Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[Si](C)(C)C.[Br:6][C:7]1[CH:30]=[C:29]([C:31]2[C:40]3[C:41]4[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=4[S:43][C:39]=3[C:38]([Br:48])=[C:37]3[C:32]=2[CH:33]=[CH:34][CH:35]=[CH:36]3)[CH:28]=[C:27]([Br:49])[C:8]=1[O:9][CH:10]([P:19](=[O:26])([O:23]CC)[O:20]CC)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Br:6][C:7]1[CH:30]=[C:29]([C:31]2[C:40]3[C:41]4[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=4[S:43][C:39]=3[C:38]([Br:48])=[C:37]3[C:32]=2[CH:33]=[CH:34][CH:35]=[CH:36]3)[CH:28]=[C:27]([Br:49])[C:8]=1[O:9][CH:10]([P:19](=[O:20])([OH:26])[OH:23])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOP(=O)(OCC)C(CCc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=P(O)(O)C(CCc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Iodotrimethylsilane (0.56 mL, 3.93 mmol) was added dropwise to a stirred, 0° C. solution of {1-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenoxy ]-3-phenyl-propyl}-phosphonic acid, diethyl ester (1.07 g, 1.31 mmol) in methylene chloride (26 mL) under a dry nitrogen atmosphere over a period of 10 min. After 1 h at 0° C., the reaction mixture was quenched with 10% aq sodium bisulfite (1 mL), stirred at ambient temperature for 30 min. The mixture was partitioned in methylene chloride (100 mL) and water (100 mL). The methylene chloride phase was washed with 18% aq HCl (100 mL), concentrated, and triturated with pet. ether to afford a crude solid (0.894 g). The solid was then recrystalized from 85% aq. acetic acid (50 mL) to provide the title compound as a off-white solid (0.466 g, 47%): NMR (CDCl3); δ8.33 (d, J=9 Hz, 1 H), 7.76 (d, J=7 Hz, 1 H), 7.59 (ddd, J=8, 7, 1 Hz, 1 H), 7.48-7.40 (m, 3 H), 7.36-7.28 (m, 2 H), 7.06-6.98 (m, 5 H), 6.91-6.83 (m, 1 H), 6.77 (d, J=8 Hz, 1 H), 5.47-5.42(m, 1 H), 4.50 (s, 2 H), 3.05-2.85 (m, 2 H), 2.59-2.41 (m, 2 H); MS (FAB-): [M-H]-, 3 bromine isotope pattern, 756; Anal. Calc. for C31H22Br3O4PS: C, 48.91, H, 2.91, N, 0.00. Found: C, 49.29, H, 2.90, N, -0.02.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[CH3:26][NH:25][CH2:24][C:11]1[CH:10]=[C:9]([C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)[N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])(=[O:16])=[O:15])[CH:12]=1
Reactant: Cc1ccccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)cc1-c1cccnc1C#N
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of tert-butyl ({5-(2-cyanopyridin-3-yl)-1-[(2-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (202 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol-water to give the title compound as a white solid (yield 157 mg, 90%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][C:9]=1[OH:17]>>[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:15])[OH:16])=[CH:10][C:9]=1[OH:17]
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1ccc(OCCCCl)c(O)c1
Temperature: 10 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
To a flask charged with sodium borohydride (1.5 g, 39.4 mmol) under nitrogen and chilled to 10° C. was added, slowly, a solution of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (6.0 g, 26.2 mmol) dissolved in ethanol-tetrahydrofuranl (120 ml, 2:1). After total addition, the ice bath was removed and the reaction was stirred at ambient temperature for 3 hours. An additional amount of sodium borohydride (0.2 g, 5.3 mmol) was carefully added. After stirring at ambient temperature for one hour, the solvent was removed in vacuo. The resultant solid residue was diluted with water (100 ml) and left overnight. The product was isolated by vacuum filtration yielding 3.8 g. Two consecutive recrystallizations from toluene provided 3.3 g (55%) of 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzene methanol as a light brown solid, m.p.=107°-109° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][C:7]1([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(C1C=CC(CN2C(CC(O)=O)=CN=C2)=CC=1)#N.[Cl-].[Li+].[C:40]([C:42]1[CH:56]=[CH:55][C:45]([CH2:46][N:47]2[C:51]([C:52](O)=[O:53])=[CH:50][N:49]=[CH:48]2)=[CH:44][CH:43]=1)#[N:41]>>[C:40]([C:42]1[CH:56]=[CH:55][C:45]([CH2:46][N:47]2[C:51]([C:52]([N:10]3[CH2:9][CH2:8][C:7]([CH2:6][C:5]4[CH:17]=[CH:18][CH:19]=[C:3]([CH3:2])[CH:4]=4)([C:13]([O:15][CH3:16])=[O:14])[CH2:12][CH2:11]3)=[O:53])=[CH:50][N:49]=[CH:48]2)=[CH:44][CH:43]=1)#[N:41]
Reactant: N#Cc1ccc(Cn2cncc2C(=O)O)cc1
Reactant: COC(=O)C1(Cc2cccc(C)c2)CCNCC1
Agent: Cl
Agent: N#Cc1ccc(Cn2cncc2CC(=O)O)cc1
Agent: [Cl-]
Product: COC(=O)C1(Cc2cccc(C)c2)CCN(C(=O)c2cncn2Cc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 38, Step B substituting 4-(3-methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with methyl 4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt (Example 61, Step B), and 1-(4-cyanobenzyl)imidazole-5-acetic acid·lithium chloride with 1-(4-cyanobenzyl)imidazole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([OH:11])[CH2:9][OH:10])=[CH:4][C:3]=1[F:12].O.[C:14]1(C)[CH:19]=CC(S(O)(=O)=O)=C[CH:15]=1>COC(OC)(C)C>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([C@H:8]2[CH2:9][O:10][C:14]([CH3:19])([CH3:15])[O:11]2)=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OC[C@@H](O)c1cnc(Cl)c(F)c1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)OC[C@H](c2cnc(Cl)c(F)c2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 864.9 %

