Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].O.C(OP([CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])(OCC)=O)C.[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[CH:12][CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=CC=C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
Under an atmosphere of nitrogen, 0.583 g of sodium hydride (as a 50% w/w dispersion in mineral oil) were added to a 4 ml of tetrahydrofuran and the mixture was cooled with water. A solution of 3.04 g of ethyl 4-(diethylphosphono)crotonate in 5 ml of tetrahydrofuran was added dropwise to the cooled mixture, which was then stirred for 30 minutes. At the end of this time, a solution of 1.84 g of 1-benzyl-4-piperidone in 2 ml of tetrahydrofuran was added to the mixture over a period of 30 minutes, whilst the mixture was kept at 0° C. by ice-cooling, and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was then stirred at room temperature for 2 hours, after which it was concentrated by evaporation under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with water. The solvent was then removed by distillation under reduced pressure. The red brown residue was subjected to column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 0.81 g (29% yield) of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH3:8])=[C:6]([OH:9])[O:5][N:4]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>O>[F:11][C:2]([F:1])([F:10])[C:3]1[C:7]([CH3:8])=[C:6]([O:9][CH2:23][C:24]([O:26][CH3:27])=[O:25])[O:5][N:4]=1
Reactant: COC(=O)CBr
Reactant: Cc1c(C(F)(F)F)noc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)COc1onc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To 1.00 g (6 mmole) of 3-trifluoromethyl-4-methyl-5-hydroxyisoxazole were added 10 ml of dry acetone and 1.00 g (7.2 mmole) of anhydrous potassium carbonate and the resulting mixture was stirred at room temperature for one hour. After addition of methyl bromoacetate (1.10 g, 7.2 mmole), the mixture was refluxed for 30 hours. The reaction mixture was mixed with water (100 ml) and, extracted with diethyl ether. The diethyl ether phase was dried with anhydrous magnesium sulfate, evaporated under reduced pressure, and the residue was purified by chromatography on silica gel to give 0.73 g of the title compound as colorless viscous liquid, yield 53.6%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[N:37]2[CH2:38][CH2:39][NH:40][CH2:41][C:36]2=[CH:35][N:34]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[O:13]=[C:11]([N:40]1[CH2:39][CH2:38][N:37]2[C:33]([C:32]([F:43])([F:31])[F:42])=[N:34][CH:35]=[C:36]2[CH2:41]1)[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23]
Reactant: FC(F)(F)c1ncc2n1CCNC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(cnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
(R)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (8.6 g, 45 mmol) and 9.4 mL of triethylamine were dissolved in 300 mL of dichloromethane. After stirring for 5 minutes, 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 1k (15.0 g, 45 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (17.1 g, 67.3 mmol) were added to the solution successively. The reaction mixture was reacted for 2 hours and then concentrated under reduced pressure. The resulting residues were purified by silica gel column chromatography with system B as eluant to obtain the title compound tert-Butyl (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamate 1m (20.0 g, yield 88%) as a white solid. 1H NMR (400 MHz, CD3OD, ppm): δ 7.25 (m, 1H), 7.11 (m, 1H), 7.032 (s, 1H), 4.93 (m, 2H), 4.35 (m, 3H), 4.05 (m, 2H), 2.99 (m, 2H), 2.73 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [S:1](O)(=O)(=O)[CH3:2].[CH2:6]1[CH:15]2C([CH2:11][CH2:12][CH2:13][CH2:14]2)CC[NH:7]1>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[SH:1][C:2]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:6]#[N:7]
Reactant: CS(=O)(=O)O
Reactant: C1CCC2CNCCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccccc1S

Procedure:
Following the procedures for Example 22, Step C, decahydroisoquinoline mesylate from preparation 3 (102 mg, 0.28 mmol) in acetone (0.5 mL), potassium carbonate solid (38 mg, 0.28 mmol, twice) and 2-mercaptobenzonitrile (38 mg, 0.286 mmol, twice) gave, after flash chromatography (hexanes-ethyl acetate 2:1), the desired product as an oil (64 mg) in 57% yield.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([NH2:10])[CH2:9][O:8][CH2:7]1)C.[CH3:12][NH2:13]>>[NH2:10][C:6]1([CH2:5][C:4]([NH:13][CH3:12])=[O:3])[CH2:9][O:8][CH2:7]1
Reactant: CN
Reactant: CCOC(=O)CC1(N)COC1
Product: CNC(=O)CC1(N)COC1
Yield: 102 %

Procedure:
A solution of (3-Amino-oxetan-3-yl)-acetic acid ethyl ester (CAN 1207175-54-9, 0.3 g, 1.88 mmol) in methanamine 41% aqueous solution (1.86 g, 2.09 ml, 24.5 mmol) was stirred overnight at 60° C. The reaction was evaporated down to dryness and to yield the title compound (278 mg, 102%) as a crude solid which was used without any purification. MS (ESI, m/z): 145.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[C:30]1([C:36]2([CH2:39]O)[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:39][C:36]3([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:38][CH2:37]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: OCC1(c2ccccc2)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2(c3ccccc3)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a solution of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), (1-phenylcyclopropyl)methanol (0.87 g) and tributylphosphine (2 mL) in THF (100 mL) was added 1,1′(azodicarbonyl)dipiperidine (2 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.43 g, 21%).
