Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:26]([CH2:36]O)[C:12]2=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]2[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:58]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:26]([CH2:36][Cl:58])[C:12]2=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]2[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(OCc3ccccc3)cc3c(c12)C(CO)CN3C(=O)OC(C)(C)C
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(OCc3ccccc3)cc3c(c12)C(CCl)CN3C(=O)OC(C)(C)C
Reaction time: 5 h

Procedure:
104.1 Milligrams (0.2 mmol) of methyl 5-benzyloxy-3-t-butoxycarbonyl-1-hydroxymethyl-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate, and 104.9 mg (0.4 mmol) of triphenylphosphine were suspended in 1 ml of anhydrous acetonitrile. Thereto 115.3 μl (1.2 mmol) of carbon tetrachloride was added dropwise. The mixture was stirred for 5 hours under atmosphere of argon. After removal of the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain methyl 5-benzyloxy-3-t-butoxycarbonyl-1-chloromethyl-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate in a yield of 106.7 mg (99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][OH:12])[CH2:3]1.[H][H]>C(O)C>[CH3:1][C:2]1([CH3:13])[CH2:3][CH:4]([CH2:11][OH:12])[CH:5]2[CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: [H][H]
Reactant: CC1(C)CC(CO)c2ccccc21
Solvent: CCO
Product: CC1(C)CC(CO)C2CCCCC21
Reaction time: 7 h
Yield: 82.8 %

Procedure:
11.3 g (64 mmol) of 1,1-dimethyl-3-hydroxymethylindane (IX), 3 g of 5% luthenium-carbon (manufactured by Engerhard Industries Corp.), and 300 ml of ethanol was placed in a 100 ml autoclave. After internal air was displaced by hydrogen, the mixture was heated at an initial hydrogen pressure of 100 kg/cm2. The reaction temperature reached 140° C. 1 hour after the heating was started. The absorption of hydrogen terminated when the reaction was continued at this temperature for 7 hours. After cooling, the pressure was released and the catalyst was separated out by filtration. The filtrate was distilled under reduced pressure to produce 9.7 g (53 mmol) of the title compound (Ic) at a yield of 83%. Capillary gas chromatography analysis revealed that the compound is comprised of two major components each having a peak of which the area ratio was 59:41.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:59]=[CH:58][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][C@H:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][C@@H:45]3[F:57])=[N:26]2)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH:41][C:15]([C:12]5[C:13](=[O:14])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[N:9]=[CH:10][CH:11]=5)=[O:17])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][C@H:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:54])[CH3:55])=[O:51])[CH2:46][C@@H:45]3[F:57])=[N:26]2)=[CH:58][CH:59]=1
Reactant: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3F)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Product: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3F)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1

