Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].CC(C)([O-])C.[Na+].Cl[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].Cl.C>C(OCC)(=O)C.O.CN(C=O)C>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1OCC(F)(F)F
Temperature: 120 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
To a solution of 2,2,2-trifluoroethanol (40.0 g) and DMF (100 ml) was added sodium tert-butoxide (23.0 g) at 0° C. The solution was stirred at 20 to 25° C. for 1 hour at which point 2-chlorobenzoic acid (25.0 g) was added followed by cupric bromide (2.0 g). The mixture was stirred at 120° C. for 5 hours, cooled to 10° C., and water (30 ml) was added followed by 20% HCl solution (90 ml). The solution was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with water (3×50 ml) and the volume was concentrated to 90 ml. Hexane (150 ml) was added to the residues, and the mixture was concentrated to volume of 120 ml and a further portion of hexane (30 ml) was added. The mixture was heated at 50° C. for 30 minutes and then stirred at room temperature for 1 hour. The solids were filtered to yield the crude product. This material was dissolved in ethyl acetate (50 ml), charcoal (1.7 g) was added and the mixture was stirred at room temperature a further 2 hours. The solution was filtered through Celite™ and crystallized from ethyl acetate/hexane to yield the pure product (30.9 g, yield 88.0%) as a white solid, m.p. 85–86° C.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1.[CH2:23]([N:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.O>[CH2:23]([N:30]1[CH2:35][CH2:34][C:33]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)([OH:36])[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(Br)cc1OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A solution of n-butyllithium in hexane (1.56 M, 93.0 mL, 145 mmol) was added dropwise a solution of 4-bromo-1,2-dimethoxybenzene (34.4 g, 158 mmol) in THF (350 ml) under −70° C. and stirred for 30 minutes under argon atmosphere. A solution of 1-benzyl piperidin-4-one (25.0 g, 132 mmol) in THF (50 ml) was added dropwise to the reaction mixture under −60° C., and the mixture was allowed to warm to 0° C. and stirred under ice cooling for 30 minutes. The reaction mixture was diluted with water, concentrated under reduced pressure, and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography and the obtained crystals were washed with hexane to obtain 26.6 g (yield 71%) of the title compound. mp. 112–114° C.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[F:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]O)=[CH:27][CH:26]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:30][CH2:29][C:28]3[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=3)=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:22][CH:23]=1)#[N:2]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1F
Reactant: OCCc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OCCc2ccc(F)cc2)cc1F

Procedure:
In analogy to example 22.1, (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-hydroxy-phenyl)-2-methoxy-acetamide (example 70.4) was reacted with 4-fluorophenethyl alcohol, diethyl azodicarboxylate and triphenyl-phosphine in THF to give (RS)-N-(4-cyano-benzyl)-2-{2-fluoro-4-[2-(4-fluoro-phenyl)-ethoxy]-phenyl}-2-methoxy-acetamide. Colorless oil. MS 437.3 ([M+H]+)
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([S:28]([N:31]([C:41]4[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][CH:50]5[CH2:54][CH2:53][CH2:52][CH2:51]5)=[CH:43][C:42]=4[F:55])[CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)(=[O:30])=[O:29])[CH:24]=3)[CH2:19]2)=O)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].O.[Cl-].[NH4+]>O1CCCC1.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([S:28]([N:31]([C:41]5[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][CH:50]6[CH2:54][CH2:53][CH2:52][CH2:51]6)=[CH:43][C:42]=5[F:55])[CH2:32][C:33]5[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=5)(=[O:29])=[O:30])[CH:24]=4)[CH2:19]3)[CH2:2][CH2:1]2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: COc1ccc(CN(c2ccc(CCCC3CCCC3)cc2F)S(=O)(=O)c2ccc3c(c2)CCN(C(=O)Cc2ccc(C(C)(C)C)cc2)C3)cc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccc(CCCC3CCCC3)cc2F)S(=O)(=O)c2ccc3c(c2)CCN(C2(Cc4ccc(C(C)(C)C)cc4)CC2)C3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tetraisopropyl orthotitanate (97 μL, 0.33 mmol) and ethyl magnesium bromide (diethyl ether solution, 3 mol/L, 0.25 mL, 0.75 mmol) were added to a solution of 2-[(4-tert-butylphenyl)acetyl]-N-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-N-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (213 mg, 0.30 mmol) in tetrahydrofuran (5 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hr. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture and the mixture was stirred and then filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure, 1 mol/mL aqueous sodium hydroxide solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The desiccant was filtered off, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=3:2) to afford 2-[1-(4-tert-butylbenzyl)cyclopropyl]-N-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-N-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as a pale yellow amorphous substance (142 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1>O.C(O)C.[Na].[Hg]>[NH2:1][C:2]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1
Reactant: Nc1ccc(-c2cc(N)nc3ccc(Cl)cc23)cc1
Agent: [Hg]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: NC1=Nc2ccc(Cl)cc2C(c2ccc(N)cc2)C1

