Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=1[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.[I:38]I>C1C=CC=CC=1.S([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][I:38])=[CH:8][C:7]=1[CH3:14]
Reactant: II
Reactant: COC(=O)CCc1ccc(CO)cc1C
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)CCc1ccc(CI)cc1C
Temperature: 25 °C

Procedure:
A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methyl ester (0.62 g, 2.98 mmol), triphenyl phosphine (0.86 g, 3.27 mmol) and dichloromethane (10 mL) is stirred at room temperature. A solution of iodine (0.83 g, 3.27 mmol) in benzene (5 mL) is added and the black mixture is stirred at room temperature 2 hr. The brown mixture is diluted with 10% aqueous sodium hydrogen sulfite (5 mL) and the resulting clear mixture is washed with ethyl acetate (3×50 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified via silica chromatography eluting with 9:1 hexanes:ethyl acetate to afford the title compound as a crystalline ivory solid, 0.689, 72%. MS M++1 319. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([N:11]2[C:10](=[O:19])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]2[S:1][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-n2c(S)nc3ccccc3c2=O)cc1
Reactant: ClCc1ccncc1
Agent: Cl
Product: Cc1ccc(-n2c(SCc3ccncc3)nc3ccccc3c2=O)cc1
Yield: 60.8 %

Procedure:
The title compound was prepared in a yield of 60.8%, using 2-mercapto-3-(4-methylphenyl)-4(3H)-quinazolinone in place of 2-mercapto-3-phenyl-4(3H)-quinazolinone and 4-chloromethylpyridine hydrochloride in place of 2-chloromethyl4-methylpyridine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.[CH3:21][N:22]([CH3:39])[CH2:23][CH2:24][CH2:25][N:26]([CH3:38])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=1[C:34]([F:37])([F:36])[F:35]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH:33][C:30]1[CH:31]=[CH:32][C:27]([N:26]([CH2:25][CH2:24][CH2:23][N:22]([CH3:21])[CH3:39])[CH3:38])=[C:28]([C:34]([F:35])([F:36])[F:37])[CH:29]=1)=[O:20]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Reactant: CN(C)CCCN(C)c1ccc(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCCN(C)c1ccc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2Cl)cc1C(F)(F)F

Procedure:
The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 16.1) and 4-[(3-dimethylamino-propyl)-methyl-amino]-3-trifluoromethyl-phenylamine (Step 5.1). Title compound: ES-MS: 544.9 [M+H]+; single peak at tR=3.66 min (System 1); Rf=0.28 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[Cl-].[Cl:25]CC(O)C[N+](C)(C)C>O>[ClH:25].[CH2:10]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13]
Reactant: C[N+](C)(C)CC(O)CCl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Cl-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Cl
Temperature: 30 °C

Procedure:
While stirring, 18.54 g (100 mmole) of tri-n-butylamine was added drop by drop to 7.50 g (50 mmole) of L-(+)-tartaric acid, which was dissolved in 50 ml of water, whereby the solution was heated to 30° C. Subsequently, 18.81 g (100 mmole) of 3-chloro-2-hydroxy-propyltrimethylammonium chloride, which was dissolved in 100 ml of water, was added to the solution. The resultant clear solution was extracted with 8 separate portions of 150 ml of methylene chloride. The extractions were evaporated under vacuum. 21.65 g (97.6 percent yield) of tributylamine hydrochloride was obtained. (Together, the two last extractions only still contained 0.14 g of material.) The aqueous layer was evaporated in a rotary evaporator until dry. 23.22 g of a very viscous oil (102.5 percent) resulted. This was dissolved hot in 30 ml of methanol. It was mixed slowly with 93 ml of acetone until it became cloudy. The latter was again made to disappear by the addition of a few drops of methanol. After 72 hours, the mother liquor was decanted. The crystal crust was washed with acetone/methanol (3:1) and was dried under vacuum. The yield was 7.20 g of crystals (31.8 percent or 63.6 percent of the theory). The crystals had a melting point of 147° to 170° C. The crude tartrate was dissolved in 10 g of hot methanol and gradually 45 ml of acetone were added, whereupon the crystallization immediately started. The crystallization vessel was kept overnight in the refrigerator. The mother liquor was decanted off; the crystal cake was washed with acetone and dried. 5.78 g of crystals, corresponding to 51 percent of the theory, were obtained. The crystals had a melting point of 150° to 152° C. and a [α]D24 of -7.5° (c=1.04 in water). The tributylamine was recovered from the methylene chloride residue (raw tributylamine hydrochloride) with a yield of 96 percent by placing the residue in a solution of methylene chloride, shaking the solution with 1N of caustic soda solution and removing the solvent under vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:22])C(=O)C1>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:9][C:10]=2[I:22])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1nccn2c(C3CCC3)ncc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1nccn2c(C3CCC3)nc(I)c12

