Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)=O)=[CH:6][CH:5]=[C:4]([C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]2)[N:3]=1.C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:9]3[S:1][C:2]4[C:7]([N:8]=3)=[CH:6][CH:5]=[C:4]([C:20]3([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:22][CH2:21]3)[N:3]=4)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: O=C(Nc1ccc(C2(c3ccccc3)CC2)nc1S)c1ccc2[nH]ccc2c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(C2(c3ccc4nc(-c5ccc6[nH]ccc6c5)sc4n3)CC2)cc1
Temperature: 100 °C

Procedure:
To N-(2-mercapto-6-(1-phenylcyclopropyl)pyridin-3-yl)-1H-indole-5-carboxamide (360 mg, 0.934 mmol) was added toluene (9.3 mL) and camphor sulfonic acid (195 mg, 0.841 mmol) before it was heated to 100° C. for 16 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 1 time with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after after flash chromatography. MS (ESI) m/z: Calculated: 367.1; Observed: 368.1 (M++H).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>ClCCl>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:17][C:18]3[CH:22]=[CH:21][S:20][C:19]=3[C:23]([O:25][CH3:26])=[O:24])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1ccc(C2CCCCC2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
To a solution of 4-cyclohexylbenzene-1-sulfonyl chloride (0.45 g; 1.74 mmol) in dichloromethane (4.0 mL) at room temperature, methyl 3-aminothiophene-2-carboxylate (0.25 g; 1.6 mmol) was added followed by pyridine (0.25 g; 3.2 mmol) and then stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and then taken up in ethyl acetate (50 mL) and extracted with water. The aqueous layer separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 900 mL gradient elution) to give the title product as an off-white solid (0.55 g).
Reaction SMILES: [OH2:1].[CH2:2](O)[CH2:3][CH2:4][CH2:5][OH:6]>C1COCC1>[CH3:2][CH2:3][CH2:4][CH2:5][O:1][C@H:4]([CH2:5][OH:6])[CH2:3][CH3:2]
Reactant: O
Reactant: OCCCCO
Solvent: C1CCOC1
Product: CCCCO[C@@H](CC)CO
Reaction time: 4 h

Procedure:
Polymerization was carried out by using the continuous polymerization device as shown in FIG. 3. First, into a 300 ml of polymerization tank 1 having a stirring means and a reflux condenser was charged 200 g of 12-tungstophosphoric acid having a coordinated water number of 3.5 (H3PW12O40.3.5H2O). 150 g of a monomer mixture containing THF and 1.8 wt. % of 1,4-butane diol was added thereto, and the mixture was stirred. By setting the polymerization tank temperature at 60° C., stirring was continued in a nitrogen atmosphere for 4 hours and feeding of a mixture containing THF and 1.8 wt. % of 1,4-butane diol was commenced at the rate of 32 ml/Hr. The reaction was carried out while circulating the liquid from the lower layer in the phase separation tank 2 to the reaction tank and removing the upper layer after phase separation by allowing it to overflow. From the upper layer liquid overflown, unreacted THF was removed by distillation to obtain PTMG. Substantially no unreacted 1,4-butane diol was detected. After continuous running for 100 hours, 850 g of PTMG having a number average molecular weight of 1750 was obtained.
Reaction SMILES: [OH-].[K+].[CH3:3]I.[CH2:5]([N:8]1[C@H:22]2[C@@H:12]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:23]=3[C:20]([CH2:21]2)=[CH:19][NH:18]4)[CH2:11][C@H:10]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=2)[CH2:9]1)[CH2:6][CH3:7].O>CS(C)=O>[CH3:3][N:18]1[C:17]2[C:23]3[C:20]([CH2:21][C@@H:22]4[C@@H:12]([C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[O:32][CH2:31][CH2:30][C:29]=3[CH:33]=2)[CH2:9][N:8]4[CH2:5][CH2:6][CH3:7])=[CH:19]1
Reactant: CCCN1C[C@@H](Nc2ccc3c(c2)CCO3)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCN1C[C@@H](Nc2ccc3c(c2)CCO3)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21
Reaction time: 5 h

