Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.[CH2:36]([C:38]([C:58]1[CH:59]=[C:60]2[C:65](=[CH:66][CH:67]=1)[CH:64]=[C:63]([C:68](O)=[O:69])[CH:62]=[CH:61]2)([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH:48]([CH2:55][CH3:56])[CH:49]([OH:54])[C:50]([CH3:53])([CH3:52])[CH3:51])=[C:43]([CH3:57])[CH:42]=1)[CH2:39][CH3:40])[CH3:37]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:68]([C:63]1[CH:62]=[CH:61][C:60]2[C:65](=[CH:66][CH:67]=[C:58]([C:38]([CH2:36][CH3:37])([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH:48]([CH2:55][CH3:56])[CH:49]([OH:54])[C:50]([CH3:51])([CH3:52])[CH3:53])=[C:43]([CH3:57])[CH:42]=3)[CH2:39][CH3:40])[CH:59]=2)[CH:64]=1)=[O:69]
Reactant: COC(=O)CN
Reactant: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)O)ccc3c2)cc1C)C(O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)NCC(=O)OC)ccc3c2)cc1C)C(O)C(C)(C)C
Yield: 94.6 %

Procedure:
Add glycine methyl ester hydrochloride (95 mg, 0.755 mmol), HOBT (102 mg, 0.755 mmol), EDCI (206 mg, 1.08 mmol), and Et3N (0.4 ml, 0.726 mmol) to diastereomeric isomer pair 1 of 6-{1-ethyl-1-[4-(1-ethyl-2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-naphthalene-2-carboxylic acid (343 mg, 0.72 mmol) and CH2Cl2 (5 ml). Stir the reaction for 14 h. Concentrate the reaction mixture in vacuo, and chromatograph the residue (CH2Cl2 to 15% EtOAc/CH2Cl2) to give the title compound as a colorless foam (373 mg, 95%). 1NMR (400 MHz, CDCl3) δ ppm: 0.64 (t, J=7.6 Hz, 6H), 0.93 (t, J=8.4 Hz, 3H), 0.93 (s, 9H), 1.68 (m, 1H), 1.81 (m, 1H), 2.12 (s, 3H), 2.18 (q, 4H), 2.60 (bs, 1H), 3.27 (s, 1H), 3.83 (s, 3H), 4.27 (dd, J=5.6, 3.2 Hz, 1H), 4.31 (d, J=5.2 Hz, 2H), 6.63 (d, J=8.0 Hz, 1H), 6.75 (t, J=4.8 Hz, 1H), 6.89 (d, J=2.4 Hz, 1H), 6.93 (dd, J=6.4, 2.0 Hz, 1H), 7.18 (dd, J=6.8, 2.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.83 (d, J=2.0, 1H), 7.86 (m, 2H), 8.26 (s, 1H). High Res. ES-MS: 570.3116; calc. for C34H45NO5+Na: 570.3196.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[C:15]=2[Cl:22])[C:7]=1[N:8]1[CH:11]([CH3:12])[CH2:10][C:9]1=[O:13])#[N:2].[CH2:23]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[C:15]=2[Cl:22])[C:7]=1[NH:8][CH:11]([CH3:12])[CH2:10][C:9]([N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:13])#[N:2]
Reactant: CCCCNCCCC
Reactant: CC1CC(=O)N1c1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Product: CCCCN(CCCC)C(=O)CC(C)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl

Procedure:
A solution of 4-cyano-5-(4-methyl-2-oxo-azetidin-1-yl)-1-(2,3,4-trichlorophenyl)pyrazole (1.0 g; prepared as described in Example 32) in di-n-butylamine (20 ml) was heated under reflux for 31/2 hours. The reaction mixture was evaporated to dryness and the residue chromatographed using dichloromethane-ethyl acetate (40:1) as eluent. Evaporation of the eluate containing the major component gave 4-cyano-5-[2-di-(n-butyl)aminocarbonyl-1-methylethyl]amino-1-(2,3,4-trichlorophenyl)pyrazole (0.95 g), m.p. 101°-103° C., in the form of a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1)=[O:23]
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Reactant: COc1ccc(C(=O)Cl)cc1F
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccc(-c3cn4cc(C)ccc4n3)cc2)cc1F
Yield: 71 %