Procedure:
A suspension of 113 (5.39 g, 28.2 mmol) in 2,2-dimethoxypropane (58 mL, Sigma-Aldrich) was cooled with an ice bath. Para-toluene sulfonic acid monohydrate (PTSA, 0.54 g, 2.82 mmol, Sigma-Aldrich) was added to form a reaction mixture. The ice bath was removed and the reaction mixture was stirred at a temperature of about 25° C. for 16 hrs. Thereafter, the mixture was cooled with an ice bath, treated with saturated aqueous sodium bicarbonate, and extracted with EtOAc. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated to provide 5.65 g of 114 as an oil (87% yield). 1H NMR (CDCl3) δ: 1.48 (3H, s), 1.54 (3H, s), 3.71 (1H, m), 4.37 (1H, m), 5.11 (1H, t, J=6.76 Hz), 7.53 (1H, dd, J=1.93, 8.63 Hz), 8.18 (1H, d, J=1.88 Hz). LC/MS (M+1): m/z=232.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH:11]([NH:18]C(=O)OC(C)(C)C)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl.O1CCOCC1>[NH2:18][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1NCC(NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1NCC(N)c1ccccc1
Yield: 90 %

Procedure:
Tert-butyl 2-(2-methoxyphenylamino)-1-phenylethylcarbamate (0.54 g, 1.6 mmol) was dissolved in 10 mL 4N HCl in dioxane. After one hour the reaction mixture was concentrated to dryness, taken up in ethyl acetate, and the organic layer washed with 1N NaOH and then dried over sodium sulfate and concentrated to give the free amine as a brown oil, 0.35 g, 1.45 mmol, 90% yield.
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:20](=[O:24])([OH:23])([OH:22])O.P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:15][CH2:16][C:17]([OH:19])([P:20]([OH:24])(=[O:22])[OH:23])[P:20]([OH:23])(=[O:24])[OH:22])[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCCCCc1ccccc1)CCC(=O)O
Reactant: O=P(O)(O)O
Agent: Cl
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: CN(CCCCCc1ccccc1)CCC(O)(P(=O)(O)O)P(=O)(O)O