Procedure:
696 mg finely powdered KOH and 0.77 ml methyliodide are added to 4.1 g 6-n-propyl-8α-(2,3-dihydro-5-benzofuranylamino)-ergoline (example 9) in 25 ml dimethylsulfoxide. The reactive mixture is stirred for 5 hours, poured onto 150 ml H2O, extracted with ethyl acetate, dried over Na2SO4 and concentrated. The residue is chromatographed on 100 g silica gel using methylene chloride/methanol (98:2) as eluant. M.P.=137°-138° C.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[C:23]([O:35]CC2C=CC=CC=2)[CH:22]=1)[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1.[H][H]>CO.[C].[Pd]>[ClH:1].[OH:2][CH:3]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:35])[CH:22]=1)[CH2:4][N:5]1[CH2:6][CH2:7][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=c1[nH]c2ccccc2n1C1CCN(CC(O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=c1[nH]c2ccccc2n1C1CCN(CC(O)c2ccc(O)c(O)c2)CC1
Yield: 95 %

Procedure:
2.31 g of 1-[2-hydroxy-2-(3,4-dibenzyloxyphenyl)-1-ethyl]-4-(2-keto-1-benzimidazolinyl)-piperidine hydrochloride is dissolved in 250 ml of methanol. 0.3 g of palladium carbon (10%) is added thereto, and the mixture is vigorously shaked in a hydrogen stream under atmospheric pressure. After discontinuation of the absorption of hydrogen, the catalyst is filtered off, and the mother liquor is concentrated. To the residual syrup is added ethyl acetate, and the mixture is well stirred. The mixture is filtered to obtain powdered product, and the product is washed with ethyl acetate and dried to obtain 1.52 g of 1-[2-hydroxy-2- (3,4-dihydroxyphenyl)-1-ethyl]-4-(2-keto-1-benzimidazolinyl)-piperidine hydrochloride as amorphous powder. When subjected to thin layer chromatography using a lower layer of a mixture of chloroform/methanol/acetic acid/water (10/10/1/10), this product provides single spot at Rf =0.15.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(I)cc2)c1Br
Yield: 65 %