Procedure:
8-Chloro-3-cyclobutylimidazo[1,5-a]pyrazine (1058 mg, 5.1 mmol) and NIS (1146 mg, 5.1 mmol) in anh DMF (10 mL) were stirred at 60° C. under Ar for 6 h. The reaction was diluted with DCM (˜400 mL), washed (H2O, brine), dried (Na2SO4) and concentrated under reduced pressure. Purification of the crude material by flash chromatography on silica gel (50 g cartridge, 10:1-8:1-7:1-6:1 hexanes:EtOAc) afforded the title compound as a pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=4.8 Hz, 1H), 7.26 (d, J=4.8 Hz, 1H), 3.75 (quintetd, J=1.2 Hz, 8.4 Hz, 1H), 2.62-2.42 (m, 4H), 2.32-1.98 (m, 2H); MS (ES+): m/z 334.0 (100) [MH+]; HPLC: tR=3.38 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6]([O:8][C:9](OCC)(OCC)[CH2:10][CH2:11][CH3:12])[CH3:7]>>[CH2:6]([O:8][C:9](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH2:10][CH2:11][CH3:12])[CH3:7]
Reactant: CCCC(OCC)(OCC)OCC
Reactant: N#CCC#N
Product: CCCC(OCC)=C(C#N)C#N
Temperature: 25 °C

Procedure:
18.69 g (283 mmol) of malononitrile and 41.94 g (283 mmol) of triethylorthobutyrate are heated for 4 hours at 150° C. The reaction mixture is cooled to room temperature and, after the ethanol has been removed, distilled in vacuo. B.p.: 85° C. (3mbar).
Reaction SMILES: F[B-](F)(F)F.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7].[F:15]C1C=C([N+]([O-])=O)C=CC=1.FC1C=CC=CC=1[N+]([O-])=O>ClC1C=CC=CC=1.C1C=CC=CC=1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: O=[N+]([O-])c1ccccc1
Agent: F[B-](F)(F)F
Agent: O=[N+]([O-])c1ccccc1F
Solvent: Clc1ccccc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(F)cc1
Temperature: 90 °C

Procedure:
A homogeneous reaction mixture was obtained in this experiment, whereas in the aforementioned fluorinations of benzene and chlorobenzene, the reaction mixtures contained suspended [(ClCN)3F]+BF4−. In order to drive the fluorination of nitrobenzene to completion, the reaction mixture was heated at 90° C. for 2 hours before it was tested with Kl solution and gave a negative result. G. C. analysis revealed the presence of only 3-fluoronitrobenzene and 2-fluoronitrobenzene with no marked change in ratio (about 2:1 ratio). Despite the presence of the 2-fluoro derivative, no evidence was obtained for the presence of 4-fluoronitrobenzene. The absence of 4-fluoronitrobenzene may have resulted from loss of this isomer during the reaction or subsequent handling operations via nucleophilic displacement of the highly mobile fluorine. In this connection, the reaction vessel became etched during the reaction.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:14][CH:15]2[CH2:20][NH:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>C(Cl)Cl>[CH:8]1([CH2:14][CH:15]2[CH2:20][N:19]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)C1CNCC(CC2CCCCC2)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(CC2CCCCC2)CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (340 mL, 2.4 mmol) was added to a solution of ethyl 5-(cyclohexylmethyl)piperidine-3-carboxylate (155 mg, 0.60 mmol) and methanesulfonyl chloride (75 mL, 0.90 mmol) in CH2Cl2 (6 mL) cooled to 0° C. The reaction was maintained at this temperature for 15 min at which point the whole was allowed to warm to RT and stir for an additional 3 h. The reaction was diluted with CH2Cl2 (20 mL) and poured into HCl (1N, 20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were sequentially washed with H2O (10 mL) and brine before being dried over Na2SO4. Concentration under reduced pressure provided the title compound. MS m/z: 332.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8].Cl.N([O-])=O.[Na+].[N-:18]=[N+:19]=[N-].[Na+]>O.C(O)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8])=[N+:18]=[N-:19]
Reactant: Nc1cccc(OCC(=O)O)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1cccc(OCC(=O)O)c1
Reaction time: 0.08 h
Yield: 63.9 %