Procedure:
6.76 g of sodium amalgam were added over the course of one hour to a solution of 255 mg of 2-amino-6-chloro-4-(4-aminophenyl)quinoline in 3.4 ml of water and 22 ml of ethanol while stirring. The mixture was stirred overnight and decanted off from the Hg precipitate, and the solvent was removed by distillation under reduced pressure. After carrying out an MPLC column chromatography in a mixture of 10 parts by volume of ethyl acetate, 5 parts by volume of methanol, 5 parts by volume of n-heptane, 5 parts by volume of dichloromethane and 1 part by volume of ammonia (concentrated) and acidification with a little concentrated hydrochloric acid, the solvent was removed by distillation and the residue was induced to crystallize with a little ethyl acetate.
Reaction SMILES: [Na].[C:2](=[N:5][N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)([CH3:4])[CH3:3].[BH4-].[Na+]>O1CCCC1.CO>[CH:2]([NH:5][N:6]1[C:10]([SH:11])=[N:9][N:8]=[N:7]1)([CH3:4])[CH3:3]
Reactant: CC(C)=Nn1nnnc1S
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Nn1nnnc1S
Reaction time: 1 h
Yield: 87.3 %

Procedure:
1-Isopropylidenamino-5-mercapto-1H-tetrazole sodium salt (5.37 g) was dissolved in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml), and sodium borohydride (1.14 g) was added gradually thereto at 5°-6° C. under stirring. The mixture was stirred at the same temperature for one hour, and then at room temperature for one hour. The mixture was evaporated to remove solvent, and the residue was dissolved in icewater. The aqueous solution was adjusted to pH 2.8 with 6N-hydrochloric acid, and the solution was extracted with ethyl acetate (20 ml) three times repeatedly. The extracts were washed with a saturated sodium chloride solution, dried and then evaporated to remove solvent. n-Hexane was added to the residue thus obtained, and crystalline precipitates were collected by filtration. 4.14 g of 1-isopropylamino-5-mercapto-1H-tetrazole were obtained as colorless needles. mp 92°-95° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[C:29]([C:31]1([NH:37][C:38]([CH:40]([NH2:48])[CH2:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:39])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)#[N:30]>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:48][CH:40]([C:38](=[O:39])[NH:37][C:31]2([C:29]#[N:30])[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH2:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: N#CC1(NC(=O)C(N)CC2CCCCC2)CCOCC1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)NC(CC2CCCCC2)C(=O)NC2(C#N)CCOCC2)cc1
Reaction time: 0.33 h
Yield: 28.7 %

Procedure:
4-Acetamidobenzoic acid (353 mg, 1.98 mmol), EDC (378 mg, 1.98 mmol), and HOBT (268 mg, 1.98 mmol) were combined in 15 mL of DMF and stirred for 20 min. Solid [1-(4-cyano-tetrahydro-pyran-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amine hydrochloride (625 mg, 1.98 mmol) was added. The reaction was stirred for 16 hours. The volatiles were removed with a pump and the resulting residue was triturated, with rapid stirring, with 250 mL of saturated aqueous sodium bicarbonate. The resulting solid was collected by filtration and washed with 250 mL of water. The solid was dried in vacuo to give the title compound (250 mg); MS, m/z 441=M+1.
Reaction SMILES: C([NH:8][C@H:9]1[C@@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12][CH:10]1[OH:11])C1C=CC=CC=1.[ClH:20]>O.[Pd]>[ClH:20].[OH:11][CH:10]1[O:12][C@H:13]([CH2:18][OH:19])[C@@H:14]([OH:17])[C@H:15]([OH:16])[C@@H:9]1[NH2:8]
Reactant: OC[C@H]1OC(O)[C@@H](NCc2ccccc2)[C@@H](O)[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: O
Product: N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To 12.0 g of N-benzyl-mannosamine of example 2A was added a suspension of 10% Pd/C (0.5 g) in 20 ml water. The pH of the reaction mixture was adjusted to 4-4.5 with 10% HCl solution. The reaction mixture was stirred for 6 hours at 40° C. under H2 pressure (2.5 bar). The pH was then adjusted to 3 with 10% HCl solution. The reaction mixture was kept unstirred overnight so that the catalyst could settle down (the catalyst remains in the reactor). The catalyst was filtered off and washed with a small amount of methanol:water (2:1). The methanol was removed in vacuo and replaced by 15 mL isopropanol. The isopropanol was distilled off and the same procedure was repeated again. To the reaction mixture, 30 ml iPrOH was added and the product crystallized overnight at 4° C. The crystals were filtered and washed with 5-8 mL isopropanol. The wet product was dried at room temperature, to give 8.4 g of D-mannosamine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7]2.S(Cl)(Cl)=O.[F:20][C:21]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:22]=1O.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][C:22]1[C:23]([F:30])=[C:24]([F:29])[C:25]([F:28])=[C:26]([F:27])[C:21]=1[F:20])(=[O:14])=[O:13])=[CH:7]2
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=S(=O)(O)c1ccc2c(Br)cccc2c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)cccc2c1
Reaction time: 2 h
Yield: 66 %

