Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]([O:51][CH3:52])([CH3:50])[CH3:49])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]([O:51][CH3:52])([CH3:50])[CH3:49])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogen carbonate (0.33 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, 4′-({2-ethyl-1-[4-(2-methoxy-2-methylpropoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.1 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (4 mL). N,N′-carbonyldiimidazole (0.05 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.048 g, 43%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][C:18](O)=O)[CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:33])=O>C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:21])[CH2:16][CH2:17][CH2:18][Cl:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]32)C1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCCCl)CC[C@@H]32)C1

Procedure:
3α-Acetoxy-5β-cholanic acid (4.18 g; 10 mmoles) was added to 60 ml of anhydrous benzene. The solution was cooled with ice, and with stirring, 4.5 ml of thionyl chloride was gradually added dropwise. After the addition, the mixture was reacted at room temperature for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure, and 20 ml of anhydrous benzene was added to the residue. The mixture was repeatedly concentrated under reduced pressure to remove the thionyl chloride contained in the residue. The resulting solid crude product, 3α-acetoxy-5β-cholanyl chloride, was used as a starting compound in the subsequent step without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([N:11]([CH:13]3[CH2:15][CH2:14]3)[CH3:12])[N:10]=[C:4]2[CH:3]=1.[C:16](=[O:23])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH2:17]>>[C:19]([O:18][C:16](=[O:23])[NH:17][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([N:11]([CH:13]3[CH2:15][CH2:14]3)[CH3:12])[N:10]=[C:4]2[CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(N)=O
Reactant: CN(c1nc2cc(Br)ccn2n1)C1CC1
Product: CN(c1nc2cc(NC(=O)OC(C)(C)C)ccn2n1)C1CC1
Yield: 55.2 %

Procedure:
The product was prepared in the same manner as described in example 8e using 7-bromo-N-cyclopropyl-N-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (540 mg, 2.02 mmol) and tert-butyl carbamate (284 mg, 2.43 mmol) as starting materials. The reaction affords [2-(cyclopropyl-methyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (338 mg, 55.03%) as light yellow crystals. mp: 323.1° C., MS: m/z=397.1 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C[Al](C)C.C[O:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[NH:26][C:27]1[C:28]2[CH:35]=[CH:34][NH:33][C:29]=2[N:30]=[CH:31][N:32]=1)=O.O>C1(C)C=CC=CC=1.CO>[CH3:12][N:4]([CH2:3][CH2:2][NH:1][C:19]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[NH:26][C:27]1[C:28]2[CH:35]=[CH:34][NH:33][C:29]=2[N:30]=[CH:31][N:32]=1)=[O:18])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: COC(=O)c1sccc1Nc1ncnc2[nH]ccc12
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(CCNC(=O)c1sccc1Nc1ncnc2[nH]ccc12)C(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2-aminoethyl)(methyl)carbamate (158 μl; 154 mg; 0.88 mmol) in anhydrous toluene (3 mL) placed in a sealed tube under nitrogen was added a solution of trimethylaluminum (354 μl; 2 M; 0.71 mmol) in toluene. The colorless solution was stirred at 25° C. for 1 h, before 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester (55 mg; 0.18 mmol) was added and the resulting yellow suspension was heated to 105° C. overnight. The reaction mixture was allowed to cool down before water (0.1 mL) was added. The resulting gray suspension was stirred at 25° C. for 2 h, diluted with methanol and purified by chromatography on a SP1 Biotage system, using hexane and ethyl acetate as eluents to afford crude tert-butyl methyl[2-({[3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-thienyl]carbonyl}amino)ethyl]carbamate as a white solid. The solid was suspended in methanol (1 mL) in a 5 mL flask with magnetic stir bar. To the white suspension was added hydrochloric acid (0.21 mL, 2.0N in diethyl ether, 0.42 mmol). The resulting solution was stirred at 25° C. overnight and the resulting precipitate was collected by filtration. The precipitate was purified using preparative HPLC to afford 3-(7H-Pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid (2-methylamino-ethyl)-amide (1 mg, 2%) as a brown solid. 1H NMR (MeOH-d4) 8.55 (d, J=5.5 Hz, 1H), 8.40 (s, 1H), 7.66 (d, J=5.2 Hz, 1H), 7.29 (d, J=3.7 Hz, 1H), 6.61 (d, J=3.3 Hz, 1H), 3.73-3.67 (m, 2H), 3.34-3.28 (m, 2H), 2.75 (s, 3H); MS (m/z) 317 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([O:20][CH2:21][C:22]([O:24]C)=[O:23])[CH:14]=[CH:13]3)[N:9]=1.[OH-].[Na+]>C1COCC1.CO.O>[Cl:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:2]([Cl:1])[C:3]=1[CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:14]=[CH:13]3)[N:9]=1
Reactant: COC(=O)COc1ccc2cc(-c3csc(Cc4c(Cl)cccc4Cl)n3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)COc1ccc2cc(-c3csc(Cc4c(Cl)cccc4Cl)n3)ccc2c1
Yield: 75.5 %