Procedure:
To a 100 mL recovery flask was added 3-aminophenoxyacetic acid 2 (2.00 g, 12.0 mmol, 1.0 eq.) and a stirbar. Acetic acid (5 mL), conc. HCl (2 mL) and H2O (3 mL) were added to the flask. The reaction mixture was cooled to 0° C. upon which a solution of NaNO2 (0.908 g, 13.2 mmol, 1.1 eq.) in H2O (3 mL) was added over a period of 20 sec. The mixture was stirred for 5 minutes. A solution of NaN3 (0.855 g, 13.2 mmol, 1.1 eq.) in H2O (3 mL) was added slowly to the reaction mixture upon which the mixture foamed. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for an additional 1 h. A light brown solid precipitates out of solution. The suspension was filtered and washed with cold H2O to yield a light-brown solid (1.48 g). Upon drying, the more precipitate formed in the filtrate. The precipitate was refiltered to yield more product (0.17 g). Total yield: 1.65 g, 71%. LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 192.1 (M−H)−1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 7.31-7.27 (t, 1H), 6.73-7.69 (m, 2H), 6.59-6.58 (m, 1H), 4.62 (s, 2H) ppm.
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1)(=O)=O.[I-:19].[Na+]>CC(C)=O.O>[I:19][C@H:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](I)C1
Yield: 42.7 %

Procedure:
A solution of tert-butyl N-[(1S,3R)-3-(methanesulfonyloxy)cyclopentyl]carbamate (2.1 g, 7.52 mmol, 1.00 equiv) and sodium iodide (7 g, 46.70 mmol, 6.21 equiv) in acetone (40 mL) was stirred at 50° C. for 30 min. The reaction mixture was diluted with 100 mL of water then extracted with 2×30 mL of ethyl acetate. The combined organic layers was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/5) to give 1.0 g (43%) of tert-butyl N-[(1S,3S)-3-iodocyclopentyl]carbamate as a white solid.
Reaction SMILES: CON(C)[C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH:11]2[O:15][CH2:14][CH2:13][O:12]2)[CH:8]=[CH:7][C:6]=1[O:16][CH3:17].[CH3:20][Mg]I.CCOCC.[Cl-].[NH4+]>O1CCCC1>[O:15]1[CH2:14][CH2:13][O:12][CH:11]1[C:9]1[CH:8]=[CH:7][C:6]([O:16][CH3:17])=[C:5]([C:4](=[O:18])[CH3:20])[CH:10]=1
Reactant: C[Mg]I
Reactant: COc1ccc(C2OCCO2)cc1C(=O)N(C)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2OCCO2)cc1C(C)=O
Yield: 79 %

