68 mg, 0.9 mmol). The resulting mixture was stirred for 1 h at room temperature followed by addition of the indoline compound 4-[5-(4-chloro-phenoxy)-pentyloxy]-2,3-dihydro-1H-indole (100 mg, 0.3 mmol). After stirred overnight at room temperature, the reaction mixture was quenched with excess saturated ammonium chloride (30 mL) and extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine, and then concentrated under vacuum. The residue was purified by silica gel chromatography to give N-{4-[5-(4-chloro-phenoxy)-pentyloxy]-2,3-dihydro-indole-1-carbothioyl}-benzamide (74 mg, 0.15 mmol, 50%) as a white solid. MS (EI): m/z 495 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:9]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O[N:32]1[C:36]2C=CC=C[C:35]=2[N:34]=N1.[CH:41]1(N=[C:48]=[N:49][CH:50]2[CH2:55]CCCC2)CCCCC1>O1CCCC1>[CH3:41][N:34]1[CH2:23][CH2:28][NH:32][CH2:36][CH2:35]1.[Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[C:9]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:32]1[CH2:55][CH2:50][N:49]([CH3:48])[CH2:35][CH2:36]1)=[O:5]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1ccc(COc2ccc(C(=O)O)c(Cl)c2OCc2ccc(OC)cc2)cc1
Reactant: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN1CCNCC1
Product: COc1ccc(COc2ccc(C(=O)N3CCN(C)CC3)c(Cl)c2OCc2ccc(OC)cc2)cc1
Yield: 198.4 %

Procedure:
A mixture of 2-chloro-3,4-bis(p-methoxybenzyloxy)benzoic acid (0.61 g: 1.42 mMol.) is reacted with 1-hydroxybenzotriazole (231 mg: 1.2 Eq.) and dicyclohexylcarbodiimide (352 mg: 1.2 Eq.) in tetrahydrofuran at room temperature for 1 hour, and then with N-methylpiperazine (0.32 ml: 2 Eq.) for 1 hour to give 1-(2-chloro-3,4-bis(p-methoxybenzyloxy)benzoyl)-4-methylpiperazine (0.72 g). Yield: 99%.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[F:11][C:12]1[C:17]([F:18])=[CH:16][N:15]=[C:14]2[NH:19][CH:20]=[C:21]([NH2:22])[C:13]=12>N1C=CC=CC=1>[F:11][C:12]1[C:17]([F:18])=[CH:16][N:15]=[C:14]2[NH:19][CH:20]=[C:21]([NH:22][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=3)[C:13]=12
Reactant: Nc1c[nH]c2ncc(F)c(F)c12
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1c[nH]c2ncc(F)c(F)c12)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.6 %

