Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[N:26]1([CH2:32][CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:34][CH2:33][CH2:32][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCCCC2)cc1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCN4CCCCC4)cc32)nc1-c1cccc(Cl)c1
Yield: 70.6 %

Procedure:
A mixture of 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.060 g (0.2 mmole) of toluene-4-sulfonic acid 3-piperidin-1-yl-propyl ester, 1 mL of dimethylformamide and 0.160 g (0.5 mmole) of cesium carbonate was heated at 100 degrees for 30 minutes. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 40:60-100:0) to give 0.035 g of 4-(3-chloro-phenyl)-2-[6-(3-piperidin-1-yl-propoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.32) as a white powder. MH+/Z=496
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=1>>[CH3:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[CH2:38][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CBr)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: Cc1cccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-3-methylbenzene following the procedure of Example 478: MS (ESI) m/z 498.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][O:22][CH2:23][C@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][CH2:27][CH2:28][C@@H:24]3[CH2:23][O:22][CH3:21])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: COC[C@H]1CCCN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1CCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (R)-2-(methoxymethyl)pyrrolidine (84025-81-0) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=382.5 [MH+].
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[OH-].[K+].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH3:20][O:19][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[N+:16]([O-:18])=[O:17])[O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C)CCO
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: COc1cc(OCCN(C)C)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
N,N-Dimethylethanolamine (0.80 g, 9.0 mmol) was added to a mixture of powdered KOH (0.50 g, 9.0 mmol) and Aliquat 336 (0.36 g, 0.9 mmol) and the resulting mixture was stirred for 5 minutes at 80° C. Then 4-fluoro-2-methoxy-1-nitrobenzene (1.28 g, 7.5 mmol) was added, and stirring proceeded at this temperature for 30 minutes. The mixture was cooled and partitioned between methylene chloride (80 mL) and dilute aqueous HCl (50 mL), and the organic layer was extracted with dilute aqueous HCl (2×50 mL). The combined aqueous phases were washed with methylene chloride (3×75 mL), basified (3N NaOH), and extracted with methylene chloride (3×75 mL). The combined organic extracts were washed with water (3×100 mL), dried (MgSO4), and evaporated, providing 1.1 g as a yellow oil, in 62% yield: 1H NMR (CDCl3) δ 2.34 (s, 6H), 2.75 (t, J=5.5 Hz, 2H), 3.93 (s, 3H), 4.12 (t, J=5.5 Hz, 2H), 6.51 (dd, J=9.1 Hz, J=2.5 Hz, 1H), 6.60 (d, J=2.5 Hz, 1H), 8.00 (d, J=9.1 Hz, 1H).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[N:31]=[CH:30][N:29](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:28]=5)[CH:25]=4)[N:20](C4CCCCO4)[N:19]=3)[CH:13]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:28]1[C:27]([C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:14]2[CH:13]=[C:12]([C:10]([NH:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[O:11])[CH:17]=[CH:16][CH:15]=2)=[N:31][CH:30]=[N:29]1
Reactant: C[C@@H](NC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.4 %

Procedure:
To a stirred solution of N-((1R)-1-phenylethyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.393 g, 0.535 mmol) was added 4.0 M hydrochloric acid in dioxane (10.0 mL) and the mixture stirred at ambient temperature for 16 h. The mixture was cooled and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0860 g, 39% yield). 1H NMR (CD3OD) δ 8.81 (s, 1H), 8.51 (t, 1H), 8.23 (dd, 1H), 8.13 (br d, 1H), 7.93 (d, 1H), 7.70 (m, 2H), 7.47 (m, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 5.28 (q, 1H), 1.59 (d, 3H). ES-MS (m/z) 409 [M+1]+
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1
Reactant: CC1CNCCN1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: c1ccncc1
Product: CC1CN(c2cc3c(c(N)c2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Yield: 62.2 %

Procedure:
A mixture of 1.0 g of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.18 g of 2-methylpiperazine and 10 ml of pyridine was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 28% aqueous ammonia. The solution was neutralized with a 10% aqueous solution of acetic acid and cooled with ice. The crystals were collected by filtration, dissolved in a 10% aqueous solution of acetic acid, treated with activated charcoal, adjusted to pH 8-9 with 29% aqueous ammonia, and cooled with ice. The crystals were collected by filtration and washed successively with water and ethanol to give 0.80 g of 5-amino-1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 181°-183° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[N:18]1[CH2:21][CH:20]([OH:22])[CH:19]=1>>[OH:22][CH:20]1[CH2:21][N:18]([C:7]([C:6]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:19]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: OC1C=NC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(O)C1
Yield: 62 %