Procedure:
Prepared as described in the Amide Coupling section using 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.30 g, 1.34 mmol) and 3-fluoro-4-methoxybenzoyl chloride (0.25 g, 1.34 mmol) in dry pyridine (14 ml) to give the title compound (0.357 g, 71%) as small, colourless needles after work-up, flash chromatography (DCM/MeOH 18:1) and recrystallisation from 1,4-dioxane.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].CI.[CH3:39]N(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][CH3:39])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(O)CC2)c2ncnn12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a mixture of 4′-{[7-butyl-4-(4-hydroxycyclohexyl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.37 g), methyl iodide (0.053 mL) and N,N-dimethylformamide (10 mL) was added sodium hydride (0.034 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.16 g, 42%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH:13]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:13]/[CH2:12][C:11]([CH3:16])([CH3:15])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CC=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
A mixture of glycine tert-butyl ester (Alfa) (2.71 g, 20.0 mmol) and 3,3-dimethyl-butyraldehyde (Alfa) (2.21 g, 21.0 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried in vacuo to give [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (4.29 g, 100%) as colorless oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1.C(N(CC)CC)C.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27]Br)[CH3:22]>CO>[CH2:21]([O:23][C:24]([CH2:25][CH2:26][CH2:27][NH:1][CH2:2][CH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[O:29])[CH3:22]
Reactant: NCCC1COc2ccccc2C1
Reactant: CCOC(=O)CCCBr
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNCCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
17.7 g (0.1 mol) of 3-(2-aminoethyl)chroman are dissolved in 100 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 19.5 g (0.1 mol) of 4-bromobutyric acid ethyl ester are added to the solution. The reaction mixture is stirred for 15 hours at room temperature and is then concentrated under a water-jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation. Oily N-(3-ethoxycarbonylpropyl)-N-[2-(chroman-3-yl)ethyl]-amine is thus obtained and can be used further in crude form.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22])[CH:8]=[CH:9][CH:10]=O)([CH3:3])[CH3:2].[O:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35]>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:8][CH2:9][CH2:10][CH:33]2[O:29][C:30](=[O:35])[NH:31][C:32]2=[O:34])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22])([CH3:2])[CH3:3]
Reactant: O=C1COC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=CC=O)cc1OC(C)C
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCC2OC(=O)NC2=O)cc1OC(C)C

Procedure:
In substantially the same manner as in Working Example 11, 3-isopropoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[3-[3-isopropoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.120-121° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC.C(Cl)[Cl:37]>Cl>[ClH:37].[ClH:37].[ClH:37].[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:14])[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(CCOC(=O)N2CCN(c3ccccc3)CC2)CC1
Agent: Cl
Solvent: CCOCC
Product: O=C(OCCN1CCNCC1)N1CCN(c2ccccc2)CC1
Reaction time: 8 h
Yield: 98 %

Procedure:
2-(4-(tert-Butoxycarbonyl)piperazin-1-yl)ethyl 4-nitrophenyl carbonate (7.01 g, 17.7 mmol) was dissolved in DMF (150 mL). Phenylpiperazine (2.8 mL, 18.3 mmol) and NEt3 (3.0 mL, 21.5 mmol) were added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, dissolved in EtOAc (250 mL), washed with 1M aq Na2CO3 solution (5×250 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, 0-100%) to give 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl 4-phenyl-piperazine-1-carboxylate (5.68 g, 77%) as a yellow oil. 2-(4-(tert-Butoxycarbonyl)-piperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate (0.45 g, 1.07 mmol) was dissolved in a mixture of DCM (30 mL) and 2M HCl in Et2O (4 mL, 8 mmol) and stirred overnight. The supernatant was discarded. The residue washed with DCM (3×15 mL) and dried in vacuo to give 2-(piperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate trihydrochloride (0.42 g, 98%) as a pale brown glass.
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:9])C=C[CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[N:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1>C(O)CCC>[CH2:3]([O:9][C:11]1[N:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1)[CH2:4][CH2:5][CH3:6]
Reactant: Oc1ccccc1
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCOc1ccc(N2CCN(c3cccc(C)c3)CC2)nn1
Yield: 64 %

Procedure:
To a stirred mixture of 80 parts of 1-butanol, 0.4 parts of sodium hydroxide and 0.94 parts of phenol were added 2.2 parts of 3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine at 60° C. The whole was stirred and refluxed over weekend. The reaction mixture was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 2 parts (64%) of 3-butoxy-6-[4(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 105.2° C. (compound 257).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][NH:21][C:2]2[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(CN)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COC(=O)c1ccc(NCC(C)(C)c2ccc(F)cc2)nn1
Temperature: 120 °C
Yield: 40.9 %