Procedure:
A mixture of methyl ({6-[2-(2,6-dichlorobenzyl)-1,3-thiazol-4-yl]-2-naphthyl}oxy)acetate (205 mg, 0.447 mmol), prepared in the previous step, and 1 N NaOH (671 μL, 0.671 mmol) in 20 mL of THF plus 20 mL of methanol plus 10 mL of water was refluxed under nitrogen for 2.5 h. The reaction was filtered, acidified by the addition of 3 mL of 1 N HCl and then concentrated under reduced pressure to remove the THF and methanol. The solid present was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (150 mg, 74%) as an off-white solid, mp 205-207° C. Elemental Analysis for C22H15Cl2NO3S+0.30H2O Calc'd: C, 58.75; H, 3.50; N, 3.11. Found: C, 59.09; H, 3.58; N, 2.92.
Reaction SMILES: CCCP(=O)=O.[CH3:7][NH:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH:10]=1.[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26].CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:20]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:11]3[CH:10]=[C:9]([NH:8][CH3:7])[N:14]=[CH:13][N:12]=3)=[CH:24][CH:23]=2)=[O:22])[CH2:29][CH2:28]1)[CH3:26]
Reactant: CCN1CCNCC1
Reactant: CNc1cc(Nc2ccc(C(=O)O)cc2)ncn1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1CCN(C(=O)c2ccc(Nc3cc(NC)ncn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Propylphosphonic anhydride (50% in DMF, 2.72 mL, 4.7 mmol, 2 equiv) is added to a solution of 4-(6-methylamino-pyrimidin-4-ylamino)-benzoic acid (0.570 g, 2.33 mmol), N-ethyl-piperazine (0.33 mL, 2.57 mmol, 1.1 equiv), DMAP (7 mg), and Et3N (3.3 mL, 23.3 mmol, 10 equiv) in DMF (25 mL), at RT and under an argon atmosphere. The reaction mixture is stirred at RT for 1 h, diluted with EtOAc and washed with H2O. The aqueous layer is extracted with EtOAc. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM→DCM/2 N NH3 in MeOH, 86:14) to provide the title compound as a yellow foam: ES-MS: 341.2 [MH]+; tR=1.00 min (system 1); Rf=0.33 (CH2Cl2/2 N NH3 in MeOH, 9:1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:17][CH:16]=2)=[O:14])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C(N(C(C)C)CC)(C)C.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[NH2:1][C:2]1[C:3]([C:9]2[O:14][C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:19][CH:20]=3)=[N:12][N:11]=2)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: CN(Cc1ccc(C(=O)NNC(=O)c2nc(Br)cnc2N)cc1)C(=O)OC(C)(C)C
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(-c2nnc(-c3nc(Br)cnc3N)o2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.75 h

Procedure:
tert-butyl N-[[4-[[(3-amino-6-bromo-pyrazine-2-carbonyl)amino]carbamoyl]phenyl]methyl]-N-methyl-carbamate (7.66 g, 15.98 mmol) was dissolved in dry acetonitrile (114.9 mL) and cooled in an ice bath and put under a nitrogen atmosphere. Diisopropylethylamine (6.196 g. 8.350 mL, 47.94 mmol) was added via a syringe followed by dibromo(triphenyl)phosphorane (8.767 g, 20.77 mmol) portion wise. Reaction mixture started to precipitate out therefore left to stir for 45 minutes in an ice bath and isolated precipitated product by filtration as a beige powder (4.5 g). This material was then sonicated, triturated in acetonitrile, filtered and dried to give the sub-titled compound as yellow solid. (3.17 g, 40.9%). 1H NMR (400 MHz, DMSO-d6) δ 1.38-1.45 (br d, 9H), 2.80 (s, 3H), 4.45 (s, 2H), 7.48-7.51 (br s, 2H), 7.80 (br s, 2H), 8.10-8.20 (m, 2H), 8.45 (s, 1H) ppm; LC/MS m/z 463.1, 464.2 [M+H]+.
Reaction SMILES: [Br-].C([N+:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:10][CH:9]=1)CCCCC.N1C=CC(O)=CC=1.COCCOCCOCCOCCOS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1
Reactant: CCCCCC[n+]1ccc(OCCOCCOCCOCCOC)cc1
Agent: COCCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: Oc1ccncc1
Agent: [Br-]
Product: COCCOCCOCCOCCOc1ccncc1
Temperature: 100 °C