Procedure:
N-Methoxy-N-methyl-5-(1,3-dioxolan-2-yl)-2-methoxybenzamide (6.60 g, 24.7 mmol) and dehydrated tetrahydrofuran (200 mL) were mixed, and under an atmosphere of argon, the mixture was cooled using dry ice-acetone bath, and 3.0 mol/L solution of methyl magnesium iodide in ether (24.7 mL, 74.1 mmol) was added dropwise slowly under stirring. After completion of the dropwise addition, the mixture was stirred for 1.5 hours under cooling with ice. A saturated aqueous solution of ammonium chloride (200 mL) was added dropwise thereto under cooling with ice and stirring. After separated the organic layer, the aqueous layerwas extracted with ethyl acetate. Respective organic layers were combined, washed with water and saturated brine in sequence, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=4:1 v/v) to obtain 4.31 g (79%) of the title compound as colorless crystals.
Reaction SMILES: C([Li])CCC.C(O[CH:9]([O:15]CC)[N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)C.[CH3:18][C:19]1[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=1[O:21][CH2:22][C:23]1[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=1C(N1CCCC1)=O.[Cl-].[NH4+]>O1CCCC1.CO>[CH3:18][C:19]1[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=1[O:21][CH2:22][C:23]1[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=1[C:9]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[O:15]
Reactant: CCOC(OCC)n1ccnn1
Reactant: Cc1ccccc1OCc1ccccc1C(=O)N1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1OCc1ccccc1C(=O)n1ccnn1
Reaction time: 0.25 h
Yield: 34.1 %

Procedure:
At −20° C., 2.8 g (0.01 mol) of 23% pure n-butyllithium are added dropwise within 15 minutes to a solution of 1.7 g (0.01 mol) of N-diethoxymethyltriazole in 10 ml of tetrahydrofuran. Stirring is continued for 15 minutes at −20° C., and 1.48 g (0.005 mol) of N-[2-(2-methylphenoxymethyl)-benzoyl]-pyrrolidine dissolved in 10 ml of tetrahydrofuran are then added, and the mixture is stirred for a further 30 minutes at −20° C. 2 g of ammonium chloride and 10 ml of methanol are added and the mixture is heated under reflux for 15 minutes. The volatile components are removed under reduced pressure, the residue is admixed with water and extracted with ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The residue crystallizes when treated with a mixture of diethyl ether and petroleum ether in the ratio of 1:1. 0.5 g (17% of theory) of 3-[2-(2-methylphenoxymethyl)-benzoyl]-triazole of melting point 179° C. is obtained.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH2:41])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])([CH3:31])[CH3:30]>>[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH:41][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:26])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[C:17]([CH3:25])[CH:16]=4)=[N:6][C:7]=23)=[O:14])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])([CH3:31])[CH3:30]
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4nc(C)c(S(=O)(=O)NC(C)(C)CO)s4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 617.2 [(M−H)−]; mp 271° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](OCC)(=O)C>>[CH3:10][C:7]1[C:2]([C:1]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccccc1
Product: Cc1ccccc1C(=O)O