Procedure:
Prepared in analogy to Example 1 from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and azetin-3-ol. The crude material was purified by flash chromatography (methanol/dichloromethane) to yield the title compound as a pink solid (yield 62%). MS (m/e): 314.0 (M+H+, 100%).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([O:30]C)=[O:29])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].CC(C)([O-])C.[K+]>>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=[O:29])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(C#N)CC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1

Procedure:
1.69 g (about 2.62 mmol) of the compound from Example 107A and 2.9 g (26.2 mmol) of potassium tert-butoxide were reacted according to the General Method 9A. Yield: 1.53 g (90% of theory, 65% pure)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:11]=[CH:10][S:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][OH:26].O>C1(C)C=CC=CC=1>[CH3:2][C:1]1([C:4]2[CH:5]=[CH:6][C:7]3[CH:11]=[CH:10][S:9][C:8]=3[CH:12]=2)[O:26][CH2:25][CH2:24][O:3]1
Reactant: CC(=O)c1ccc2ccsc2c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc3ccsc3c2)OCCO1
Temperature: 25 °C
Yield: 73 %

Procedure:
A mixture of 6-acetyl benzo[b]thiophene (10.57 g, 60 mmole), p-toluenesulfonic acid (1.65 g) and ethylene glycol (33 ml) was heated to reflux in toluene (250 ml) for 2 hours with the continuous removal of H2O using a Dean-Stark trap. The reaction mixture was allowed to cool to room temperature. Then extracted with 20% saturated NaHCO3 (150 ml) and H2O (2×150 ml). After drying over Na2SO4, the solvent was evaporated in vacuo and the residue was crystallized from hexanes (50 ml) yielding 9.66 g (73%) of product.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:48][C:49]1[CH:71]=[CH:70][C:52]([CH2:53][N:54]2[C@@H:58]([CH3:59])[CH2:57][N:56]([C:60]3[S:61][C:62]([C:66]([OH:68])=O)=[C:63]([CH3:65])[N:64]=3)[C:55]2=[O:69])=[CH:51][CH:50]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>>[F:48][C:49]1[CH:71]=[CH:70][C:52]([CH2:53][N:54]2[C@@H:58]([CH3:59])[CH2:57][N:56]([C:60]3[S:61][C:62]([C:66]([NH2:7])=[O:68])=[C:63]([CH3:65])[N:64]=3)[C:55]2=[O:69])=[CH:51][CH:50]=1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(N)=O
Yield: 67 %