Procedure:
12.75 g (0.0446 mol) of 3-[N-(5-phenylpentyl)-N-methylamino]-propionic acid hydrochloride are heated under reflux at 100° with 6.1 ml of 85% phosphoric acid and 30 ml of chlorobenzene, while stirring. 11.7 ml of phosphorus trichloride are then added dropwise at 100°, evolution of the gas taking place. The reaction mixture precipitates a thick mass in the course of 30 minutes. The mixture is heated at 100° for a further 3 hours and the supernatant chlorobenzene is then decanted off. The viscous mass which remains is heated at the boil under reflux with 45 ml of 9N hydrochloric acid for 3 hours, while stirring. It is filtered hot, with addition of charcoal, and the filtrate is concentrated under reduced pressure. Addition of acetone gives the crude 3-[N-(5-phenylpentyl)-N-methyl-amino]-1-hydroxypropane-1,1-diphosphonic acid, which is recrystallized from water: melting point 124°-127° (decomposition).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:12])[C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:46][C:47]1[CH:48]=[CH:49][C:50]([F:65])=[C:51]([C@@:53]2([CH3:64])[N:58]=[C:57]([NH2:59])[C@:56]([F:61])([CH3:60])[CH2:55][C:54]2([F:63])[F:62])[CH:52]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:59][C:57]1[C@:56]([F:61])([CH3:60])[CH2:55][C:54]([F:63])([F:62])[C@:53]([C:51]2[CH:52]=[C:47]([NH:46][C:9](=[O:11])[C:6]3[C:5]([CH3:12])=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:48]=[CH:49][C:50]=2[F:65])([CH3:64])[N:58]=1
Reactant: C[C@]1(F)CC(F)(F)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: Cc1cc(C#N)cnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)[C@@](C)(F)CC2(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.7 %

Procedure:
5-Cyano-3-methylpicolinic acid (232 mg, 1.432 mmol) (Prepared as described in Badiger, Sangamesh et al. PCT Int. Appl., 2012095469) was placed in a round bottom flask and dissolved in DMF (7 mL). HATU (669 mg, 1.760 mmol) was added and the reaction was stirred at room temperature for 5 min, N,N-diisopropylethylamine (0.7 mL, 4.1 mmol) was added. The reaction mixture was cooled to 0° C. and added dropwise to a solution of (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethyl-3,4,5,6-tetrahydropyridin-2-amine (470 mg, 1.63 mmol) in DMF (7 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min then at 30 min at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water. The phases were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified using a RediSep Automated flash system on 80 g silica gel (eluent: ethyl acetate/heptane). The product was further purified by the following procedure: The product was dissolved in ethyl acetate (50 mL) and washed with a solution of saturated aqueous NaHCO3/water (1/1). The organic phase was washed total of 15 times (using 10 mL each time). The organic phase was dried over MgSO4, filtered, and evaporated to give N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide (153 mg, 26% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:35]=[N:36][CH:37]=[C:38]([O:40][CH3:41])[CH:39]=4)=[CH:30][CH:29]=3)([CH3:27])[CH:24]([CH3:26])[CH3:25])=[CH:21][CH:22]=2)[N:13]=1)(=O)C.C(=O)(O)[O-].[Na+]>O.CO>[CH3:41][O:40][C:38]1[CH:39]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:23]([C:20]3[N:19]=[CH:18][C:17]([C:14]4[N:13]=[C:12]([CH2:11][OH:10])[O:16][N:15]=4)=[CH:22][CH:21]=3)([CH3:27])[CH:24]([CH3:25])[CH3:26])=[CH:29][CH:30]=2)[CH:35]=[N:36][CH:37]=1
Reactant: COc1cncc(-c2ccc(C(C)(c3ccc(-c4noc(COC(C)=O)n4)cn3)C(C)C)cc2)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cncc(-c2ccc(C(C)(c3ccc(-c4noc(CO)n4)cn3)C(C)C)cc2)c1
Reaction time: 1 h

Procedure:
A mixture of potassium carbonate (743 mg, 5.38 mmol) in water (1.00 mL) was added to a stirred solution of 1c (0.896 mmol) in methanol (3.00 mL) at rt. After approximately 1 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-6% methanol/DCM as eluent) to furnish the title compound 1d. m/z (ES) 431 (MH)+. 1HNMR (500 MHz, CD3OD): δ 9.19 (d, 1H, J=2.1 Hz), 8.65 (d, 1H, J=1.4 Hz), 8.46 (d, 1H, J=2.5 Hz), 8.32 (dd, 1H, J=2.2, 8.5 Hz), 8.24 (m, 1H), 7.72 (d, 2H, J=8.4 Hz), 7.62 (d, 2H, J=8.4 Hz), 7.59 (d, 1H, J=8.7 Hz), 4.88 (s, 2H), 4.07 (s, 3H), 3.24 (m, 1H), 1.80 (s, 3H), 0.91 (d, 3H, J=6.6 Hz), 0.87 (d, 3H, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][CH:33]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([NH:22][C:23](=[O:30])OCC(Cl)(Cl)Cl)[N:21]=2)[N:18]=1)=[O:7].[NH2:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45].C(N(C(C)C)C(C)C)(C)C>CS(C)=O>[OH:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][NH:39][C:23]([NH:22][C:20]1[N:21]=[C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:34]=[CH:35][CH:36]=[C:3]([C:2]([F:37])([F:1])[F:38])[CH:4]=4)[CH:33]=[CH:32][CH:31]=3)=[N:18][N:17]2[CH:19]=1)=[O:30]
Reactant: O=C(Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1)OCC(Cl)(Cl)Cl
Reactant: NCCOCCO
Agent: CC(C)N(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(NCCOCCO)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 66.6 %