Reaction SMILES: [CH2:1]([C:4]#[N:5])[C:2]#[N:3].C(O)C.Cl.N[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]>C(Cl)(Cl)Cl>[S:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:3]=[C:2]1[CH2:1][C:4]#[N:5]
Reactant: N#CCC#N
Reactant: Nc1ccccc1S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N#CCc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of malonodinitrile (13.22 g, 0.200 mole) in dry chloroform (100 mL) was added ethanol (9.2 g, 0.200 mole). Hydrogen chloride (8.0 g, 0.220 mole) was passed into the solution at room temperature and the resulting suspension was stirred for an additional 16 hours at room temperature. The excess of hydrogen chloride was removed by passing dry nitrogen into the reaction mixture. A solution of o-aminothiophenol (25 g, 0.200 mole) in chloroform was added to the reaction mixture dropwise during 30 min and the reaction mixture was stirred for 1 hour at 60° C. After that the reaction mixture was cooled to room temperature, washed with water (2×100 mL) and dried with magnesium sulfate. Chloroform was removed using a rotary evaporator. The solid residue was recrystallized from ethyl alcohol. White crystals. The yield was 26.1 g (75% of theory). Mp=101-103° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[NH:16][S:15]2(=[O:25])=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.O.[H][H]>[C].[Pd].CO>[O:25]=[S:15]1(=[O:24])[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[NH:16]1
Reactant: O=S1(=O)Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=S1(=O)Nc2ccccc2CN1C1CCNCC1
Temperature: 40 °C
Yield: 93.6 %

Procedure:
In this reference example, 7.14 g (20 m.mols) of 1-benzyl-4-(3,4-dihydro-2,2-dioxo-1H-2,1,3-benzothiadiazin-3-yl)-piperidine, 2 g of 10% palladium carbon, 20 ml of 1 N hydrochloric acid, 60 ml of water and 120 ml of methanol are mixed. While the mixture is stirred at 40° C., hydrogen gas is blown into the mixture at 40° C. for 20 hours. The reaction mixture is filtered to remove palladium carbon. The filtrate is concentrated to dryness to obtain 5.0 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:32]1([C:35]2[CH:39]=[CH:38][N:37]([CH2:40][C:41](O)=[O:42])[N:36]=2)[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][N:37]3[CH:38]=[CH:39][C:35]([CH:32]4[CH2:33][CH2:34]4)=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cn1ccc(C2CC2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cn3ccc(C4CC4)n3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79 μmol), (3-cyclopropyl-pyrazol-1-yl)-acetic acid (17.74 mg, 106 μmol) and DIPEA (48.97 μL, 277 μmol) in THF (3 mL), T3P (166 μL, 277 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (91%, 42 mg) that was taken directly on to the next step.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[CH:12]([CH2:13][CH:14]=[CH:15][CH2:16]1)[CH2:11][CH2:10]3.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>ClCCl>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[CH:12]([CH2:13][C@@H:14]2[O:30][C@@H:15]2[CH2:16]1)[CH2:11][CH2:10]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CCC4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Product: CO[C@H]1CC[C@H]2[C@@H]3CCC4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of compound 34 (160 mg, 0.55 mmol) in anhydrous dichloromethane (10 mL) was added m-CPBA (149 mg, 0.67 mmol) at 0° C. under an atmosphere of argon. The solution was stirred at 0° C. over a period of 3 h. The solution was subsequently diluted with dichloromethane (50 mL) and washed with an aqueous sodium bicarbonate solution (10%). The organic layer was dried with sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash chromatography (Hexanes/acetone: 9:1) to yield compound 35 (127 mg, 75%). 1H NMR (CDCl3) δ: 0.73 (s, 18-CH3), 0.76 (s, 19-CH3), 0.58-2.05 (residual CH and CH2), 3.12 and 3.15 (2 m, 2×CH of epoxide), 3.21 (t, J=8.2 Hz, 17α-CH), 3.34 (s, OCH3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:26](O)[CH2:27][CH2:28][Cl:29]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:26][CH2:27][CH2:28][Cl:29])=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: OC(Br)CCCl