Procedure:
Preparation of 1-hexyl-4-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-pyridinium bromide—Pyridin-4-ol (1.50 g, 15.77 mmol) and toluene-4-sulfonic acid 2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethyl ester (5.62 g, 19.71 mmol) were combined in a 50 mL round bottomed flask equipped with condenser, magnetic stir bar, and a positive flow of nitrogen. The solution was heated in a 100° C. oil bath for 24 hrs. The solution was then cooled and placed on a vacuum line at 1 mmHg and heated at 80° C. for 6 hrs to removed residual starting materials. The by-product was removed via washing with deionized water (3×15 mL) to afford 4-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-pyridine. The product may be subsequently purified employing column chromatography techniques at this point or may proceed directly to the addition of 1-bromohexane (3.90 g, 23.66 mmol) in 25 mL tetrahydrofuran. Stirring the resulting reaction mixture at 50° C. for 24 hrs resulted in the desired product, 1-hexyl-4-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-pyridinium bromide in a 38% yield (2.70 g, 5.99 mmol).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10](OC)=[N:9]1.[Cl-:17].[NH4+:18]>>[ClH:17].[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH:8]1[NH:9][C:10](=[NH:18])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(CCC2OCCO2)CCCC1
Product: Cl
Product: N=C1CCCCC(CCC2OCCO2)N1

Procedure:
The product of Example 106 is reacted with ammonium chloride by the method of Example 5 to generate the t compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:32][OH:33])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1.O>N1C=CC=CC=1>[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([O:33][CH2:32][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-c2nnc3n2CCCC3(CO)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(-c2nnc3n2CCCC3(COS(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of {8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methanol (178 mg) in pyridine (3 mL) was added 4-methylbenzenesulfonyl chloride under ice-cooling, and the mixture was stirred at room temperature for 4 hr. 4-Methylbenzenesulfonyl chloride (84 mg) was further added, and the mixture was stirred at room temperature for 2 hr, and at 50° C. overnight. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (163 mg).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][N:6]1[C:14]2[C:13](=[O:15])[NH:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])=[N:10][C:9]=2[C:8]([CH2:26][CH2:27][CH3:28])=[N:7]1.[Br:29][CH2:30][C:31](Cl)=[O:32].O>ClCCl>[Br:29][CH2:30][C:31]([C:20]1[CH:19]=[CH:18][C:17]([O:22][CH2:23][CH2:24][CH3:25])=[C:16]([C:11]2[NH:12][C:13](=[O:15])[C:14]3[N:6]([CH3:5])[N:7]=[C:8]([CH2:26][CH2:27][CH3:28])[C:9]=3[N:10]=2)[CH:21]=1)=[O:32]
Reactant: O=C(Cl)CBr
Reactant: CCCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCOc1ccc(C(=O)CBr)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
Aluminium trichloride (6.0 g, 0.045 mol) was added portionwise to a stirred solution of 1-methyl-5-(2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (5.0 g, 0.0153 mol) and 2-bromoacetyl chloride (2.5 ml, 0.0303 mol) in dichloromethane (100 ml) at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for 18 hours, heated under reflux for 3 hours and then added cautiously to ice and water (100 g). The resulting mixture was stirred for 1 hour and extracted with dichloromethane (2×50 ml). The combined organic extracts were washed with brine (2×50 ml), dried (Na2SO4), then evaporated under vacuum to give an off-white solid, which was triturated with ether to give the title compound as a white solid (4.1 g, 60%). A small sample was crystallised from ethyl acetate-hexane to give the pure product, m.p. 136°-137° C. Found: C,53.82; H,5.24; N,12.57. C20H23BrN4O3 requires C,53.70; H,5.18; N,12.52%.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[H-].[Na+].Br[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.[Cl-:18].[Na+].O>CN(C=O)C>[ClH:18].[ClH:18].[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1
Reactant: CN1CCC[C@H]1CO
Reactant: Brc1cncnc1
Reactant: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC[C@H]1COc1cncnc1
Product: Cl
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a sample of 1-methyl-2(S)-pyrrolidinemethanol (Aldrich, 16.81 mmol) in 2 mL of DMF was added 0.74 g of NaH (60% dispersion in oil, 18.49 mmol) and 2.68 g (16.81 mmol) of 5-bromopyrimidine. The reaction mixture was stirred at 60° C. for 18 hours, then poured onto ice. The mixture was diluted with brine, and extracted with methylene chloride. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on silica gel, eluting with 20:1 chloroform:methanol. The compound was then taken up in methylene chloride, HCl in ether was added, and the volatiles removed under vacuum. The salt was recrystallized from acetonitrile/ether to afford 822 mg of the title compound. mp >160° C. (dec). MS (DCI/NH3) m/e: 194 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 8.88 (s, 1H-), 8.65 (s, 2H), 4.64 (dd, J=11.2, 3.1 Hz, 1H), 4.47 (m, 1H), 3.95 (m, 1H), 3.77 (m, 1H), 3.29 (m, 1H), 3.05 (s, 3H), 2.43 (m, 1H), 2.24 (m, 1H), 2.11 (m, 2H). Anal. Calc. for C10H15N3OCl2 : C, 45.13; H, 6.44; N, 15.79; Found C, 45.13; H, 6.74; N, 15.69. [α]25D =-2.6° (c=0.57, methanol).
Reaction SMILES: C1C=CC(NC2C=CC(N)=CC=2)=CC=1.[OH:15]C1C2N=NNC=2C=CC=1.[CH:25]1([N:31]=[C:32]=[N:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1COCC1>[C:32]([NH:31][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)([NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:15]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Oc1cccc2[nH]nnc12
Agent: Nc1ccc(Nc2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 15 h
Yield: 65 %