Procedure:
Prepared from 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50.8 mg, 0.217 mmol, prepared according to the procedure for Example 19, Step C) and ±(3S*,4S*)-tert-butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fluoropiperidine-1-carboxylate (63 mg, 0.109 mmol) according to the procedure described for Example 143, Step B. Yield: 17 mg (20%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]1>CN1C(=O)CCC1.CS(C)=O.CO>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]2[CH2:17][CH:15]2[C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:26]3[CH2:31][CH2:30][CH:29]([NH:32][C:33]([NH2:35])=[O:34])[CH2:28][CH2:27]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:14])=[CH:19][CH:20]=1
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccc(F)cc3)cc(Cl)n2n1
Reactant: NC(=O)NC1CCNCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cc2nc(NC(=O)C3CC3c3ccc(F)cc3)cc(N3CCC(NC(N)=O)CC3)n2n1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
The title compound was prepared by combining N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(4-fluorophenyl)cyclopropanecarboxamide (13B, 0.15 g, 0.435 mmol), Et3NH (0.121 ml, 0.870 mmol), and the 1-(piperidin-4-yl)urea hydrochloride (0.156 g, 0.870 mmol) in NMP (1.450 ml) and heating the mixture at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory 45-50% HPLC ([1:1 MeCN/MeOH]/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a tan solid (85 mg, 43%). 1H NMR (DMSO-d6) δ: 10.95 (s, 1H), 7.19-7.31 (m, 3H), 7.07-7.18 (m, 3H), 6.08 (s, 2H), 4.26 (d, J=12.6 Hz, 2H), 3.66 (br. s., 1H), 3.17 (t, J=11.7 Hz, 2H), 2.41-2.49 (m, 1H), 2.35 (s, 3H), 2.24-2.31 (m, 1H), 1.90 (br. s., 2H), 1.74-1.82 (m, OH), 1.43-1.57 (m, 3H), 1.35-1.43 (m, 1H), 1.32 (ddd, J=8.3, 6.6, 4.3 Hz, 0H); ESI-MS: m/z 452.3 (M+H)+. It was noted that rotamers were present.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[N:14]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([N:22]3[CH2:23][CH2:24][CH:19]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:20][CH2:21]3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2ccncc2)nn1
Reactant: C1CCN(C2CCNCC2)C1
Product: c1cc(-c2ccc(N3CCC(N4CCCC4)CC3)nn2)ccn1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(pyridin-4-yl)-pyridazine and 4-(1-pyrrolidinyl)piperidine. 1H NMR (400 MHz, CDCl3) δ 8.69 (d, 2H), 7.90 (d, 2H), 7.67 (d, 1H), 7.01 (d, 1H), 4.47 (d, 2H), 3.12 (m, 2H), 2.67 (s, 4H), 2.40 (m, 1H), 2.07 (d, 2H), 1.83 (s, 4H), 1.67 (m, 2H).
Reaction SMILES: F[C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3CCN(CCN4C(O)C5C(=CC=CC=5)C4=O)[CH2:11][CH2:10]3)=N[O:8][C:4]=2[CH:3]=1.CCN(CC)CC.C(Cl)(=[O:47])CCCCCCCCC>C(Cl)Cl>[C:4]([OH:8])(=[O:47])[CH2:3][CH2:2][CH2:29][CH2:28][CH2:5][CH2:6][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)O
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-2,3-dihydro-3-hydroxy-I H-isoindol-1-one (1.4 g, 3.5 mmol) in DCM (30 ml) was added Et3N (1.2 ml, 8.8 mmol) followed by decanoyl chloride at 0 C under nitrogen. After stirring for 1 h in the cooling bath, the solvent was removed using a stream of nitrogen. The remaining residue was diluted with EtOAc and the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated and the remaining oil was flushed through alumina with ether to give 1.6 g (83%) of the desired product as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[N:31]=[C:18]4[C:19]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=5)=[CH:20][CH:21]=[CH:22][N:17]4[N:16]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[O-:32][CH2:33][CH3:34].[Na+]>CCO>[F:30][C:25]1[CH:24]=[C:23]([C:19]2[C:18]3[N:17]([N:16]=[C:15]([NH:14][CH:11]4[CH2:12][CH2:13][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([O:32][CH2:33][CH3:34])[CH:7]=5)[CH2:9][CH2:10]4)[N:31]=3)[CH:22]=[CH:21][CH:20]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: Fc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)c5)CC4)nc23)cc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(N2CCC(Nc3nc4c(-c5ccc(F)c(F)c5)cccn4n3)CC2)ccn1
Temperature: 150 °C
Yield: 3.3 %

Procedure:
To a solution of N-(1-(2-chloropyridin-4-yl)piperidin-4-yl)-8-(3,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 169c) (88 mg, 0.20 mmol) in EtOH (1 mL) was added sodium ethoxide solution (21% in ethanol, 75 L, 0.2 mmol) and the reaction mixture was heated in the microwave to 150° C. for 30 minutes. Again sodium ethoxide solution (21% in ethanol, 75 L, 0.2 mmol) was added and the resulting mixture heated to 150° C. for another 30 minutes. The mixture was then evaporated. Purification by chromatography (silica gel, 20 g, 0 to 100% methanol in dichloromethane) afforded the title compound (3 mg, 3%) as a colourless gum.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15](=[O:31])[NH:16][C:17]2[CH:22]=[CH:21][C:20](C3C=CC(OC)=CC=3)=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(=O)=O.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.ClCCl.[CH2:41]([OH:43])C>>[CH3:41][O:43][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:15](=[O:31])[C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:12][CH:11]=2)=[CH:22][CH:21]=1
Reactant: CCO
Reactant: COc1ccc(-c2ccc(NC(=O)C#Cc3ccc(COS(C)(=O)=O)cc3)cc2)cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: COc1ccc(NC(=O)C#Cc2ccc(CN3CCCCC3)cc2)cc1

Procedure:
Prepared analogously to Example 1.2.c. from 4-[(4′-methoxybipheny-4-ylcarbamoyl)ethynyl]benzyl methanesulfonate and piperidine. Yield: 5 mg (18.8% of theory); melting point: 170° C.; C28H28N2O2 (M=424.54); calc.: molecular ion peak (M+H)+: 425; found: molecular ion peak (M+H)+: 425; Rf value: 0.28 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(#N)C>[Cl-:7].[CH2:8]([N+:4]1[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Cn1ccnc1
Reactant: CCCCCCl
Solvent: CC#N
Product: CCCCC[n+]1ccn(C)c1
Product: [Cl-]
Temperature: 25 °C

