Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:10]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[CH:4][CH:3]=1.[NH:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+].O>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[C:14]1([S:11]([N:10]2[C:5]3[C:6](=[N:7][C:2]([N:24]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:3][CH:4]=3)[CH:8]=[C:9]2[C:20]([F:23])([F:22])[F:21])(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)n1c(C(F)(F)F)cc2nc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(F)(F)F)n2S(=O)(=O)c2ccccc2)n1
Temperature: 110 °C

Procedure:
A degassed mixture of 5-chloro-1-(phenylsulfonyl)-2-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine (0.500 g, 1.39 mmol, from Step 2), di-tert-butyl hydrazine-1,2-dicarboxylate (0.35 g, 1.5 mmol, Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.13 g, 0.16 mmol, Aldrich) and Cs2CO3 (0.50 g, 1.5 mmol) in toluene (11.5 mL) was heated at 110° C. for 2 hours. After cooling to room temperature, water was added, and the aqueous layer was extracted with three portions of EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes. (Yield: 0.66 g, 86%).
Reaction SMILES: [CH2:1]([C:8]1([CH3:19])[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[NH:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C)C>>[CH2:1]([C:8]1([CH3:19])[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[NH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(Cc2ccccc2)C(=O)Nc2cc(Cl)ccc21
Solvent: CSC
Product: CC1(Cc2ccccc2)CNc2cc(Cl)ccc21
Yield: 67.4 %

Procedure:
3-Benzyl-6-chloro-3-methyl-1,3-dihydro-indol-2-one (641 mg) was reduced with BH3.Me2S following a similar method to that described in Preparation 54 to give title compound (410 mg) as a colourless gum. MS: [M+H]+=258.
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@@H:8]([C:12]([OH:14])=O)[CH:9]([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@@H:49]([NH2:51])[CH3:50])[S:48][C:44]=2[CH:43]=1>C1(C)C=CC=CC=1>[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@@H:49]([NH:51][C:12]([C@H:8]([NH:7][C:5](=[O:6])[O:4][CH:1]([CH3:2])[CH3:3])[CH:9]([CH3:10])[CH3:11])=[O:14])[CH3:50])[S:48][C:44]=2[CH:43]=1
Reactant: CC(C)OC(=O)N[C@@H](C(=O)O)C(C)C
Reactant: C[C@H](N)c1nc2ccc(F)cc2s1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N[C@@H](C(=O)N[C@@H](C)c1nc2ccc(F)cc2s1)C(C)C
Yield: 69 %

Procedure:
In 250 ml of toluene, 13.4 g (0.066 mol) of N-isopropoxycarbonyl-D-valine was dissolved. Thereto was added 14.3 g (0.144 mol) of N-methylmorpholine. Then was dropwise added at −10° C., 8.6 g (0.063 mol) of isobutyl chlorocarbonate. Thereto was added 22 g (0.06 mol) of (S)-1-(6-fluoro-2-benzothiazolyl)ethylamine p-toluenesulfonate. A reaction and a post-treatment were conducted in the same manner as in Reference Example 1, and the hot toluene solution was filtered in a hot state to remove the insoluble matter. The filtrate was cooled, whereby crystals were precipitated. The crystals were collected by filtration and dried to obtain 15.8 g (yield: 69.3%) of isopropyl {(R)-1-[(S)-1-(6-fluorobenzothiazol-2-yl)ethylcarbamoyl]-2-methylpropyl}carbamate. The compound obtained was confirmed for the structure by IR analysis and NMR analysis in comparison with its authentic material and identified.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[CH2:12]1[C:20]2[C:15](=[CH:16][C:17](C=O)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:1][C:2]3[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=3[CH3:7])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: O=Cc1ccc2c(c1)CCC2
Reactant: COC(=S)c1cc(N)c(C)s1
Product: COC(=S)c1cc(Nc2ccc3c(c2)CCC3)c(C)s1