Procedure:
4-Iodo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 4-iodobenzenesulfonyl chloride according to the procedures described in Example 1b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a yellow powder, m.p. 166°-173° C., yield 65 %.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[N:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)=[C:8]([F:22])[CH:7]=1>C(O)=O>[F:22][C:8]1[CH:7]=[C:6]([CH:2]=[O:1])[CH:21]=[CH:20][C:9]=1[O:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C3OCCO3)cc2F)cn1
Solvent: O=CO
Product: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
Combine formic acid (90%, 453 mL) and crude 5-(4-[1,3]dioxolan-2-yl-2-fluorophenoxy)pyrazine-2-carboxamide (Example 737, Part D) (32.81 g, approximately 0.09 mole) and stir initially a clear yellow solution, which becomes a thick slurry in an hour at room temperature. Stir overnight at room temperature till the reaction complete by HPLC. Quench the reaction with deionized water (1 L) and extract with dichloromethane (4×4 L). Combine the extracts and mix with aqueous sodium bicarbonate solution. Concentrate on a rotary evaporator to give a slurry of a solid in water (when the separation of layers not possible). Extract the mixture with ethyl acetate (4×1 L) and concentrate the combined extracts to a yellow solid (29.65 g). Form slurries successively four times with boiling methanol (1 L) and filter while hot. Combine the filter cakes and dissolve in enough boiling methanol to give a clear solution. Concentrate the solution to approximately 1 liter and allow to crystallize at 0° C. Filter the resulting slurry at 0° C. and dry the filter cake under vacuum at room temperature to give the title compound (17.79 g, 75.7%). 1H NMR (DMSO-d6) δ 7.70 (t, 1H, ArH), 7.78 (s, 1H. HetH), 7.86-7.93 (m, 2H, ArH), 8.14 (s, 1H, HetH), 8.73 (d, 2H, amide), 10.0 S, 1H, CHO); 13C NMR (DMSO-d6) δ 116.884, 124.606, 126.980, 133.186, 134.967, 140.765, 144.016, 152.493, 154.974, 159.276, 164.057, 190.777; MS (ES+) m/z 262.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13]C)=[O:11])=[C:6](OCC)[CH:5]=1)([O-])=O.[Mg].[C:21](OCC)(=[O:23])[CH3:22]>CO>[CH2:21]([O:23][CH:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])[CH3:22]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1OCC
Reactant: CCOC(C)=O
Agent: [Mg]
Solvent: CO
Product: CCOC(Cc1ccc(N)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
Ethyl 4-nitro2-ethoxycinnamate (10 g, 1 eq, 37.7 mmol) obtained in step (i) of preparation 1, was treated with activated magnesium turnings (18 g, 20 eq, 754 mmol) in dry methanol (400 ml). The reaction mixture was refluxed for 2-3 h, and allowed to stir at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and quenched with cold aqueous ammonium chloride. The organic layer was washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to afford the title compound as liquid (6 g, yield 72%).
Reaction SMILES: [F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[C@H:17]12[CH2:23][C@H:20]([NH:21][CH2:22]1)[CH2:19][N:18]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:21]2[CH2:22][C@@H:17]3[CH2:23][C@H:20]2[CH2:19][N:18]3[CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Reactant: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3Cc2ccc(OCC(F)(F)C(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
4-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde (250 mg, 1.06 mmol) and methyl 4-[[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate (260.7 mg, 1.06 mmol) were dissolved in dichloromethane (5.9 mL). After 15 min, sodium triacetoxyborohydride (448.7 mg, 2.12 mmol) was added. The reaction mixture was stirred overnight at room temperature. Then, saturated sodium bicarbonate solution was added. The mixture was stirred for 30 min and then extracted with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 177 mg of methyl 4-[[(1S,4S)-5-[[4-(2,2,3,3-tetrafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate; 1H NMR (300 MHz, CDCl3) δ 7.98 (d, 2H), 7.43 (d, 2H), 7.31 (d, 2H), 6.87 (d, 2H), 6.07 (tt, 1H), 4.33 (tt, 2H), 3.91 (s, 3H), 3.81 (d, 1H), 3.76 (d, 1H), 3.71 (d, 1H), 3.64 (d, 1H), 3.28 (br s, 2H), 2.84 (d, 2H), 2.65 (dd, 2H), 1.74 (s, 2H) ppm.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].O>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]2[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]=1[CH2:2][N:20]1[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]2[C:16]1=[O:26]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc2c([N+](=O)[O-])cccc2c1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
A mixture of 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (410 mg) and potassium phthalimide (506 mg) in N,N-dimethylformamide (10 ml) was stirred at ambient temperature for 3 hours. Then, the mixture was poured into cold water and the separated solid was collected, washed with water and dried to give 2-methyl-7-nitro-3-phthalimidomethylbenzo[b]furan (585 mg).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:15]([N:16]([CH:18]([CH3:20])[CH3:19])[CH3:17])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:21]([O:23]C)=[O:22])[CH:12]=3)[N:7]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2.[OH-].[Na+].O>O1CCCC1>[S:1]1[C:5]([C:6]2[C:15]([N:16]([CH:18]([CH3:20])[CH3:19])[CH3:17])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:21]([OH:23])=[O:22])[CH:12]=3)[N:7]=2)=[CH:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2
Reactant: COC(=O)c1ccc2nc(-c3cc4ccccc4s3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of methyl 2-(benzo[b]thiophen-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140 mg, 0.36 mmol) in tetrahydrofuran (25 mL) was added sodium hydroxide (43.2 mg, 1.08 mmol) and water (2 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (3 N). The solids were collected by filtration to afford 2-(benzo[b]thiophen-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (80 mg, 59%).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH2:31][C:32](=[O:38])[NH:33]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[CH:37][C:29]=4[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:22]=4[F:21])[NH:33][C:32]3=[O:38])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(-c5cccc(F)c5F)c43)c(C)c2C1=O
Yield: 22 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 5-(2-diethylamino-ethyl)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (20 mg, 22.0%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-])=O.O1CCCC1>Cl.O>[NH2:15][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9][C:8]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c([N+](=O)[O-])ccc2c1CCC(=O)CC2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1c(N)ccc2c1CCC(=O)CC2
Temperature: 25 °C
Reaction time: 36 h
Yield: 48.7 %

Procedure:
To a stirred solution of 1-methoxy-2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (400 mg, 0.002 mol) in tetrahydrofuran (10 mL, 0.1 mol) was added dichlorodihydrostannane (600 mg, 0.003 mol) in 12 M of hydrogen chloride in water (8 mL) over 15 min. The mixture was stirred at room temperature for 36 h. The reaction mixture was concentrated in vacuo, diluted with water (4 mL) and made basic with 10 N NaOH. A solid precipitated out of solution and was removed by filtration through celite. The solid was washed with chloroform and the organic layer dried over magnesium sulfate, filtered and concentrated in vacuo to a yellow solid. The solid was triturated with diethyl ether and collected by filtration to give 2-amino-1-methoxy-5,6,8,9-tetrahydrobenzocyclohepten-7-one as a tan solid (200 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 6.82 (d, 1H, J=7.8 Hz), 6.61 (d, 1H, J=7.8 Hz), 3.77 (broad s, 2H), 3.72 (s, 3H), 2.96 (m, 2H), 2.81 (m, 2H), 2.58 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:64])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:35][CH:34]=1>CN(C=O)C>[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:64][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:37][CH:38]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C