Reactant: CCOC(=O)C1(c2ccc(O)cc2)C=CC=CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(OCCCCl)cc2)C=CC=CC1

Procedure:
Following the procedure described in example 47§D, but starting from 4′-hydroxybiphenyl-1-carboxylic acid ethyl ester (3 g), potassium carbonate (8.55 g) and 1-bromo-3-chloropropanol (6 mL) in N,N-dimethylformamide (30 mL) affords 4′-(3-chloropropoxy)biphenyl-1-carboxylic acid ethyl ester in quantitative yield used without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:20]=[CH:19][C:18]2[C:9]3[NH:10][C:11](=[O:17])[C:12]4[N:13]([CH:14]=[CH:15][N:16]=4)[C:8]=3[C:7](=[CH:21][C:22]([OH:24])=[O:23])[C:6]=2[CH:5]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38]=[C:39]=[O:40]>CN(C)C=O>[C:22]([CH:21]=[C:7]1[C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[C:11](=[O:17])[NH:10][C:9]=2[C:18]2[CH:19]=[CH:20][C:4]([NH:3][C:39]([NH:38][CH3:37])=[O:40])=[CH:5][C:6]1=2)([OH:24])=[O:23]
Reactant: CN=C=O
Reactant: Nc1ccc2c(c1)c(=CC(=O)O)c1c2[nH]c(=O)c2nccn21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc2c(c1)c(=CC(=O)O)c1c2[nH]c(=O)c2nccn21
Reaction time: 30 h

Procedure:
To 11 g of 8-amino-10-(carboxymethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one dihydrochloride dissolved in 110 ml of dimethylformamide and 110 ml of dioxane at a temperature in the region of 20° C. are added 12.42 g of potassium carbonate, followed by dropwise addition of 5.3 ml of methyl isocyanate. The stirring is continued for 30 hours at the same temperature. The reaction medium is then filtered. The solid recovered is dried under reduced pressure (15 mmHg; 2 kPa). The residue is taken up in 50 ml of water and the precipitate is filtered off. The solid is acidified with 2 ml of concentrated hydrochloric acid in 50 ml of water and then filtered and dried under reduced pressure (15 mmHg; 2 kPa). The insoluble product thus formed is taken up in 700 ml of dimethylformamide and brought to 50° C. in the presence of 1 g of animal black. The solution is filtered on Celite and the filtrate is concentrated on a rotary evaporator at 40° C. under reduced pressure (15 mmHg; 2 kPa). (1 mmHg; 0.13 kPa). The residue is taken up in 200 ml of ethyl ether and then filtered and dried for 8 hours at 50° C. under reduced pressure (1 mmHg; 0.13 kPa). 3.67 g of 10-(carboxymethylene)-8-(3-methylureido)-5H,10H-imidazo(1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of an orange-coloured powder, the melting point of which is greater than 260° C. (Analysis, C17 H13N5O4.0.9 DMF.0.9 H2O, % calculated C: 58.12; H: 3.73; N: 19.93, % found C: 58.1; H: 3.4; N: 19.6).
Reaction SMILES: [CH:1](/[P:4](=[O:15])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:2]\[CH3:3].[O-2].[Al+3].[O-2].[O-2].[Al+3].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:3]/[CH:2]=[CH:1]/[P:4](=[O:15])([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: C/C=C/P(=O)(OC(C)(C)C)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [O-2]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OP(=O)(/C=C/CBr)OC(C)(C)C
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
(1)-2 To a solution of di-tert.-butyl trans-1-propenylphosphonate (12.0 g.) in carbon tetrachloride (120 ml.) were added basic aluminum oxide (24.0 g.), N-bromosuccinimide (10.95 g.) and then dibenzoylperoxide (1.4 g.). The mixture was heated to reflux for an hour and then stirred for 30 minutes under ice-cooling. The resultant mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give oily di-tert.-butyl 3-bromo-trans-1-propenylphosphonate (17.2 g.).