Procedure:
Using the procedure described in Example 220, step (a), 60 mg (0.29 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 42.3 mg (0.29 mmol) of 5-indancarboxaldehyde, and 135 mg (2.2 equiv, 0.63 mmol) of NaHB(OAc)3 were allowed to react to give methyl 4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C17H19NO2S2, 334.09 (M+H), found 332.3 (imine), 333.4.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[C:17]#[N:18]>C1COCC1>[F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([C:15]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:16]=3[C:17]#[N:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2c1OCCN2
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2c(F)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a flask charged with 8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (AAT Pharmaceuticals) (0.237 g, 1.547 mmol) was added THF (6.19 ml). The solution was cooled in an ice water bath prior to the addition of sodium hydride (60% in mineral oil) (0.068 g, 1.702 mmol). The resulting suspension was stirred for 30 min at 0° C., the 30 min at rt. The resulting pale yellow suspension was cooled in an ice water bath prior to the addition of 2-fluoro-5-(trifluoromethyl)benzonitrile (0.322 g, 1.702 mmol). The resulting mixture was stirred for 30 min at 0° C., then 1 hr at room temperature. The mixture was heated to 60° C. overnight then at reflux for 2 hr. The mixture was cooled to room temperature and added carefully to ice water and extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered and dried under reduced pressure. The crude material was purified with a 25 g SNAP column ramping EtOAc in heptane (0-25%, 10% DCM throughout) yielding product, obtained as a yellow oil, 2-(8-fluoro-2H-benzo[b][1,4]oxazin-4(3 H)-yl)-5-(trifluoromethyl)benzonitrile (0.168 g, 0.521 mmol, 33.7% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.89-3.97 (m, 2 H) 4.36 (dd, J=4.94, 3.86 Hz, 2 H) 6.61 (dt, J=7.78, 1.79 Hz, 1 H) 6.70-6.80 (m, 2 H) 7.50 (d, J=8.80 Hz, 1 H) 7.71-7.77 (m, 1 H) 7.92-7.95 (m, 1 H). m/z (ESI) 323.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (301 mg) in DMF (5 mL) was added potassium carbonate powder (298 mg) and 4-fluorobenzyl bromide (841 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a peach colored solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:1][C:2]1[CH:11]=[C:10]([O:12][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a solution of methyl 2,4-dihydroxybenzoate (388 mg, 2.0 mmol) in dimethylformamide (5 mL) was added triethylamine, Et3N, (0.556 mL, 4.0 mmol) followed by trityl chloride (557.5 mg, 2.0 mmol) and 4-dimethylaminopyridine (DMAP) (20 mg). The reaction mixture was kept on stirring at room temperature overnight, poured into a mixture of ice-water, the white precipitate was collected by filtration. This precipitate was subjected to silica gel flash chromatography (0-5% ethyl acetate in petroleum ether) to give the subtitled compound (350 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.Cl.[NH:11]1[CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CN2CCC2)cn1
Temperature: 80 °C
Yield: 52.1 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (0.34 g, 2.1 mmole) in 4 mL of dry acetonitrile is 389 mg (4.14 mmol) of azetidine-hydrochloride followed by 572 mg (4.14 mmol) of potassium carbonate. The reaction is heated at 80° C. for 3 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 200 mg (53% yield) of 1-(6-Chloro-pyridin-3-ylmethyl)-azetidine. Diagnostic 1H NMR (400 MHz, CDCl3) 2.06–2.14 (m, 2H), 3.23 (t, 4H, J=7.0 Hz), 3.55 (s, 2H), 7.27 (d, 1H, J=7.9 Hz), 7.61 (dd, 1H, J=8.3 and 2.5 Hz), 8.26 (d, 1H, J=2.5 Hz); MS 183.2 (M+H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].O.[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[Na+].[Na+].[Al+3].[Al+3].[Si+4].C([O-])([O-])=O.[K+].[K+]>>[C:9]([C:11](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(C#N)=Cc1ccccc1
Temperature: 90 °C
Reaction time: 0.07 h
Yield: 98 %

Procedure:
10.61 g of benzaldehyde (0.1 mol) and 11.31 g of ethyl cyanoacetate (0.1 mol) are placed in a flask equipped with a reflux condenser and heated to 90° C. 1.0 g of zeolite A (supplied by Merck: MS 3 Å) and 0.5 g of K2CO3 are then added in succession. The reaction starts immediately and is complete after about 4 minutes. The reaction mixture is filtered while still hot, giving ethyl cyanocinnamate in a purity of >96%. The yield is 98%.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH2:13][N:12]([CH3:14])[C:11](=O)[CH2:10][CH2:9]1>C1COCC1>[Cl:22][C:18]1[CH:17]=[C:16]([C:8]2([NH2:7])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH2:13]2)[CH:21]=[CH:20][CH:19]=1
Reactant: CN1CC(N)(c2cccc(Cl)c2)CCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC(N)(c2cccc(Cl)c2)C1
Yield: 86.5 %