Procedure:
Dry 1-methylimidazole (9.03 g, 0.11 mol) was mixed with 1-chloropentane (10.66 g, 0.1 mol) in a Schlenk round bottomed flask. The two components formed two layers, and acetonitrile (40 ml) was added to make the mixture homogeneous. The mixture was heated under reflux, under cover of dry nitrogen, for 5 hours. The resultant solution was allowed to cool to room temperature and evaporated to dryness in vacuo. The solid so formed was redissolved in acetonitrile (20 ml) and cooled to -13° C. for 5 days. This resulted in the formation of crystals which were isolated by Schlenk filtration and dried in vacuo for 48 hours. The yield of 1-pentyl-3-methyl imidazolium chloride was 8.2 g (69.9%), had a melting point of 58.2° C., m/z of 341. An 1H NMR spectrum of the product of this Example A1 is shown below in Tables 1 and
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.[NH:26]1[C:30]([CH:31]=O)=[CH:29][N:28]=[CH:27]1>>[NH:26]1[C:30]([CH2:31][NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]3[CH2:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=4[O:14][B:13]3[OH:25])=[O:10])[CH2:4][CH2:3]2)=[CH:29][N:28]=[CH:27]1
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: O=Cc1cnc[nH]1
Product: O=C(C[C@H]1CC[C@H](NCc2cnc[nH]2)CC1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6) and 1H-imidazole-5-carbaldehyde following the procedure in Example 27. The product was purified using reverse phase HPLC to afford the titled compound. ESI-MS m/z 427 (MH)+.
Reaction SMILES: [CH2:1]=O.[CH3:3][C:4]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(O)=O>[CH3:3][C:4]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH3:1])[CH2:25][CH2:26]2)=[CH:17][CH:16]=1)([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C=O
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(N2CCNCC2)cc1
Solvent: O=CO
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(N2CCN(C)CC2)cc1
Yield: 70 %

Procedure:
A mixture of formaldehyde (2 ml), formic acid (2 ml) and diethyl 2-methyl-2-(4-(piperazin-1-yl)phenyl)malonate (4.80 g, 14.4 mmol) was heated at reflux for 2 h and the reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 3.50 g (70.0%) of diethyl 2-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)malonate as brown oily liquid.
Reaction SMILES: [CH2:1]([Si:3]([O:12][C:13]([CH3:15])=[O:14])([O:8][C:9]([CH3:11])=[O:10])[O:4][C:5]([CH3:7])=[O:6])C.C1([Si](OC(C)=O)(OC(C)=O)OC(C)=O)C=CC=CC=1.C(CC[Si](OC(C)=O)(OC(C)=O)OC(C)=O)(F)(F)F.C(CC[Si](OC(C)=O)(OC(C)=O)OC(C)=O)#N>>[CH3:1][Si:3]([O:4][C:5]([CH3:7])=[O:6])([O:12][C:13]([CH3:15])=[O:14])[O:8][C:9]([CH3:11])=[O:10]
Reactant: CC[Si](OC(C)=O)(OC(C)=O)OC(C)=O
Agent: CC(=O)O[Si](CCC#N)(OC(C)=O)OC(C)=O
Agent: CC(=O)O[Si](CCC(F)(F)F)(OC(C)=O)OC(C)=O
Agent: CC(=O)O[Si](OC(C)=O)(OC(C)=O)c1ccccc1
Product: CC(=O)O[Si](C)(OC(C)=O)OC(C)=O

Procedure:
C2H5Si(OCOCH3)3; (CH2═CH)Si(OCOCH3)3; C6H5Si(OCOCH3)3; CF3CH2CH2Si(OCOCH3)3; NC—CH2CH2Si(OCOCH3)3; CH2ClSi(OCOCH2CH3)3; CH3Si(ON═C(CH3)C2H5)2OCH2CH2OCH3; CH3Si(ON═CH—CH3)2OCH2CH2OCH3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:29][CH2:28][CH:25]4[CH2:27][CH2:26]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: NCC1CC1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNCC3CC3)n1-2