Procedure:
Nicotinoyl chloride hydrochloride (0.70 g, 3.90 mmol) was added to 4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.22 g, 1.30 mmol) in pyridine (5 mL). The reaction was stirred at room temperature for 10 minutes, and then the pyridine was removed. THF (5 mL) and 2N LiOH (3 mL) were added, and the reaction was stirred for 20 minutes. The THF was removed, and water (20 mL) was added. The solid formed was collected by filtration and dried to give N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.33 g, 92% yield) as a solid.
Reaction SMILES: C(N(C(C)C)[P:5]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)C.N1C=NN=N1.[C:30]([O:33][C:34]1[C:43]([CH3:44])=[CH:42][C:41]([CH2:45][CH2:46][CH2:47][OH:48])=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37])(=[O:32])[CH3:31].ClC1C=C(C=CC=1)C(OO)=[O:54]>C(Cl)Cl.CCOC(C)=O>[C:30]([O:33][C:34]1[C:43]([CH3:44])=[CH:42][C:41]([CH2:45][CH2:46][CH2:47][O:48][P:5]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:54])=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37])(=[O:32])[CH3:31]
Reactant: COC(=O)c1cc(CCCO)cc(C)c1OC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Agent: c1nnn[nH]1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(CCCOP(=O)(OCc2ccccc2)OCc2ccccc2)cc(C)c1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dibenzyl N,N-diisopropylphosphoramidite (0.252 mL, 0.751 mmol) was added to a stirred solution of 1H-tetrazole (3 wt % in CH3CN) (4.40 mL, 1.502 mmol) and methyl 2-(acetyloxy)-5-(3-hydroxypropyl)-3-methylbenzoate (100 mg, 0.376 mmol) in dry CH2Cl2 (4.50 mL) at 25° C. under N2. The reaction was stirred for 2 h at 25° C. After this time another 0.5 eq dibenzyl N,N-diisopropylphosphoramidite was added and the reaction was stirred for 30 min. The reaction mixture was cooled to 0° C. and a solution of 3-chloroperoxybenzoic acid (337 mg, 1.502 mmol) in dry CH2Cl2 (3.00 mL) was added via cannula. After 30 min another 1 eq 3-chloroperoxybenzoic acid was added and the reaction was stirred at 0° C. After 30 min the reaction was diluted with EtOAc (30 mL) and washed with successive portions of saturated Na2SO3 (20 mL) and saturated NaHCO3 (20 mL), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 60% EtOAc in hexanes over 2394 mL) to afford methyl 2-(acetyloxy)-5-(3-{[bis(benzyloxy)phosphoryl]oxy}propyl)-3-methylbenzoate, as a colorless oil. LCMS calc.=527.2; found=527.0 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 7.62 (d, J=2.2 Hz, 1 H); 7.36-7.31 (m, 10 H); 7.18 (d, J=2.2 Hz, 1 H); 5.11-4.98 (m, 4 H); 4.00 (q, J=6.6 Hz, 2 H); 3.84 (s, 3 H); 2.61 (t, J=7.8 Hz, 2 H); 2.36 (s, 3 H); 2.17 (s, 3 H); 1.93-1.85 (m, 2 H).
Reaction SMILES: [Mg].[Na+].C1(S([O-])=[O:10])C=CC=CC=1.[F:12][C:13]1[CH:18]=[C:17]([CH:19]2[CH2:24][CH2:23]C(CCCCC)C[CH2:20]2)[CH:16]=[CH:15][C:14]=1C1CCC(C2CCC(O)CC2)CC1.Cl.[C:44]([O:47][CH2:48][CH3:49])(=[O:46])[CH3:45]>C1COCC1>[F:12][C:13]1[CH:18]=[C:17]([C:19]2([OH:10])[CH2:24][CH2:23][C:44]3([O:46][CH2:49][CH2:48][O:47]3)[CH2:45][CH2:20]2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(C)=O
Reactant: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(O)CC4)CC3)c(F)c2)CC1
Reactant: O=S([O-])c1ccccc1
Agent: Cl
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1(c2cccc(F)c2)CCC2(CC1)OCCO2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Well-dried magnesium (8.3 g) and THF (20 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 50° C. 1-Bromo-3-fluorobenzene (14) (60.0 g) dissolved in THF (300 ml) was slowly added dropwise thereto in the temperature range of 40° C. to 60° C., and the mixture was stirred for another 60 minutes. Then, 1,4-dioxaspiro[4.5]decan-8-one (15) (64.3 g) dissolved in THF (150 ml) was slowly added dropwise thereto in the temperature range of 50° C. to 60° C., and the mixture was stirred for another 60 minutes. The reaction mixture was cooled to 30° C., and then poured into a vessel containing an aqueous 1N—HCl solution (900 ml) and ethyl acetate (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with water and a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, giving 74.6 g of 8-(3-fluorophenyl)-1,4-dioxaspiro[4,5]decan-8-ol (16).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][NH:13]/[N:14]=[CH:4]/[C:3]1[C:2]([F:1])=[CH:9][C:8]([F:10])=[CH:7][C:6]=1[F:11]
Reactant: O=Cc1c(F)cc(F)cc1F
Reactant: CNN
Solvent: CCO
Product: CN/N=C/c1c(F)cc(F)cc1F