Procedure:
To a 25 mL round bottom flask was added methyl 6-chloropyridazine-3-carboxylate (0.50 g, 2.90 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (0.60 g, 3.6 mmol, 1.2 equiv), potassium carbonate (300 mg, 2.2 mmol, 0.75 equiv), and isopropanol (3 mL). The reaction mixture was stirred and heated at 120° C. for 12 h. The reaction was then filtered through celite, concentrated, and purified by silica gel chromatography (0-40% EtOAC/hexanes) to afford 360 mg (43%) of methyl 6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-3-carboxylate as an off-white foam.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[OH-].[Na+:38]>O>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[Na+:38]
Reactant: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A suspension of the product of Example 42G in water (3 mL) and treated with 0.997N sodium hydroxide solution (0.410 mL) and stirred at 25° C. for 1 hour. The solution was lyophilized to give 209 mg (74%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): 5 ppm 0.43 (m, 1H) 0.70 (s, 9H) 0.81 (m, 1H) 1.38 (s, 3H) 1.71 (m, 1H) 2.16 (m, 1H) 2.90 (s, 3H) 7.28 (m, 3H) 7.44 (m, 3H) 8.05 (d, J=7.35 Hz, 1H) 9.87 (s, 1H) 15.44 (s, 1H); MS (ESI−) m/z 530 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33](=[O:34])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:37]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A170) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1]C(C)=O.C(=O)([O-])[O-].[K+].[K+].CI.[OH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[O:20][C:19]([CH3:28])([CH3:27])[CH2:18][C:17]2=[O:29]>>[CH3:1][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[O:20][C:19]([CH3:28])([CH3:27])[CH2:18][C:17]2=[O:29]
Reactant: CCOc1cc2c(cc1O)C(=O)CC(C)(C)O2
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOc1cc2c(cc1OC)C(=O)CC(C)(C)O2
Temperature: 0 °C
Yield: 92 %

Procedure:
In 100 ml of acetone 4.7 g (20 millimoles) of 6-hydroxy-7-ethoxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 4.1 g (30 millimoles) of potassium carbonate and 4.5 b (2 ml, 30 millimoles) of methyl iodide are added. The reaction mixture is refluxed for 4 hours, the inorganic salt is filtered off, washed twice with 20 ml of acetone and the half of the solvent is removed. The residue is cooled to 0° C., the precipitated product is filtered off and dried to constant weight. Thus 4.6 g of the desired compound are obtained, yield 92%. Mp.: 120°-122° C.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[C:10]([S:12][CH:13]([CH3:15])[CH3:14])[C:9]([Cl:16])=[CH:8][C:6]=1[NH2:7])(=[O:4])(=[O:3])[NH2:2].[Cl:17][CH2:18][C:19](Cl)=O.C([O-])(=O)C.[K+].O>O1CCOCC1>[Cl:17][CH2:18][C:19]1[NH:2][S:1](=[O:3])(=[O:4])[C:5]2[CH:11]=[C:10]([S:12][CH:13]([CH3:14])[CH3:15])[C:9]([Cl:16])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)Sc1cc(S(N)(=O)=O)c(N)cc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Sc1cc2c(cc1Cl)N=C(CCl)NS2(=O)=O