Procedure:
Using 2,2,2-trichloroethyl [6-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate (140 mg, 0.237 mmol), 2-(2-aminoethoxy)ethanol (43 μL, 0.435 mmol), N,N-diisopropylpropane-2-amine (76 μL, 0.435 mmol) and dimethyl sulfoxide (5 mL) as starting materials and in the same manner as in Example 386, the title compound (86 mg, 62%) was obtained as a pale-yellow powder.
Reaction SMILES: C([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[C:21](=[O:27])[CH2:20]2)=[C:16]([F:18])[CH:17]=1)=[O:10])C1C=CC=CC=1.C([Li])CCC.[CH2:33](OC(=O)CCC)[C@@H:34]1[O:36][CH2:35]1.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C.CN1CCCN(C)C1=O>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:33][C@H:34]([CH2:35][OH:36])[O:8][C:9]2=[O:10])[CH:13]=[CH:14][C:15]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[C:21](=[O:27])[CH2:20]1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: CCN1CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCN1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5-Benzyloxycarbonylamino-2-(4-ethyl-3-oxopiperazin-1-yl)fluorobenzene (3.25 g) was dissolved in dry THF (100 ml) under argon. The solution was cooled to -78° C., and treated with a solution of n-butyllithium (1.6 M in hexane, 6.02 ml), keeping the temperature below -60° C. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU, 10 ml) was added to the resulting mixture to facilitate stirring, and (R)-glycidylbutyrate (1.29 ml) added. Stirring was continued at -78° C. for 30 minutes, before allowing the temperature to rise to ambient over 16 hours. Sodium bicarbonate solution (50 ml) was added, followed by sufficient ethyl acetate to form two layers. The organic layer was separated, washed twice with water, dried (MgSO4) and evaporated. The residue was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 6% methanol in dichloromethane. Relevant fractions were combined and evaporated to give (5R)-3-(3-fluoro-4-{4-ethyl-3-oxopiperazine-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one (990 mg).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[NH2:19][C:20]1[N:24]([CH2:25][CH3:26])[N:23]=[CH:22][CH:21]=1>O.[Cu]>[CH2:25]([N:24]1[C:20]([NH:19][C:8]2[C:9](=[CH:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[C:10]([OH:12])=[O:11])=[CH:21][CH:22]=[N:23]1)[CH3:26]
Reactant: COc1ccc(C(=O)O)c(I)c1
Reactant: CCn1nccc1N
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCn1nccc1Nc1cc(OC)ccc1C(=O)O
Temperature: 25 °C
Yield: 56.2 %

Procedure:
K2CO3 (13.94 g, 0.101 mol) is dissolved in water (67 ml), and then 2-iodo-4-methoxybenzoic acid (25.3 g, 0.091 mol) is added, followed by 5-amino-1-ethylpyrazole (11.2 g, 0.101 mol) and finally copper (2.7 g). The reaction mixture is refluxed for 20 hours, cooled to room temperature. Then water (350 ml) is added, and the mixture is refluxed for 0.75 hours. The reaction mixture is cooled, and the product is collected by filtration, recrystallized from ethanol, and dried in an oven at 40° C. to afford 13.37 g (56%) of N-(1-ethylpyrazol-5-yl)-4-methoxyanthranilic acid, m.p. 130°-135° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>CCO>[CH:18]1([CH2:24][NH:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCCCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
N-(4-Fluoro-3-nitrophenyl)-2,2-dimethylpropanamide (158 mg, 0.658 mmol) and cyclohexylmethylamine (0.100 mL, 0.790 mmol) were stirred in 3 mL of EtOH containing triethylamine (0.140 mL, 0.987 mmol) at 75° C. for 24 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. Yield: 217 mg (99%). 1H NMR (400 MHz, CHLOROFORM-D): δ 0.98-1.09 (m, 2H), 1.17-1.28 (m, 3H), 1.31 (s, 9H), 1.65-1.73 (m, 2H), 1.74-1.80 (m, 2H), 1.82-1.84 (m, 1H), 1.85-1.88 (m, 1H), 3.15 (dd, J=6.64, 5.47 Hz, 2H), 6.83 (d, J=9.37 Hz, 1H), 7.23 (br.s, 1H), 7.82 (dd, J=9.18, 2.54 Hz, 1H), 8.10 (d, J=2.54 Hz, 1H), 8.11-8.13 (m, 1H).
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](OCC)=[O:11]>>[OH:11][CH:10]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9]
Reactant: O=C1CCCCCCC1
Reactant: CCOC=O
Product: O=C1CCCCCCC1=CO