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:15][CH2:16]I.[Li+].CC([N-]C(C)C)C.C(O)(=O)C>C1COCC1>[Cl:15][CH2:16][C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: ClCI
Reactant: COC(=O)c1cccc2c1OCCO2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(CCl)c1cccc2c1OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid methyl ester (100 mg, 0.515 mmol) and chloroiodomethane (0.075 ml, 1.03 mmol) in 1 ml of THF was added a solution of LDA in THF (2M, 0.57 ml, 1.13 mmol) dropwise at −78° C. over 15 min. The reaction mixture was stirred at −78° C. for 10 min. A solution of acetic acid (0.75 ml) in THF (5 ml) was added dropwise over 5 min at −78° C. The resulting solution was stirred at the same temperature for additional 10 min. and was then partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate, brine, dried over MgSO4 and concentrated in vacuo to give the crude 2-chloro-1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethanone as a light brown liquid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]([Cl:14])(Cl)Cl.[C]=[O:16].Cl>[Fe](Cl)(Cl)Cl.C(O)=O>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]([Cl:14])=[O:16]
Reactant: [C]=O
Reactant: Fc1cc(C(Cl)(Cl)Cl)c(F)c(F)c1F
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O=CO
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F

Procedure:
268 g of 2,3,4,5-tetrafluorobenzotrichloride were placed in a stirred apparatus and 5.3 [lacuna] of iron(III) chloride were added, 45 g of formic acid (98-100%) were pumped in over 8 hours at 60° C. Vigorous gas development (carbon monoxide, hydrogen chloride) began immediately. The gas stream was fed to an absorption tower via a cooler. After addition was complete, the mixture was stirred until the end of gas development. The product was then distilled. 195 g of 2,3,4,5-tetrafluorobenzoyl chloride were obtained (91.5% of theory); b.p.: 70°-72° C./20 mbar, nD25 : 1.4773.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[C:19]([F:20])=[C:18]([C:21]2[N:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:23][N:22]=2)[CH:17]=[CH:16][C:15]=1[OH:36].[CH3:37][Si:38]([CH3:51])([CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:51][Si:38]([CH3:37])([CH2:46][Si:47]([CH3:48])([CH3:49])[CH3:50])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:36][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][N:26]=2)=[C:19]([F:20])[C:14]=1[F:13]
Reactant: C[Si](C)(C)C[Si](C)(C)CCCCCCO
Reactant: CCCCCCCCCc1cnc(-c2ccc(O)c(F)c2F)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCc1cnc(-c2ccc(OCCCCCC[Si](C)(C)C[Si](C)(C)C)c(F)c2F)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethylazodicarboxylate (0.087 g, 0.500 mmol) in THF (5.0 ml) was added dropwise to a stirred solution of 2,3-difluoro-4-(5-nonylpyrimidin-2-yl)-phenol (0.134 g, 0.400 mmol), compound 14 (0.108 g, 0.440 mmol) and triphenylphosphine (0.130 g, 0.500 mmol) in THF (20 ml). The treaction mixture was stirred at room temperature for 24 h, the solvent removed in vacuo and the residues purified by column chromatography [silica gel eluted with hexane/ethyl acetate (9:1)] to yield a colorless solid that was recrystallized from acetonitrile.
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OC(Cl)=O)C.C(N(CC)CC)C.[NH2:20][C:21]1[CH:29]=[C:25]([C:26]([OH:28])=[O:27])[C:24]([OH:30])=[CH:23][CH:22]=1.Cl>C(#N)C>[C:26]([C:25]1[CH:29]=[C:21]([NH:20][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH:22]=[CH:23][C:24]=1[OH:30])([OH:28])=[O:27]
Reactant: C=C(C)C(=O)O
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
Into a 1 liter flask were added 600 ml of acetonitrile, 95.2 g (1.1 mol) of methacrylic acid and 120.1 g (1.1 mol) of chloroformic acid ethyl ester. To this mixture 111.8 g (1.1 mol) of triethylamine was added over a period of 1 hour in a cold bath. Stirring was continued for 1 hour at room temperature and 141.2 g (1 mol) of 5-aminosalicylic acid was added. The mixture was heated for 2 hours at 60° C. The mixture was poured into 5 liter of 1% HCl solution. The deposit was filtered, washed and dried to produce 164.7 g of N-(3-carboxy-4-hydroxyphenyl)methacrylamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[C-]#N.[K+].[CH3:16][N:17](C=O)C>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:16]#[N:17])[CH:5]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 42.5 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromomethyl-benzoic acid methyl ester (3.00 g, 13.10 mmol), potassium cyanide (1.02 g, 15.71 mmol) and DMF (25 mL) was heated at 40-45° C. for 45 minutes and was stirred at room temperature for 18 h. The reaction was heated at 40° C. for 24 h, was cooled to room temperature, and additional potassium cyanide (1.02 g, 15.71 mmol) was added. The reaction was heated at 40° C. for 18 h and was cooled to room temperature. Water (25 mL) was added and the product was extracted into EtOAc (3×25 mL). The combined organic layers were washed with 1N LiCl followed by brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (9:1 hexanes:EtOAc to 4:1 hexanes:EtOAc) provided 3-cyanomethyl-benzoic Acid methyl ester (1.36 g). MS 193 (M+18).