Procedure:
A 15-mL round-bottom flask was charged with 5-bromonaphthalene-2-sulfonic acid (2.346 g, 8.17 mmol) and DMF (8.17 mL) to give a green suspension. Thionyl chloride (1.193 mL, 16.34 mmol) was added dropwise, and the resulting orange mixture was stirred for 2 h. The mixture was poured into ice and extracted with DCM (three times). The combined organic extracts were washed with water, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in DCM (35 mL), and the resulting solution was added to 2,3,4,5,6-pentafluorophenol (2.256 g, 12.26 mmol). Triethylamine (1.708 mL, 12.26 mmol) was added dropwise, and the resulting mixture was stirred for 30 min and then concentrated. The residue was taken up in DCM and filtered. The filtrate was concentrated, and the product was purified by chromatography on silica gel (0 to 20% EtOAc/Heptane) to afford perfluorophenyl 5-bromonaphthalene-2-sulfonate (2.4426 g, 5.39 mmol) as a light-yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.64-8.46 (m, 2H), 8.13-7.95 (m, 3H), 7.63-7.47 (m, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:8][N:9]([C:15]1[C:20]([N+:21]([O-])=O)=[CH:19][N:18]=[C:17]([Cl:24])[N:16]=1)[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][CH3:7])C.Cl>C(O)C>[Cl:24][C:17]1[N:18]=[CH:19][C:20]2[NH:21][C:4](=[O:3])[CH:5]([CH2:6][CH3:7])[CH2:8][N:9]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:15]=2[N:16]=1
Reactant: CCOC(=O)C(CC)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: Cl
Solvent: CCO
Product: CCC1CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Yield: 52.6 %

Procedure:
To a solution of 0.37 g (0.001 mole) of (rac)-2-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-butanoic acid ethyl ester in 5 mL of ethanol was added 0.562 g (0.0025 mole) of stannous chloride dihydrate and 0.1 mL of hydrochloric acid. The mixture was heated to 60 degrees for 2 hrs. The solvent was evaporated under reduced pressure. The residue was taken up in 20 mL of water and extracted with three times with 20 mL of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (100:0-95:5) gave 0.155 g of (rac)-2-chloro-9-cyclopentyl-7-ethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-12) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:13][C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.Cl.[C:15](=O)([O:18]C)[O:16][CH3:17]>>[CH3:17][O:16][C:15]([CH:13]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]1=[O:12])=[O:18]
Reactant: COC(=O)OC
Reactant: O=C1CCCc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCc2ccccc2C1=O
Temperature: 90 °C