Procedure:
A solution of 2,4,6-trifluorobenzaldehyde (3 g, 18.74 mmol) and methyl hydrazine (40% in water, 2.6 mL, 18.74 mmol) in 20 mL of anhydrous ethanol was stirred at rt for 1 h. Solvent was evaporated to give the crude title compound as a white solid which was used in the next step without purification (3.95 g, 100%). LCMS (method B): [MH]+=189, tR=2.16 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[C:16](C)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C[C:26]1[C:27]([CH3:42])=[C:28](C)[C:29]([CH3:40])=[C:30]2[C:34]=1[N:33]([CH3:35])[C:32](C)=[C:31]2[CH2:37]NI.[C:43]([O-])([O-])=[O:44].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[N:20]([CH2:37][C:31]2[C:30]3[C:34](=[CH:26][C:27]([CH3:42])=[CH:28][C:29]=3[CH3:40])[N:33]([CH3:35])[CH:32]=2)[C:43]1=[O:44])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: Cc1c(C)c(C)c2c(c1C)c(CNI)c(C)n2C
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C[C@@H](Nc1nc(C)ccc1[N+](=O)[O-])c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cc(C)cc(C)c23)c2cccnc21
Temperature: 100 °C
Yield: 79.7 %

Procedure:
To a solution of (R)-3-(2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-3-phenyl-propionic acid ethyl ester (refer to example 2) (80 mg, 0.26 mmol) in DMF (10 mL) were added trimethyl-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-amino iodide (138 mg, 0.39 mmol) and K2CO3 (71 mg, 0.51 mmol) at room temperature. The solution was heated at 100° C. for 4 hours. The solution was cooled and was extracted with water and EtOAc. The combined organic layer was dried with MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography with 20% EtOAc in Hexane as the eluent to afford the title compound (100 mg, 81%) as white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[NH:12][CH2:11][CH2:10]2.[H-].[Na+].[CH2:23]([O:25][C:26](=[O:30])[CH:27](Br)[CH3:28])[CH3:24].O>CN(C=O)C>[CH2:23]([O:25][C:26](=[O:30])[CH:27]([N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=3)[CH:8]=2)[C:13]1=[O:17])[CH3:28])[CH3:24]
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1NCCc2cc(OCc3cccc(F)c3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Temperature: 70 °C
Yield: 69.3 %

Procedure:
A mixture of 6-(3-fluoro-benzyloxy)-3,4-dihydro-2H-isoquinolin-1-one (0.100 g, 0.369 mmol) and sodium hydride (55%, 22 mg, 0.51 mmol) in N,N′-dimethylformamide was heated at 70° C. for 1 h. Then ethyl-2-bromopropionate (0.072 mL, 0.55 mmol) was added and the resulting mixture was heated at 80° C. overnight. After cooling to room temperature, water was added and the reaction was extracted with dichloromethane. After drying of the organic layer with MgSO4, filtration and evaporation, the residue was purified by chromatography (SiO2, hexane/ethyl acetate 1:0 to 3:2 v:v gradient) to give the title compound as a white solid (0.095 g, 69%). MS: m/e=372.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH2:5][OH:6].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:6][CH2:5][C:4]1[CH:7]=[C:8]([OH:10])[CH:9]=[C:2]([O:1][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: OCc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1cc(O)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 20.8 %

Procedure:
3,5-Dihydroxybenzyl alcohol (5.0 g, 40 mmol), 2-chloro-5-trifluoromethyl-pyridine (7.13 g, 39.2 mmol) and potassium carbonate (6.16 g, 44.6 mmol) were suspended in dimethylformamide (100 mL) and heated to 100° C. After stirring for 16 h, the reaction was cooled to room temperature and partitioned between water (500 mL) and ethyl acetate. The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-75%, EtOAc:heptane) to afford the title compound (2.32 g, 20% yield) as a thick oil.