Procedure:
In the manner given in Preparation 25, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with (cyclopropylmethyl)amine in tetrahydrofuran at room temperature to give 8-chloro-1-[[(cyclopropylmethyl)amino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 29 8 -Chloro-1-[[(cyclopropylmethyl)methylamino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19]>CCO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:9]([C:8]([OH:13])=[O:12])=[CH:11][C:20]2[C:18](=[CH:17][C:16]([O:15][CH3:14])=[C:22]([O:23][CH3:24])[CH:21]=2)[N:19]=1
Reactant: COc1ccc(N)cc1OC
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1cccs1
Solvent: CCO
Product: COc1cc2cc(C(=O)O)c(-c3cccs3)nc2cc1OC
Reaction time: 8 h

Procedure:
To a boiling solution of 2-thiophenecarboxaldehyde (1.22 ml), pyruvic acid (0.904 ml) and 50 ml absolute EtOH is added dropwise a solution of 3,4-dimethoxyaniline (2.00 g) in 100 ml EtOH. The mixture is refluxed for approximately 4 hours, then stored at room temperature overnight. The greenish-yellow precipitate is collected by filtration, washed with fresh EtOH then with ether and allowed to air dry to obtain 2-(thien-2-yl) carboxy-6,7-dimethoxyquinoline m.p. 260°-263° C.).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(O)C.[OH-].[Na+].[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=[O:24])=[CH:17][CH:16]=1)=[O:14])[CH3:11]>C(OCC)(=O)C>[N+:1]([CH2:4][CH:23]([OH:24])[CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)c1ccc(CCC=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1ccc(CCC(O)C[N+](=O)[O-])cc1
Temperature: 38 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a stirred mixture of 2.25 (37 mmol) of nitromethane, 1.2 mL of ethanol and 0.06 mL of 10N aqueous sodium hydroxide solution was added 7.18 g (37 mmol) of 3-(4-ethoxycarbonylphenyl)-1-propanal at room temperature. After addition of the aldehyde, 0.06 mL of 10N aqueous sodium hydroxide and 0.23 mL of ethanol were added, and the resulting mixture was stirred at 38° C. for 48 hours and then poured into a mixture of ethyl acetate (100 mL) and hexanes (100 mL). The resulting solution was washed with water (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual solid was purified by column chromatography on silica gel, eluting with 1:4 ethyl acetate:hexanes, to afford 4.1 g (72%) of 1-nitro-4-(4-ethoxycarbonylphenyl)-2-butanol as a white solid, IR (KBr) 3439, 2929, 1700, 1619, 1553, 1362, 1289, 1180, 1137, 1105, 1019, 882, 739 cm-1. 1H NMR (CDCl3) δ 7.98 (2H, d, J=8.5 Hz), 7.28 (2H, d, J=8.0 Hz), 4.42 (2H, d, J=5.5 Hz), 4.38 (2H, q, J=7.0 Hz), 4.34-4.29 (1H, m), 3.03 (1H, br s), 2.96-2.90 (1H, m), 2.84-2.78 (1H, m), 1.92-1.78 (2H, m), 1.40 (3H, t, J=7.0 Hz); 13C NMR (CDCl3) 8166.86, 146.36, 130.05, 128.70, 128.61, 80.76, 67.85, 61.15, 34.99, 31.50, 14.46; EIMS m/z 267 (M+), 265, 252, 249, 232, 222, 206, 177, 161, 149, 133, 105, 91, 77; HRMS calc'd for C13H17NO5 267.1107, found 267.1095.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:24])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Reactant: CCNCc1ccccn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(C)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[C:11]([F:14])[C:12]=1[F:13].Br[CH2:20][CH2:21][Cl:22].Cl>CCCCCC.C1COCC1.C(OCC)(=O)C>[Cl:22][CH2:21][CH2:20][CH:15]([C:9]1[CH:8]=[C:7]([F:6])[C:12]([F:13])=[C:11]([F:14])[CH:10]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(O)Cc1cc(F)c(F)c(F)c1
Reactant: ClCCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C(CCCl)c1cc(F)c(F)c(F)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A 2.66 M solution of butyl lithium in hexane (20 mL) was added to a solution of 3,4,5-trifluorophenylacetic acid (5.00 g) in THF (150 mL) in a nitrogen atmosphere at −78° C., and the reaction solution was stirred at −78° C. for 20 minutes. The reaction solution was further stirred at 0° C. for one hour. Then, 1-bromo-2-chloroethane (2.2 mL) was added at 0° C., and the reaction solution was stirred at room temperature for 14 hours. Ethyl acetate and 1 N hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer washed with a saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 4.54 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])[CH:6]=1.[CH3:16][C:17]([CH3:21])([CH3:20])[C:18]#[CH:19].O>N1CCCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C:17]([CH3:21])([CH3:20])[C:18]#[C:19][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1-n1cc(I)cn1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)(C)C#Cc1cnn(-c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-iodo-1-(2-nitro-phenyl)-1H-pyrazole (24 g, 76 mmol) in piperidine (215 ml) were added successively copper(I) iodide (0.7 g, 3.8 mmol), bis(triphenylphosphine)palladium(II) chloride (2.7 g, 3.8 mmol) and 3,3-dimethyl-1-butyne (12.5 g, 0.15 mol). This mixture was stirred for 16 hours at room temperature. Subsequently, it was poured into 1 litre of water, stirred for 15 minutes and extracted with tert-butyl methyl ether. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated. The remaining oil was purified by silica gel chromatography using ethyl acetate and hexane as eluents, giving Compound No. 6.030.r (20 g).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1.C[O:21][B:22](OC)[O:23]C.C[Si](Cl)(C)C.[C:32]12([OH:43])[CH2:40][CH:36]([C:37]1([CH3:39])[CH3:38])[CH2:35][CH2:34][C:33]2([OH:42])[CH3:41]>CCCCCC.C1COCC1.CCOCC>[C:32]12([OH:43])[CH2:40][CH:36]([C:37]1([CH3:39])[CH3:38])[CH2:35][CH2:34][C:33]2([OH:42])[CH3:41].[CH3:18][C:16]1([CH3:19])[CH2:15][O:14][C:13]([C:9]2[CH:8]=[C:7]([B:22]([O-:23])[O-:21])[CH:12]=[CH:11][CH:10]=2)=[N:17]1
Reactant: COB(OC)OC
Reactant: CC1(C)COC(c2cccc(Br)c2)=N1
Agent: CC1(O)CCC2CC1(O)C2(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)COC(c2cccc(B([O-])[O-])c2)=N1
Reaction time: 1.5 h
Yield: 49.6 %