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid and 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) with (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), the title compound was obtained as a colorless solid in 67% yield: mp 192-194° C. (ethyl acetate/diethyl ether); 1H NMR (300 MHz, DMSO-d5) δ 7.40-7.32 (m, 4H), 7.18 (dd, J=8.8, 8.8 Hz, 2H), 4.59 (d, J=15.6 Hz, 1H), 4.30 (d, J=15.6 Hz, 1H), 4.18 (dd, J=10.0, 9.1 Hz, 1H), 3.79-3.68 (m, 1H), 3.54 (dd, J=10.0, 6.8 Hz, 1H), 2.45 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.5, 161.5 (d, 1JC-F=243 Hz), 157.3, 154.9, 150.7, 133.1 (d, 4JC-F=3 Hz), 129.9 (d, 3JC-F=8 Hz), 118.5, 115.4 (d, 2JC-F=21 Hz), 49.4, 48.6, 43.7, 18.4, 17.0; MS (ES+) m/z 348.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](O)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9].C(N(CC)C(C)C)(C)C.Cl.[CH3:37][NH:38][O:39][CH3:40].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]([N:38]([O:39][CH3:40])[CH3:37])=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9]
Reactant: C#Cc1c(Cl)cc(C(=O)O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Reactant: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
A solution of 4-chloro-6-[(1E)-3,3-diethyltriaz-l-en-l-yl]-5-ethynyl-3′-fluorobiphenyl-2-carboxylic acid (2.7 g, 7.1 mmol) in N,N-dimethylformamide (14 mL) was treated with N,N-diisopropylethylamine (4.3 mL, 25 mmol) followed by O-(benzotriazol-1-yl)-N,N,N,′N′-tetramethyluronium hexafluorophosphate (3.5 g, 9.3 mmol) and stirred at 20° C. for 5 minutes. The reaction mixture was treated with N,O-dimethylhydroxylamine hydrochloride (0.9 g, 9.3 mmol) and stirred at 20° C. for 1 hour. The reaction mixture was poured into 0.5 M hydrogen chloride in water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with saturated sodium bicarbonate (50 mL), brine (25 mL), dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0%-40%) gave the desired product (2.7 g, 92% for 2 steps). LCMS for C21H23ClFN4O2 (M+H)+: m/z=417.1; Found: 417.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1)([O-:3])=[O:2].C=O.[BH3-][C:24]#N.[Na+].CC(O)=O>CC#N>[CH3:24][N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:8][O:7][C:6]1[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(OCC2CCCN2)cc(C(F)(F)F)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCCC1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (6 mmol) was dissolved in CH3CN (20 ml) and formaldehyde (2.4 ml, 37% aqueous) was added. NaBH3CN (607 mg) was added, an exotherm was observed. The pH is monitored every 15 min and adjusted to ˜7 with AcOH. After 45 min, the mixture was concentrated in vacuo and the residue is dissolved in EtOAc, washed with 6N NaOH, 1N NaOH, and 2N HCl (3×). The acid washings were combined, adjusted to ˜pH 10 with solid Na2CO3 and extracted with EtOAc (2×). The EtOAc fractions were combined, dried with Na2SO4, and purified with flash chromatography (SiO2, 95:5:0.5 CH2Cl2:MeOH:NH4OH) to afford 1-methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11]Br)=[CH:6][CH:5]=1.FC(F)(F)C1C=CC(Br)=CC=1.FC(F)(F)OC1C=CC(Br)=CC=1.[CH2:38]([CH:43]1[CH2:48][CH2:47][CH:46]([CH:49]2[CH2:54][CH2:53][C:52](=[O:55])[CH2:51][CH2:50]2)[CH2:45][CH2:44]1)[CH2:39][CH2:40][CH2:41][CH3:42].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:52]2([OH:55])[CH2:51][CH2:50][CH:49]([CH:46]3[CH2:47][CH2:48][CH:43]([CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:44][CH2:45]3)[CH2:54][CH2:53]2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(CCBr)cc1
Reactant: CCCCCC1CCC(C2CCC(=O)CC2)CC1
Agent: FC(F)(F)Oc1ccc(Br)cc1
Agent: FC(F)(F)c1ccc(Br)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCCC1CCC(C2CCC(O)(CCc3ccc(OC(F)(F)F)cc3)CC2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 120.8 %

Procedure:
A mixture of 2-(4-trifluoromethyloxyphenyl)ethyl bromide (10.0 g, 0.037 mol) prepared in the same manner as in Example 1 except that 4-trifluoromethylbromobenzene was replaced by 4-trifluoromethyloxybromobenzene, with THF (50 ml), was heated at 90° C. for 40 minutes in a sealed tube reactor, to obtain a yellow, uniform solution, followed by adding this solution to a THF (40 ml) solution of 4-(4-pentylcyclohexyl)cyclohexanone (9.27 g, 0.037 mol), stirring the mixture at room temperature for 2 hours, feeding the reaction substance into a saturated aqueous solution of NH4Cl, twice extracting with ethyl acetate (50 ml), washing the resulting organic layer with an aqueous solution of NaCl, drying over anhydrous MgSO4, removing the anhydrous MgSO4, distilling off the solvent under reduced pressure, to obtain a pale yellow, oily 1-(2-(4-trifluoromethyloxyphenyl)ethyl-4-(4-pentylcyclohexyl)cyclohexanol (19.7 g), adding thereto toluene (50 ml) and Amberlyst (0.9 g), heating the mixture under reflux for one hour, while removing formed water, allowing the resulting substance to cool, feeding it to a saturated aqueous solution of NH4Cl, twice washing the separated organic layer with water, drying over anhydrous MgSO4, filtering off the anhydrous MgSO4, distilling off the solvent under reduced pressure, subjecting the residue to column chromatography (silica gel, eluent: heptane) and twice recrystallizing from a mixed solvent of ethanol (10 ml) with benzene (1 ml), to obtain 1-(2-(4-trifluoromethyloxyphenyl)ethyl)-4-(4-pentylcyclohexyl)cyclohexene (1.0 g). Yield: 6%.
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.[CH:23]1(CN)[CH2:28][CH2:27]C[CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH:4]2[CH2:27][CH2:28][CH2:23][CH2:24][CH2:25]2)=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: NCC1CCCCC1
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(COC(=O)NCC2CCCCC2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 52 %