Procedure:
As in previous examples, 126 g of cyclooctanone, XXVIc, was reacted with ethyl formate to give 95 g (0.62 mol) of 2-hydroxymethylene-cyclooctanone, XXVIIc, bp 87°-92° C (0.4 mm).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[NH:25])[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([O:34][C:35](=[O:41])[C:36](=O)[CH:37](Br)[CH3:38])[CH3:33]>C1COCC1>[CH2:32]([O:34][C:35]([C:36]1[N:25]=[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[C:37]=1[CH3:38])=[O:41])[CH3:33]
Reactant: N=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(OCc3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To N-(4-benzyloxyphenyl)-2,4-dichlorobenzamidine, from Ex. 1, Step 1 (6.88 g, 18.5 mmol) dissolved in 50 ml THF was added potassium carbonate (2.56 g, 18.5 mmol) and the suspension was stirred for 10 minutes. Ethyl-3-bromo-2-oxobutanoate (4.65 g, 22.2 mmol) was dropwise added over 1 hour, and the mixture was stirred for 66 hours at room temperature. The solution was filtered and evaporated to dryness. The residue was dissolved in acetic acid and refluxed for 1 hour. The mixture was cooled to room temperature, 100 ml water added and the product extracted with EtOAc (2×200 ml). The combined organic phases were washed with saturated sodium hydrogen carbonate, dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 70:30, 60:40) afforded 5.75 g (65%) of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(O)(=O)=O)=CC=1.[Cl:12][CH2:13][C@H:14]([OH:17])[CH2:15][OH:16]>CC(C)=O>[Cl:12][CH2:13][C@H:14]1[CH2:15][O:16][C:1]([CH3:6])([CH3:11])[O:17]1
Reactant: OC[C@@H](O)CCl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OC[C@H](CCl)O1
Yield: 7726 %

Procedure:
p-Toluenesulfonic acid (0.86 g) was added to a mixture of (R)-3-chloro-1,2-propanediol (50.13 g, 0.454 mol, optical purity 98.7% e.e.) and acetone (660 ml) and the resulting mixture was stirred for 12 hours at 25C. After completion of the reaction, acetone was removed in vacuo and the crude product was distilled to give 58.11 g of (R)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane (yield 85%, b.p. 63° C. at 25 mmHg).
Reaction SMILES: [Br:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([CH2:13][C:14]#[C:15][Si](C)(C)C)[C:8]2=[O:12])=[CH:4][C:3]=1[O:26][CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([CH2:13][C:14]#[CH:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)COc1cc2c(c(Br)c1Br)C(=O)C(CC#C[Si](C)(C)C)(c1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#CCC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Br)c(Br)c2C1=O

Procedure:
Desilylation and hydrolysis of ethyl [6,7-dibromo-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate with sodium hydroxide in ethanol according to the procedure of Example 1, STEP (c), affords the title compound.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18]([O:20]C)=[O:19])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[Li+].[OH-]>CO>[C:1]([NH:4][CH:5]([CH3:25])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18]([OH:20])=[O:19])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC(C)Cc1ccc(C#Cc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C

Procedure:
To a mixture of 6.00 g (17.9 mmol) methyl 3-((4-(2-acetamido-propyl)phenyl)ethynyl)-benzoate (I71.1) in 150 mL MeOH are added at 0° C. 18 mL LiOH solution (3 M in water). The reaction mixture is stirred at r.t. over night. The MeOH is removed in vacuo and the desired product is precipitated by acidification with 2N aq. HCl. The resulting solid is filtered, washed with pentane and dried in vacuo.