Procedure:
1.65 g (8.98 mmol) of 4-aminodiphenylamine, 1.77 g (8.98 mmol) of intermediate 3.2 and 1.27 g (9.42 mmol) of hydroxybenzotriazole are dissolved in 40 ml of THF in a 100 ml flask, under a nitrogen atmosphere. When all have dissolved, 1.94 g (9.42 mmol) of 1,3-dicyclohexylcarbodiimide is added and the reaction medium is left under agitation for 15 hours. The precipitate of dicyclohexylurea formed is filtered and rinsed with ethyl acetate. The filtrate is evaporated under vacuum and the evaporation residue is taken up in ethyl acetate, it then forms a precipitate which is filtered and rinsed using the same solvent. A greenish solid is obtained with a yield of 65%. The product obtained is sufficiently pure to be used directly in the following stage. Melting point: 192-195° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[H-].[Na+].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.O>CN(C)C=O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](=[O:4])[C:2]([F:14])([F:15])[F:1]
Reactant: O=C(NCCc1ccccc1)C(F)(F)F
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N(CCCCCCBr)CCc1ccccc1)C(F)(F)F
Yield: 63.1 %

Procedure:
2,2,2-Trifluoro-N-(2-phenylethyl)acetamide (21.7 g., 0.1 mole) in dry dimethyformamide (100 ml) was added dropwise with stirring and under nitrogen to sodium hydride (2.4 g ., 0.1 mole, ether washed) in dry dimethylformamide (150 ml). Stirring was continued until a clear solution was obtained and 1,6-dibromohexane (73.2 g., 0.3 moles) was added. The solution was heated at 60°. for 3 hr then poured into water and extracted with ether. The extracts were washed well with water dried and evaporated. Excess dibromohexane was recovered by distillation (b.p. 60°-70°/0.1 mmHg) and the residue was separated on a silica gel column using ether-light petroleum (1:2) as eluant. The major fraction was evaporated to give the title compound as a pale yellow oil (24 g). A sample was distilled to give a colourless viscous liquid, b.p. 146°-152°/0.05 mmHg, (with slight decomposition)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12]2.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=1>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=1)[CH2:13][CH2:12]2
Reactant: COc1ccc2c(c1)CCN2
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN2Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
An ice cold slurry of 5.89 g (42.6 mmole) of K2CO3 and 5.3 g (35.5 mmole) of 5-methoxyindoline in 55 ml of DMF was treated dropwise with a solution of 7.28 g (37.3 mmole) of α-bromo-m-tolunitrile in 50 ml of DMF. After stirring for 1 hour at room temperature, the reaction mixture was concentrated under high vacuum. The residue was partitioned between methylene chloride (250 ml) and water (250 ml). The organic layer was separated, washed with 5% NaOH (300 ml), brine (300 ml), dried over Na2SO4 and concentrated under vacuum to yield 9.28 g (98.9% yield) of α-(5-methoxy-1-indolinyl)-m-tolunitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:12]=3[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:33][CH:32]=[CH:31][CH2:30]4)=[O:28])=[CH:23][CH:22]=3)[C:10](=[O:34])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:42]=CC=C[CH:38]=1.C(O)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([O:19][CH:37]([CH3:42])[CH3:38])=[CH:18][C:12]=3[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]4[CH2:30][CH:31]=[CH:32][CH2:33]4)=[O:28])=[CH:23][CH:22]=3)[C:10](=[O:34])[CH2:9]2)=[O:7])=[CH:35][CH:36]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccc(O)cc32)cc1)N1CC=CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)Oc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22 mg (0.044 mmol) of 4-(4-chlorobenzoyl)-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-8-hydroxy-1,3,4,5-tetrahydrobenzo[e][1,4]-diazepin-2-on was dissolved in 5 ml of THF. 15 mg (0.05 mmol) of triphenylphosphine, 0.004 ml (0.05 mmol) of isopropyl alcohol and 25 mg (0.05 mmol) of diethylazo dicarboxylate were added to the obtained solution, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent, the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.