Procedure:
To a stirred yellow solution of VII (293.8 mg, 0.861 mmol) in anhydrous THF (10 mL) was added cyclohexylmethanamine (165 mg, 123 μL, 1.1×0.861 mmol) and then, dropwise, triethylamine (96 mg, 133 μL, 1.1×0.861 mmol). The solution was stirred for 45 minutes at room temperature. The colorless solution was then diluted with CH2Cl2 and washed with 1N HCl, distilled water, and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel using hexanes/ethyl acetate (1:1, v/v) to yield 150.2 mg (52%) of 13 as a clear colorless oil: Rf=0.55 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 6.98 (d, 3J=8.0 Hz, 1H), 6.95 (d, 1H), 6.91 (dd, 3J=8.0 Hz, 1H), 5.04 (s, 2H, CH2O), 4.75 (bs, 1H, NH), 3.81 (s, 3H, OCH3), 3.01 (t, 3J=6.4 Hz, 211, NCH2), 2.29 (s, 3H), 1.70-1.62 (m, 5H), 1.42 (bs, 1H), 1.23-1.11 (m, 3H) and 0.92 (q, 3J=11.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][N:11]([C@@H:12]([C:13](=[O:14])[NH2:15])[CH2:16][CH:17]([CH3:19])[CH3:18])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(N)=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of (2R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (4.2 grams, 14 mmol) in DMF (50 mL) was added cesium carbonate (13.6 grams, 417 mmol). To this reaction was added 4-(toluene-4-sulfonyloxymethyl)-piperidine 1-carboxylic acid tert-butyl ester (ref.: Gilissen, C.; Bormans, G.; De Groot, T.; Verbniggen, A. J. Labeled Cmpd. Radiopharm. 1999, 42, 1289; 10.4 g, 282 mmol). The reaction was stirred at 70° C. for 18 h. The reaction was then quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO4, and concentrated to a clear oil. The oil was then purified on a Biotage 40S (eluted with 30% EtOAc in hexanes) to afford a white solid (3.0 g, 44%). MS (ESI), (M+H)+ 502.1; 1H NMR (DMSO-d6, 500 MHz) δ 7.86 (dd, 2H, J=2.0, 6.8), 7.65 (dd, 2H, J=2.0, 6.8) 7.37 (br s, 1H), 7.07 (br s, 1H), 4.19 (t, 1H, J=7.6), 3.92 (br s, 2H), 3.35 (dd, 1H, J=15, 6.8), 3.05 (dd, 1H, J=15, 8.1), 1.85 (br s, 1H), 1.50-1.70 (m, 4H), 1.38 (s, 9H), 1.10-1.20 (m, 1H), 0.80-1.00 (m, 3H), 0.82 (d, 6H, J=7.6).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11](=[O:13])C)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:15]OCOC>>[C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][O:13][CH3:15])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COCOC
Reactant: CC(=O)OS(=O)(=O)c1ccc(C)cc1
Product: COCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.08 h

Procedure:
To the acetic p-toluenesulfonic anhydride obtained above was then added at room temperature 100 ml. (1.13 mole) of dimethoxymethane. The temperature of the reaction rose to 38° C. within about 5 minutes. The reaction mixture was stirred for one hour. NMR analysis indicated the title product was obtained in 90% purity after removal of excess dimethoxymethane by stripping at room temperature.
Reaction SMILES: C([NH:11][CH2:12][C:13](=[O:44])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:17])(OCC1C=CC=CC=1)=O.[ClH:45].[H][H]>[Pd].CC(O)C>[ClH:45].[NH2:11][CH2:12][C:13](=[O:44])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:17]
Reactant: [H][H]
Reactant: O=C(CCC(=O)OCCCCCCCCCCCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NCC(=O)CCC(=O)OCCCCCCCCCCCCCCCC(=O)O
Yield: 19.2 %

Procedure:
This compound was prepared from the product of 15b (0.45 g; 0.74 mmol), 12 M HCl (0.062 mL; 0.74 mmol), 10% Pd/C (100 mg), hydrogen gas, and 2-propanol (25 mL) using the procedure in Example 8d. 0.06 g (19%) product was obtained (white solid).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:10]([OH:13])([OH:12])[OH:11]>C(O)C>[NH2:9][C:8]([P:10]([OH:13])([OH:12])=[O:11])([P:10]([OH:13])([OH:12])=[O:11])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: OP(O)O
Solvent: CCO
Product: NC(Cc1ccccc1)(P(=O)(O)O)P(=O)(O)O
Temperature: 150 °C
Yield: 40 %

Procedure:
Phenylacetonitrile (5.6 g, 0.05 mole) was mixed with phosphorous acid (8.2 g, 1.0 mole), ISOPAR-M (20 g), and wetting agents (0.25 g each). The mixture was heated at ambient pressure for 4 hours at 150° C. The product was worked up with ethanol to get colorless crystals of 1-amino-1,1-diphosphono-2-phenyl ethane (40%), m.p. 238° C (decomposition).