Procedure:
A suspension of 60% dispersion of sodium hydride in mineral oil (1.64 g, 41 mmol) in dimethyl carbonate (50 mL) was treated dropwise with alpha-tetralone (4.6 mL, 34 mmol). The mixture was heated at 90° C. for 20 minutes, cooled to ambient temperature, treated with 2 M HCl (40 mL), and extracted with EtOAc (100 mL and 25 mL). The combined EtOAc layers were washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with a gradient of hexane:EtOAc (20:1 and 10:1) to provide the title compound. MS (M+H)+ m/z 205.
Reaction SMILES: [Br:1][C:2]1[C:16]2=[C:17]3[C:5]([NH:6][CH2:7][CH:8]3[CH2:9][C@@H:10]3[C@@H:15]2[CH2:14][C@H:13]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:12][N:11]3[CH3:26])=[CH:4][CH:3]=1.ClOC(C)(C)C.N>O1CCCC1.C(N(CC)CC)C>[Br:1][C:2]1[C:16]2=[C:17]3[C:5]([NH:6][CH:7]=[C:8]3[CH2:9][C@@H:10]3[C@@H:15]2[CH2:14][C@H:13]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:12][N:11]3[CH3:26])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Br)ccc4c3C(CN4)C[C@H]2N(C)C1
Agent: CC(C)(C)OCl
Agent: N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Br)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
A solution of 4.2 g of 3-(12-bromo-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea in a mixture of 300 ml of absolute tetrahydrofuran and 50 ml of absolute triethylamine is combined at -40° C. with a solution of 1.58 ml of tert-butyl hypochlorite in 250 ml of absolute tetrahydrofuran, and the mixture is stirred for 15 minutes at -40° C. The reaction mixture is poured on 1 liter of ice, combined with 25% strength ammonia solution until the reaction is alkaline, and extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated. The crude product is crystallized from ethyl acetate/pentane, thus obtaining 3 g of 3-(12-bromo-6-methyl-8α-ergolinyl)-1,1-diethylurea.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[C:27]4[CH2:28][CH2:29][CH2:30][CH2:31][C:26]=4[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:33])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[C:27]4[CH2:28][CH2:29][CH2:30][CH2:31][C:26]=4[S:25][C:23]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c4c(sc3n2)CCCC4)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3c4c(sc3n2)CCCC4)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-5 ,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[O:4]1.[P:10]([S-:20])([O:16][CH2:17][CH2:18][CH3:19])([O:12][CH2:13][CH2:14][CH3:15])=[S:11].[K+]>CC(C)=O>[P:10]([S:20][CH2:2][N:3]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[O:4]1)(=[S:11])([O:16][CH2:17][CH2:18][CH3:19])[O:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1cc(=O)n(CCl)o1
Reactant: CCCOP(=S)([S-])OCCC
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOP(=S)(OCCC)SCn1oc(C)cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 1.48 g of the 2-chloromethyl-5-methyl-4-isoxazolin-3-one thus obtained in 30 ml of acetone were added 2.52 g of crystalline potassium O,O-di-n-propyl dithiophosphate, and the resulting mixture was then stirred for 1 hour at ambient temperature. The acetone was then evaporated off and the residue was purified by column chromatography through silica gel eluted with a 20:1 by volume mixture of benzene and acetone. There were obtained 2.39 g (73.5% of theory) of O,O-di-n-propyl S-(5-methyl-3-oxo-4-isoxazolin-2-ylmethyl) phosphorodithioate, in the form of a pale yellow oil, n20D =1.5314.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([NH:31][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:6][CH:7]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NCc1ccccc1)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
Into a 4 mL vial is added 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (75 mg, 0.289 mmol), anhydrous pyridine (1 mL) and benzyl isocyanate (0.036 mL, 0.289 mmol). The reaction mixture was stirred at r.t. for 2 days. To the reaction mixture is added H2O to precipitate the product. The solid is filtered and purified by preparative TLC (MeOH/CHCl3 10:90) to give a colorless solid (84.3 mg, 75%). m.p. 163-164° C. (dec). 1H NMR (DMSO & CHCl3) 4.23 (d, 2H), 6.05 (t, 1H), 7.05 (m, 1H), 7.08 (m, 4H), 7.25 (t, 3H), 7.42 (d, 2H), 8.02 (s, 1H); ESIMS: m/z 393 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][NH:28][CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][N:28]([CH3:35])[CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3ccccc3)n12
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CN(C)C5)n4)n3Cc3ccccc3)n12
Reaction time: 0.3 h

Procedure:
To a mixture of {3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (11 mg, 0.026 mmol, from Example 90) in DCM (0.50 mL) was added formaldehyde (10 mg, 0.13 mmol, 37 wt % in water, Aldrich), followed by sodium triacetoxyborohydride (16 mg, 0.078 mmol). The reaction was complete in 18 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded product. Yield: (8.2 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:14]([S:15][CH:14](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:13]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:12]=1[Cl:11])[C:13]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:12]=1[Cl:11]
Reactant: SCc1ccc(Cl)cc1Cl
Reactant: C#Cc1ccc(F)cc1F
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2F)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2Cl)c(F)c1

Procedure:
A solution of 2,4-difluorophenylacetylene (0.02 mol), 2,4-dichlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-difluorostyryl-2,4-dichlorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH3:20])=[CH:7][C:6]=1[C:21](=[O:23])[CH3:22].[CH:24](OCC)=O.Cl>O.COCCOC>[CH2:12]([O:11][C:9]1[CH:10]=[C:5]2[C:6]([C:21](=[O:23])[CH:22]=[CH:24][NH:4]2)=[CH:7][C:8]=1[O:19][CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC=O
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A mixture of sodium methylate (270 mmol, 14.75 g, favorable prepared from sodium metal and methanol before use), 1,2-dimethoxyethane (122 ml) and 1-(2-amino-4-benzyloxy-5-methoxy-phenyl)-ethanone (6.68 g 24 mmol) was stirred at 0° C. for 1 hour. Ethyl formate (10.7 ml, 9.81 g, 132 mmol) was added to the reaction mixture, that was allowed to come to room temperature and stirred for further 4 hours. The mixture was diluted with water (50 ml) and acidified to pH 1 by adding hydrochloric acid (1N, 185 ml). The precipitate was filtered, washed with water and dried to give 6.51 g of product [D]. Yield: 94%.