Procedure:
2f (4.7 g, 9.3 mmol) and n-propanethiol (5.1 mL, 6 eq) were mixed in dimethylformamide (70 mL), potassium t-butoxide (5.7 g, 5 eq) was added thereto, and the mixture was stirred at 135° C. for 2.5 hours. After cooling, the reaction solution was transferred into a mixture of toluene (200 mL) and distilled water (200 mL), methanesulfonic acid (5 g) was added thereto, and the mixture was then stirred. Thereafter, saturated aqueous sodium bicarbonate was added until the aqueous phase became alkalized. Liquid separation was performed, extraction with toluene (200 mL×3) was performed, and the organic phase was washed with distilled water (200 mL×2). The resultant was dried over magnesium sulfate and concentrated. The resulting crude product was purified by recrystallization from THF. Thus, 3.47 g of a free base substance of the object product was obtained. This product was dissolved in ethyl acetate, a solution of benzoic acid (1 eq) in ethyl acetate was added, and the solvent was removed by distillation. The resultant was suspended in ether and collected by filtration, thereby obtaining the object product 2-benzoate. Also, 3f was used as a starting material instead of 2f to obtain 3. This product was converted to methanesulfonate, and the object product 3-methanesulfonate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:35]I)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:35][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(OC)cc2)C1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)nc1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(Cl)cc3)nc2)CCN(C(=O)c2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 6-(4-chloro-phenyl)-pyridin-3-ol (Preparation 23) and 3-iodomethyl-1-(4-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 14) to afford the racemate as a white solid (94 mg, 46%)
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[I:13])=[N+:2]=[N-:3].[F:14][C:15]([F:19])([F:18])[CH2:16][NH2:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[O:10])=[CH:6][C:5]=1[I:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1I
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(C(=O)NCC(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 4-azido-3-iodobenzoic acid (5.00 g, 17.3 mmol) obtained in Example 379a) in DMF (80 ml) were added sequentially 2,2,2-trifluoroethylamine (2.5 g), triethylamine (3.6 ml), HOBt (1.3 g) and WSC (5.0 g), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/20 to 1/1) to give the title compound as a pale-yellow solid (2.93 g, 46%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH:11]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Si](OCC(C)(C)CO)(C(C)(C)C)(C)C.[NH2:51][C:52]1[N:57]=[CH:56][N:55]=[C:54]2[N:58]([C@@H:75]3[CH2:80][CH2:79][CH2:78][N:77]([C:81](=[O:85])[CH2:82][C:83]#[N:84])[CH2:76]3)[N:59]=[C:60]([C:61]3[CH:66]=[CH:65][C:64]([O:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[CH:63][C:62]=3[F:74])[C:53]=12.[Si](Cl)(C)(C)C.N1CCCC1>C(Cl)Cl>[NH2:51][C:52]1[N:57]=[CH:56][N:55]=[C:54]2[N:58]([C@@H:75]3[CH2:80][CH2:79][CH2:78][N:77]([C:81]([C:82](=[CH:11][C:10]([CH3:14])([CH3:13])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:83]#[N:84])=[O:85])[CH2:76]3)[N:59]=[C:60]([C:61]3[CH:66]=[CH:65][C:64]([O:67][C:68]4[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=4)=[CH:63][C:62]=3[F:74])[C:53]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Reactant: CC(C)(C=O)CO[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
A crude mixture of 3-[tert-butyl(dimethyl)silyl]oxy-2,2-dimethyl-propanal (1.15 g, 5.31 mmol) was prepared by addition of 1.1 equivalents of Dess-Martin periodinane to a solution of 3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropan-1-ol in 25 mL of DCM at 0° C. After 1 h, the slurry was diluted with hexanes and filtered over a plug of silica. The residue was concentrated to a thick oil and then dissolved in DCM (O1 mL). 3-[(3R)-3-[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-3-oxo-propanenitrile (236.79 mg, 0.5000 mmol) was added, then TMS-Cl (0.2 mL, 1.59 mmol), followed by pyrrolidine (0.13 mL, 1.59 mmol). The solution was stirred at rt, monitoring the reaction by LCMS. After 16 h, the mixture was partitioned between water and DCM and then the organic phase was washed with brine and dried over sodium sulfate. Filtration and removal of solvents afforded a colorless oil that was purified by silica gel chromatography (9:1 to 90:10 methylene chloride:MeOH gradient) to afford ˜350 mg of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-5-((tert-butyldimethylsilyl)oxy)-4,4-dimethylpent-2-enenitrile.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[CH3:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=1[OH:19]>C(#N)C.C(OCC)(=O)C>[CH2:7]([O:19][C:12]1[C:11]([CH3:10])=[C:16]([CH3:17])[CH:15]=[CH:14][C:13]=1[CH3:18])[CH3:8]
Reactant: CCI
Reactant: Cc1ccc(C)c(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOc1c(C)ccc(C)c1C

Procedure:
734 mmol (101.5 g) of potassium carbonate and 917 mmol (143.1 g) of ethyl iodide are added in succession to a solution of 367 mmol (50 g) of 2,3,6-trimethylphenol in 1500 ml of acetonitrile. The whole is heated at reflux for 48 hours. The reaction mixture is subsequently cooled and then filtered and the filtrate is concentrated. The residue obtained is dissolved in ethyl acetate and washed with water and then with 10% aqueous sodium chloride solution. After drying the organic phase and then concentrating, an oily residue is obtained which is purified by chromatography on silica gel, using a petroleum ether: ethyl acetate mixture 95:5 as eluant, to yield the expected product.