Procedure:
A mixture of 2-sulfamoyl-4-isopropylthio-5-chloroaniline (0.02 mole) and chloroacetyl chloride (0.022 mole) in dioxane (75 ml.) is heated under reflux for 24 hours. The solution then is concentrated to dryness in vacuo, the residue dissolved in ethanol (60 ml.) and heated under reflux with potassium acetate (0.022 mole) and water (10 ml.) for 2 hours. The alcohol is removed in vacuo and the solution then acidified with hydrochloric acid. The precipitated product is recrystallized from a mixture of methanol and water to provide 3-chloromethyl-6-chloro-7-isopropylthio-1,2,4-benzothiadiazine-1,1-dioxide, m.p. 248°-250° C.
Reaction SMILES: [ClH:1].O1CCOCC1.[OH:8][CH:9]([C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:10][N:11](C)[C:12](=O)OC(C)(C)C>CO>[ClH:1].[ClH:1].[CH3:27][O:26][C:23]1[N:22]=[CH:21][C:20]([CH:9]([OH:8])[CH2:10][NH:11][CH3:12])=[CH:25][CH:24]=1
Reactant: COc1ccc(C(O)CN(C)C(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNCC(O)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of HCl-dioxane (4.0 M, 50 mL) was added tert-butyl 2-hydroxy-2-(6-methoxypyridin-3-yl)ethyl(methyl)carbamate (1.0 g, 3.5 mmol). The suspension was stirred at room temperature for 16 hours. The solvent and excess HCl was evaporated, leaving a white solid. The solid was dissolved in methanol and purified with a silica gel column, diluting with 1% NH4OH/5% Methanol/dichloromethane, to yield the title compound (0.63 g) as a colorless oil.
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]([CH2:11][OH:12])[CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:12][CH2:11][CH:3]1[CH2:4][N:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1][CH2:2]1)(=[O:23])=[O:22]
Reactant: OCC1CCC2CCCCN2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCC2CCCCN2C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 90.7 %

Procedure:
Octahydro-2H-quinolizin-3-ylmethanol (600 mg, 3.55 mmol) was dissolved in dichloromethane (8 mL) and triethylamine (1.5 mL, 10.8 mmol) was added at 0° C. followed by dropwise addition of methanesulfonyl chloride (0.56 mL, 7.16 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford octahydro-2H-quinolizin-3-ylmethyl methanesulfonate as an orange oil (796 mg, 3.22 mmol, 91% yield). MS (EI) for C11H21NO3S: 248 (MH+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[NH2:26][C@@H:27]([CH:32]([CH3:34])[CH3:33])[CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].Cl>COCCO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)[C@H](N)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Product: CC(C)C(CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 130 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
A mixture of 1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmole), (R)-3-amino-4-methylpentanoic acid hydrochloride (52 mg, 0.31 mmole) (Chem-Impex International Inc., Wood Dale Ill.), and sodium methoxide (25 mg, 0.46 mmole) in 2-methoxyethanol was stirred at 130° C. for two hours before it was cooled to room temperature and acidified with 1 N HCl. The mixture was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of 1% acetic acid, ethyl acetate and hexanes to give the title compound as a yellow solid (9 mg): MS: (+) m/z 420.06 (M+1), (−) m/z 418.02 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[N:7][CH:8]=1.[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[C:11]=2[N+:20]([O-:22])=[O:21])[N:6]=[N:7][CH:8]=1
Reactant: COc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cnnc(Oc2c([N+](=O)[O-])c(C(F)(F)F)nn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
5-Methoxy-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (Compound No. 5, 1.2 g, 0.0043 mole) was added to a mixture of nitric acid (5 mL) and sulfuric acid (13 mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice and neutralized with 10% sodium hydroxide. Filtration gave, after drying, 5-methoxy-3-[[1-methyl-4-nitro-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (1.36 g, 99% yield) as a beige solid.
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:27][O:28][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:11]3=[O:26].FC1C(C#[N:37])=CC2C3(COC=2C=1)C1C(=CC=CC=1)N(CC1C=CC=CC=1C(F)(F)F)C3=O>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2([C:5]3[CH:6]=[C:7]4[C:2](=[CH:3][C:4]=3[O:28][CH2:27]2)[NH:37][N:9]=[CH:8]4)[C:11]1=[O:26]
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccn2)c2ccccc21
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccc2C(F)(F)F)c2ccccc21
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3[nH]ncc3cc12

Procedure:
Following the procedure as described in EXAMPLE 46 and making non-critical variations using 6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3-indole]-5-carbonitrile to replace 6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3-indole]-5-carbonitrile, 1′-(pyridin-2-ylmethyl)-1H-spiro[furo[3,2-f]indazole-5,3′-indol]-2′ (1′H)-one was obtained (33%): mp 117-119° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 10.21 (br s, 1H), 8.60-7.59 (m, 1H), 7.79 (s, 1H), 7.70-7.65 (m, 1H), 7.31-6.89 (m, 7H), 5.24-4.77 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.5, 160.7, 155.4, 149.6, 142.3, 141.7, 137.1, 134.9, 132.3, 129.0, 126.3, 123.7, 123.6, 122.8, 121.7, 119.1, 115.6, 109.7, 89.6, 80.6, 57.3, 46.1; MS (ES+) m/z 369.2 (M+1).