Procedure:
n-BuLi (2.5 mL of a 2.5 M solution in hexane, 6.23 mmol) was added dropwise with stirring to a solution of 6 (1.51 g, 5.93 mmol) in THF (9.5 mL) at −78° C. under argon. After 30 min a solution of trimethylborate (0.7 mL, 5.93 mmol) in THF (2 mL) was added and the mixture stirred for 1.5 h; thereafter, the resulting yellow solution was quenched with TMSCl (0.75 mL, 5.93 mmol) and allowed to reach rt. After 1 h (+)-pinanediol (1.01 g, 5.93 mmol) dissolved in a minimum amount of anhydrous Et2O was added one portion to the solution, and then stirred overnight. The reaction mixture was partitioned in Et2O (16 mL) and H2O (10 mL) and the aqueous phase extracted with Et2O (2×10 mL). The combined organic phases were dried on MgSO4, filtered and concentrated to give an orange oil, which was purified by chromatography (7:3 EtPet/EtOAc) and crystallization (EtPet), affording 7 (1.14 g, 54%) as a white crystalline solid, mp 98-101° C., [α]D=+11.2 (c 1.5, CHCl3). IR (KBr): 1646 cm˜1. 1H NMR (CDCl3): δ 0.81 (3H, s, pinanyl CH3), 1.22 (1H, d, J=10.5 Hz, pinanyl Hendo), 1.33 (3H, s, pinanyl CH3), 1.40 (6H, s, 2CH3), 1.50 (3H, s, pinanyl CH3), 1.5-2.5 (5H, m, pinanyl protons), 4.22 (2H, s, CH2O), 4.47 (1H, dd, J=8.8, 2.0 Hz, pinanyl CHOB), 7.43 (1H, t, J=7.7 Hz, H5 arom.), 7.92 (1H, dt, J=7.7, 1.5 Hz, H6 arom.), 8.05 (1H, dt, J=7.7, 1.5 Hz, H4 arom.), 8.43 (1H, br s, H2 arom.). 13C NMR (CDCl3): δ24.4, 26.9, 27.5, 28.8 (2C), 29.1, 35.9, 38.6, 40.0, 51.9, 68.0, 78.8, 79.5, 86.8, 128.1, 131.2, 135.0, 137.8, 162.5, (CB and aromatic quaternary C not seen). EI-MS: m/z 353 (M+), 338 (base peak), 323, 282, 242, 202, 186, 130, 103, 67, 55. Anal. Calcd for C21H28NO3B: C, 71.39; H, 7.99; N 3.96. Found: C, 71.01; H, 8.65; N, 3.89.