Procedure:
Analogously to Example 7, 106 mg (0.56 mmol) of N-methoxycarbonyl-(L)-iso-leucine, 201 mg (1.05 mmol) of EDC and 95 mg (0.7 mmol) of HOBT in 4.6 ml of DMF and 293 μl (2.1 mmol) of TEA are reacted with 0.35 mmol of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5 (S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane to form the title compound: m.p: 227°-229° C.; HPLC20-100 : tRet =14.5; FAB MS (M+H)+ =697.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[S:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[BH4-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=S)N1c1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Product: O=C1C2=C(CCCC2)C(S)N1c1ccc(Br)cc1F
Yield: 81.2 %

Procedure:
By the same procedure as described in Method (a) of Example 1, 55.0 g of 2-(4-bromo-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-thioxo-1H-isoindol-1-one was reduced with 18.0 g of sodium borohydride, thereby affording 44.9 g (yield of 81%) of the subject compound. Recrystallization from ethanol yielded white crystals, m.p. 87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH3:11][C:12]1([NH2:15])[CH2:14][CH2:13]1.C[O-].[Na+]>CN1C(=O)CCC1.O>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:15][C:12]2([CH3:11])[CH2:14][CH2:13]2)[CH:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC1(N)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1(Nc2cc(Cl)nc(N)n2)CC1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
2-amino-4,6-dichloropyrimidine (508 mg, 3.1 mmol) was added to a suspension of 1-methylcyclopropylamine hydrochloride (1.0 g, 9.3 mmol) and sodium methoxide (502mg, 9.30 mmol) in NMP (3 ml). The resulting mixture was heated at 90° C. for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water (20 ml) and the resulting precipitate filtered off, washed with further water (20 ml) and dried in vacuo to give the title compound as a colourless solid (280 mg, 15%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.C(N(CC)CC)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O:1][CH2:2][CH2:3][CH:4]([NH:14][C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(NC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.4 %

Procedure:
To a solution of tert-butyl [3-hydroxy-1-(3-nitrophenyl)propyl]carbamate (4.00 g; 13.50 mmol; 1.00 eq.) in anhydrous DCM (15 mL) and N,N-diethylethanamine (2.82 ml; 20.25 mmol; 1.50 eq.) at 0° C. was added dropwise 4-methylbenzenesulfonyl chloride (3.09 g; 16.20 mmol; 1.20 eq.). The mixture was stirred at room temperature for 15 h. After workup, the crude product was purified by flash chromatography on silica gel (EtOAc:Hex from 10:90 to 20:80) to provide 5.5 g of the 3-[(tert-butoxycarbonyl)amino]-3-(3-nitrophenyl)propyl 4-methylbenzenesulfonate.
Reaction SMILES: [H][H].[F:3][C:4]([F:30])([F:29])[C:5]1[CH:28]=[CH:27][C:8]2[NH:9][C:10]([C:12]3[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17](=[N:25]O)[C:16]=4[CH:15]=[CH:14][CH:13]=3)=[N:11][C:7]=2[CH:6]=1>C(O)C.O1CCCC1.[Ni]>[F:30][C:4]([F:3])([F:29])[C:5]1[CH:28]=[CH:27][C:8]2[NH:9][C:10]([C:12]3[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:17]([NH2:25])[C:16]=4[CH:15]=[CH:14][CH:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(C(F)(F)F)ccc2[nH]1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4cc(C(F)(F)F)ccc4[nH]3)cccc21
Yield: 81.6 %

Procedure:
The procedure used in Example 6 is followed. In a 528 ml autoclave, dissolve 2.2 g of 4-(5-trifluoromethyl-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 80 ml of ethanol and 80 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to an initial hydrogen pressure of 1 bar and heat the autoclave at 600 for 4 hours. After cooling, the volume of hydrogen absorbed is 412 ml. After filtration of the catalyst over Celite, concentrate under reduced pressure. In this way, we obtain 1.73 g of 4-(5-trifluoromethyl-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine, in the form of a grey foam with the following characteristics: