Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH3:29])[N:17]=[C:16]([NH2:30])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:28][C:25]1[N:24]=[CH:23][C:22]([C:21]#[C:20][C:19]2[C:18]([CH3:29])=[N:17][C:16]([NH2:30])=[N:15][C:14]=2[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:27][CH:26]=1
Reactant: Cc1nc(N)nc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(C2=CCNCC2)c1C#Cc1ccc(N)nc1
Reaction time: 3 h
Yield: 55.3 %

Procedure:
630 mg (1.5 mmol) of 4-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester are dissolved in DCM (40 mL) and 2 mL TFA are added. The reaction mixture is stirred for 3 h, concentrated aqueous Na2CO3 solution is added until pH 7 is reached and DCM is evaporated at reduced pressure. The residue is washed with water, taken up in acetonitrile and freeze dried yielding 253 mg (0.83 mmol) of the desired product which is used for the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15](O)=[O:16])=[C:11]([CH3:18])[N:10]=[C:9]1[C@@:19]([N:23]([CH2:33][CH2:34][CH2:35][NH:36]C(OC(C)(C)C)=O)[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)=[O:25])([CH3:22])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:58]([NH2:60])[CH3:59].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[CH2:58]([NH:60][C:15]([C:12]1[C:13](=[O:14])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([C@@:19]([N:23]([CH2:33][CH2:34][CH2:35][NH2:36])[C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[O:25])([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=1[CH3:18])=[O:16])[CH3:59]
Reactant: CCN
Reactant: CC[C@](C)(c1nc(C)c(C(=O)O)c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCNC(=O)c1c(C)nc([C@@](C)(CC)N(CCCN)C(=O)c2ccc(C)cc2)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of 1-benzyl-2-{(R)-[(3-tert-butoxycarbonylamino-propyl)-(1-p-tolyl-methanoyl)-amino]-methyl-propyl}-4-methyl-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid (100 mg, 0.169 mmol) in CH2Cl2 (1.7 mL) was added EDC (36 mg, 0.186 mmol), HOBt (25 mg, 0.186 mmol), TEA (28 uL, 0.203 mmol) followed by ethylamine (85 uL of a 2.0M solution in THF, 0.169 mmol). The reaction mixture was stirred at ambient temperature for 16 h, then TFA (1 mL) was added. After 3 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to give 47 mg (53%) of 2-{(R)-[(3-amino-propyl)-(1-p-tolyl-methanoyl)-amino]-methyl-propyl}-1-benzyl-4-methyl-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid ethylamide as a pale yellow solid: MS (ES) m/e 518.4 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][NH2:15].O>CCCCO>[F:11][C:10]([F:12])([F:13])[C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:15][N:14]=[C:4]2[NH2:5]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 25 °C

Procedure:
2-Fluoro-5-trifluoromethyl-benzonitrile (2.66 g) was dissolved in n-BuOH (51 ml) prior to the addition of NH2NH2.H2O (1.02 ml). The solution was heated to reflux for 30 min. After cooling to rt, the solution was concentrated and CH2Cl2 was added. The organic layer was washed with H2O, brine, dried, filtered, and concentrated in high vacuum to give 5-trifluoromethyl-1H-indazol-3-ylamine (2.25 g): 1H NMR (DMSO, δppm, 300 mHz) 5.70 (s, br, 2H), 7.40 (dd, 2H), 8.20 (s, 1H), 11.90 (s, br, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][N:6]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[N:9]2[CH:22]=[C:23]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[N:27]([S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)(=[O:36])=[O:35])[CH:26]=3)[CH:24]=[C:8]2[C:7]1=[O:43]>C(Cl)Cl.CO.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:10]2[N:9]3[CH:22]=[C:23]([C:25]4[C:33]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[N:27]([S:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)(=[O:35])=[O:36])[CH:26]=4)[CH:24]=[C:8]3[C:7](=[O:43])[N:6]([CH2:5][C:4]3[CH:44]=[CH:45][C:46]([O:48][CH3:49])=[CH:47][C:3]=3[O:2][CH3:1])[CH:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(Cn2cc(Cc3ccc([N+](=O)[O-])cc3)n3cc(-c4cn(S(=O)(=O)c5ccccc5)c5ncccc45)cc3c2=O)c(OC)c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Cn2cc(Cc3ccc(N)cc3)n3cc(-c4cn(S(=O)(=O)c5ccccc5)c5ncccc45)cc3c2=O)c(OC)c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 23H (6 g, 8.89 mmol) in a mixture of CH2Cl2 (400 mL) and CH3OH (50 mL) was added 10% Pd/C (0.8 g) under nitrogen. The reaction mixture was purged with H2, and stirred under hydrogen (40 psi) overnight. The solid material was filtered off, and the filtrate was concentrated to afford the title compound. LC-MS (ESI): m/z 646 (M+H), RT: 1.87 minutes.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]2[C:15]3=[C:16]4[C:21](=[CH:22][CH:23]=[C:14]3[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:12]2=[O:33])[N:20]=[CH:19][CH:18]=[CH:17]4)=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[C:34]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:13]2[C:14]3[C:15](=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[C:11]3([CH2:34][O:1][C:2]4[CH:3]=[C:4]5[C:5](=[CH:9][C:10]3=4)[CH2:6][CH2:7][O:8]5)[C:12]2=[O:33])=[CH:26][CH:27]=1
Reactant: COc1ccc(CN2C(=O)C(c3cc4c(cc3O)OCC4)c3c2ccc2ncccc32)cc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3c2ccc2ncccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 3′-(4-methoxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,1′-pyrrolo[3,2-f]quinolin]-2′(3′H)-one was obtained (9%) as a yellow solid: mp 169-170° C.; 1H NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 8.10 (m, 1H), 7.92 (m, 1H), 7.43-7.28 (m, 4H), 6.92-6.86 (m, 2H), 6.51 (s, 1H), 6.44 (s, 1H), 5.17-5.06 (m, 2H), 4.97-4.88 (m, 2H), 4.58-4.49 (m, 2H), 3.79 (s, 3H), 3.09-2.82 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 179.1, 162.2, 161.0, 159.3, 148.0, 144.6, 140.2, 130.9, 128.8, 127.8, 127.6, 124.8, 122.4, 120.4, 119.8, 118.9, 114.4, 113.9, 93.4, 79.6, 72.4, 58.5, 55.3, 43.9, 29.0; MS (ES+) m/z 451.0 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.C(=[NH:32])(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([NH2:32])[N:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccc2nc(N)cnc21
Temperature: 130 °C
Reaction time: 12 h
Yield: 113.5 %

Procedure:
A mixture of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (3.25 g, 10 mmol) sodium t-butoxide (0.600 g, 6.25 mmol), and BINAP (0.170 g, 0.27 mmol) in 120 mL of toluene was purged with nitrogen for ca. 20 min. Pd2(dba)3 (0.080 g, 0.077 mmol) and benzophenone imine (2.16 mL, 12.9 mmol) were added, and the mixture was stirred at 130° C. for 12 h. The mixture was filtered through Celite and concentrated. The resulting residue was dissolved in 50 mL of methanol. Sodium acetate (4.93 g, 36 mmol) and hydroxylamine hydrochloride (2.09 g, 30 mmol) were added, and the mixture was stirred for 45 min. then concentrated. The resulting residue was partitioned between a 0.1 M NaOH solution and dichloromethane, and the organic layer was dried over Na2SO4, filtered and concentrated to a residue. Column chromatography afforded 3.0 g (75%) of 5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine.
Reaction SMILES: [Cl:1][C:2]1[C:11](F)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[C:13]([O:17][C:18](=[O:27])[NH:19][C@H:20]1[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:27])[NH:19][C@H:20]1[CH2:21][CH2:22][C@@H:23]([O:26][C:11]2[C:2]([Cl:1])=[C:3]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[N:6][CH:5]=[CH:4]3)[CH2:24][CH2:25]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: Fc1ccc2cnccc2c1Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2ccc3cnccc3c2Cl)CC1

Procedure:
Starting from 5-chloro-6-fluoro-isoquinoline (8) and cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester the title compound was prepared by the method described for trans-[4-(5-chloro-isoquinolin-6-yloxy)-cyclohexyl]carbamic acid tert-butyl ester (10), whereas DMF was used as solvent. Rt=1.14 min (Method #4). Detected mass: 377.2/379.2 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1>C(O)C>[Cl:4][C:5]1[N:6]=[C:7]([N:2]([CH3:3])[CH3:1])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1nc(Cl)nc2ccsc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
To a solution of 50% aqueous dimethyl amine (0.77 g) in ethanol (30 mL) was added 2,4-dichlorothieno[3,2-d]pyrimidine (1.00 g) with ice cooling, and the mixture was stirred for 12 h while heating to room temperature. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine, then the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was crystallized with diethyl ether to obtain 2-chloro-N,N-dimethylthieno[3,2-d]pyrimidin-4-amine (0.90 g). (2) A mixture of 2-chloro-N,N-dimethylthieno[3,2-d]pyrimidin-4-amine (0.60 g), (S)-1-(3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (2.70 g), N,N-diisopropylethylamine (1.80 g), and ethylene glycol (18 mL) was heated at 110° C. for 20 h with stirring. The reaction mixture was diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, chloroform/methanol) and crystallized with diethyl ether to obtain white solid (S)-1-(3-(4-dimethylaminothieno[3,2-d]pyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:33]=[CH:32][C:15]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[CH:29]=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:14][CH:13]=1>C(Cl)Cl>[CH:31]1[CH:30]=[CH:29][N:21]2[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:18]([C:16]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:33][CH:32]=3)=[O:17])[CH2:19][C:20]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1Cl
Reaction time: 0.05 h
Yield: 72.1 %

Procedure:
To a solution of 347 mg of 2-chlorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamineo After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give a residue which is crystallized from methylene chloride to give 525 mg of the desired product as a white crystalline solid, m.p. 228°-230° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[C:23]12[CH2:30][NH:29][CH2:28][C:27]=1[CH2:26][NH:25][CH2:24]2.C(N(C(C)C)CC)(C)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:25]4[CH2:26][C:27]5[CH2:28][NH:29][CH2:30][C:23]=5[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1NCC2=C1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Temperature: 25 °C
Yield: 85.8 %

Procedure:
The suspension of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (14.7 g), 3,7-diazabicyclo[3.3.0] oct-1(5)-ene dihydrobromide (14.1 g) and diisopropyl-ethylamine (45 ml) in acetonitrile (1 l) was refluxed for 5 hours. The reaction mixture was cooled to room temperature and the produced precipitate was filtered and then washed with acetonitrile (200 ml) and water (200 ml) successively. Vacuum drying gave the title compound (16.6 g, yield 85%).
Reaction SMILES: [C:1]1([N+:7]#[N:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N=NN>>[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:8]=[N:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: N#[N+]c1ccccc1
Agent: N=NN
Product: Nc1ccccc1N=Nc1ccccc1

Procedure:
In the examples which follow, the yield of benzenediazonium salt was determined by reacting the benzenediazonium solution with aniline and then rearranging the intermediate triazene to give aminoazobenzene. Thus, the solution containing the diazonium salt was charged into a mixture containing aniline, in large excess (5 to 7 times the theoretical amount), aniline hydrochloride, in half the stoichiometric amount relative to the aniline, and water. The mixture was maintained at 50° C. and aminoazobenzene (ortho and para isomers) was obtained very rapidly in quantitative yield. The excess aniline hydrochloride was then neutralized, the aniline and the aminoazobenzene were extracted with ethyl acetate, and the ethyl acetate and the aniline were distilled. This yields crude aminoazobenzene (ortho+para), the composition of which was determined by vapor phase chromatography.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C=CC(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([O:29][CH3:30])[CH:22]=1.CO>COCCOC>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][C:16]#[N:17])=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: COc1cc(Br)ccc1C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: COc1cc(Br)ccc1CC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of potassium tert-butoxide (6.5 g, 0.058 mol) in 1,2-dimethoxyethane (150 mL) was added p-toluenesulfonylmethyl isocyanide (5.6 g, 0.029 mol) portionwise at −78° C. Then a solution of 4-bromo-2-methoxybenzaldehyde (6.3 g, 0.029 mol) in 1,2-dimethoxyethane was added dropwise and the reaction mixture was warmed to room temperature. The mixture was stirred at room temperature for 1 hour and methanol (150 mL) was added, then heated to reflux and stirred for 2 hours. Solvent was evaporated, and saturated ammonium chloride (100 mL) was added and extracted with ethyl acetate (100 mL×2). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to give a residue, which was purified by combiflash (Petroleum ether/EtOAc=10:1 to 5:1) to give the title compound (5.4 g, 82%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.25 (d, 1H), 7.12 (d, 1H), 7.03 (s, 1H), 3.87 (s, 3H), 3.63 (s, 2H)
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14][CH3:15])[C@@H:10]([OH:16])[CH2:9]1)=O)(C)(C)C.[ClH:17]>CO>[ClH:17].[OH:16][C@@H:10]1[C@@H:11]([CH2:13][CH2:14][CH3:15])[CH2:12][NH:8][CH2:9]1
Reactant: CCC[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1O
Agent: Cl
Solvent: CO
Product: CCC[C@H]1CNC[C@@H]1O
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
The synthesis of this compound follows the same general route outlined in scheme 5 [see Preparative Example 2.01]. To a suspension of ethyltriphenylphosphonium bromide (2.9 g, 6.93 mmol) in dry THF (15 mL) under argon at 0° C. was added 1.6 M BuLi in THF (4 mL, 6.40 mmol) and the deep red solution left stirring without cooling for 10 min. After re-cooling to 0° C., the aldehyde 46 (580 mg, 2.69 mmol) in THF (10 mL) was added and the mixture stirred at r.t. for 12 h. The reaction was then quenched with water (1 mL) and extracted with dichloromethane (100 mL). The organic phase was washed with sat. aq. NaHCO3 (15 mL) then water (15 mL), dried over MgSO4) and concentrated in vacuo. The residue was subjected to chromatography to afforded (3R,4S)-N-tert-butoxycarbonyl-3-hydroxy-4-propenyl-pyrrolidine (50) as a light yellow syrup (165 mg, 27%). To a solution of intermediate 50 (165 mg, 0.73 mmol) in ethanol (10 mL) was added 10% Pd/C (60 mg) and the suspension was stirred under an atmosphere of hydrogen for 3 h. After filtration, the solvent was removed in vacuo to give (3R,4S)-N-tert-butoxycarbonyl-3-hydroxy-4-propyl-pyrrolidine (51) as a syrup (172 mg, 102%). 1H NMR (300 MHz, CDCl3): δ ppm: 3.98-3.96 (m, 1H), 3.61-3.57 (m, 3H), 3.22-3.18 (m, 1H), 3.10-3.01 (m, 1H), 2.03 (m, 1H), 1.45 (s, 9H), 1.41-1.31 (m, 2H), 1.24-1.12 (m, 1H), 0.94-0.89 (m, 3H). 13C NMR (300 MHz, CDCl3): δ ppm (note that some peaks are doubled due to slow conversion of rotamers): 155.20, 79.69, (75.53, 74.76), (53.10, 52.80), (49.94, 49.38), (46.19, 45.67), 34.04, 28.83, 21.27, 14.47. To a solution of intermediate 51 (172 mg, 0.75 mmol) in methanol (10 mL) was added 12N (conc.) HCl (4 mL) and the solution stirred at 40° C. for 30 min. After removal of the solvent in vacuo and azeotroping with toluene, the crude title compound (3R,4S)-3-hydroxy-4-propyl-pyrrolidine hydrochloride (52) was obtained as a syrup (138 mg, 0.83 mmol, 111%). 1H NMR (300 MHz, MeOH-d4): δ ppm: 4.20-4.16 (m, 1H), 3.59-3.52 (m, 1H), 3.44-3.39 (m, 1H), 3.19-3.14 (m, 1H), 3.05-2.99 (m, 1H), 2.23-2.17 (m, 1H), 1.55-1.28 (m, 4H), 0.98-0.94 (m, 3H). 13C NMR (300 MHz, MeOH-d4): δ ppm: 75.65, 52.82, 50.30, 47.45, 34.69, 22.30, 14.78.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[Cl:11]Cl.N>CC(O)=O>[Cl:11][C:3]1[C:4]2[NH:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: ClCl
Agent: N
Solvent: CC(=O)O
Product: Nc1ccc2nc[nH]c2c1Cl

Procedure:
To a solution of 5-aminobenzimidazole (1.0 g, 7.5 mmol) in 20 ml of AcOH was added Cl2 saturated AcOH solution until it produced a precipitation. The reaction mixture was concentrated in vacuo, yielding a dark residue which was subjected to column chromatography (NH3 sat'd 30% MeOH/EtOAc) to yield 120 mg (0.72 mmol) of 4-chloro-5-aminobenzimidazole.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[C:4]([NH:8][S:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1Cl)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:4]([NH:8][S:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[S:3][CH2:1][CH3:2])(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCS
Reactant: CC(C)(C)NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Reaction time: 3 h

Procedure:
5.6 ml of ethylmercaptan are added to a suspension of 20.0 g of N-tert-butyl-2-chloro-5-nitrobenzenesulfonamide, 18.9 g of potassium carbonate and 100 ml of DMF at room temperature. After the mixture has been stirred for 3 hours, it is concentrated under a high vacuum. The residue is taken up in water and acidified with concentrated hydrochloric acid (pH 1 to 2). The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and then concentrated under reduced pressure. 21.25 g of the desired ethylmercaptan are thus obtained; melting point: 172° to 174° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].C(N(CC)CC)C.[Cl-].[CH3:21][O:22][C:23](=[O:28])[CH2:24][C:25](O)=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][N:6]([C:25](=[O:26])[CH2:24][C:23]([O:22][CH3:21])=[O:28])[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCNCC(=O)OC
Reactant: COC(=O)CC(=O)O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCN(CC(=O)OC)C(=O)CC(=O)OC

Procedure:
Analogously to the procedure described in Example 1(a), from 35.0 g (0.2 mol) of N-(methoxycarbonylmethyl)-β-aminopropionic acid methyl ester, 33 ml (0.24 mol) of triethylamine and 36.2 g (0.24 mol) of malonic acid monomethyl ester chloride in 60 ml of methylene chloride there is obtained N-methoxycarbonylacetyl-N-methoxycarbonylmethyl-β-aminopropionic acid methyl ester in the form of a yellowish oil.
Reaction SMILES: [C:1]1([N:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)NN(c2ccccc2)C1c1ccccc1
Solvent: CC(=O)O
Product: c1ccc(-c2cc(-c3ccccc3)n(-c3ccccc3)n2)cc1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
1,3,5-Triphenylpyrazoline (300 mg, 1.01 mmol), 150 mg of an oxidation catalyst and acetic acid (3.5 ml) were charged into a 100 ml three-neck flask, and were stirred at 120° C. for 2.5 hours under an oxygen atmosphere. The reaction mixture was filtered through Cerite. The filtrate was poured into a saturated aqueous solution of sodium hydrogencarbonate and then was extracted with ethyl acetate. The extract was condensed and 1,3,5-triphenylpyrazole was obtained as a pale yellow solid by means of silica gel column chromatography.