Procedure:
To a slurry of 20 mg (0.494 mmol) LiAlH4 in 0.5 ml THF was added dropwise a solution of 59 mg (0.247 mmol) rac-5-amino-5-(3-chloro-phenyl)-1-methyl-piperidin-2-one in 0.6 ml THF at room temperature. The mixture was refluxed for 30 minutes. The mixture was cooled in an ice bath and quenched carefully with 20 ul water, 20 ul 5N NaOH and finally 60 ul water. Ethyl acetate was added. The mixture was filtered and the filtrate was concentrated in vacuo to provide 48 mg (86%) of the title compound as a colorless oil. MS (m/e): 225.2 (MH+).
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].C([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[CH2:22][NH:23][C:24]([NH2:26])=[NH:25])C1C=CC=CC=1.C(N1C2C(=CC=CC=2)CC1CNC(N)=N)C1C=CC=CC=1.N1C2C(=CC=CC=2)CC1C(OCC)=O.O=S(Cl)Cl.C(N1C2C(=CC=CC=2)CC1CCl)C1C=CC=CC=1.C1(=O)NC(=O)C2=CC=CC=C12.[K].S(O)(O)(=O)=O.CSC(=N)N.CSC(=N)N>C(O)C.[Pd]>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH:23]([CH2:22][CH:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13]1)[C:24]([NH2:26])=[NH:25].[NH:23]([CH2:22][CH:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13]1)[C:24]([NH2:26])=[NH:25]
Reactant: N=C(N)NCC1Cc2ccccc2N1Cc1ccccc1
Agent: [Pd]
Agent: CCOC(=O)C1Cc2ccccc2N1
Agent: CSC(=N)N
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: N=C(N)NCC1Cc2ccccc2N1

Procedure:
10 g of 1-benzyl-2-guanidinomethyl-indoline hemisulphate (obtainable from ethyl indoline-2-carboxylate by N-benzylation, reduction and reaction with SOCl2 to give 1-benzyl-2-chloromethyl-indoline, reaction of the latter with potassium phthalimide and hydrolysis of the reaction product, and reaction of this product with S-methyl-isothiourea hemisulphate) are dissolved in 200 ml of ethanol and hydrogenated over 3 g of 5% Pd/C at 20° C. and 1 atmosphere until the reaction ceases. After filtering and evaporating the filtrate, 2-guanidinomethyl-indoline hemisulphate is obtained.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][O:5][CH2:6][O:7][C:8]1[C:17]([C:18]#[N:19])=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH3:20])=[N:15]2)=[CH:10][CH:9]=1>C1(C)C=CC=C(C)C=1>[CH:20]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[C:17]([C:18]#[N:19])[C:8]([O:7][CH2:6][O:5][CH3:4])=[CH:9][CH:10]=2)[N:15]=1)=[O:2]
Reactant: O=[Se]=O
Reactant: COCOc1ccc2ccc(C)nc2c1C#N
Solvent: Cc1cccc(C)c1
Product: COCOc1ccc2ccc(C=O)nc2c1C#N
Temperature: 74 °C
Reaction time: 20 h
Yield: 31.3 %

Procedure:
Referring to FIG. 20, under a nitrogen atmosphere selenium dioxide (0.0145 g, 0.131 mmol) was added to a solution of 8b (0.0300 g, 0.136 mmol) in m-xylene (5 mL). The mixture was stirred at 74° C. for 20 h then filtered. The filtrate was evaporated, and the residue was purified by column chromatography (3:7 EtOAc/hexane) to yield 9b (0.0100 g, 0.041 mmol, 30%) as a white solid: 1H NMR (CDCl3) δ 10.29 (1H, s), 8.34 (1H, d, J=8.0 Hz), 8.09 (1H, d, J=9.6 Hz), 8.04 (1H, d, J=8.0 Hz), 7.73 (1H, d, J=9.2 Hz), 5.50 (2H, s), 3.61 (3H, s); 13C NMR (CDCl3) δ 193.7, 163.0, 154.2, 148.6, 137.9, 133.9, 125.4, 118.5, 117.3, 114.3, 95.4, 57.3; FTIR (neat) 2922, 2846, 2224, 1710, 1260, 1165, 1043, 922, 856, 775 cm−1; MS (ESI) m/z calculated for (C13H10N2O3+H)+ 243, found 243; HRMS (ESI) m/z calculated for (C13H10N2O3+H)+ 243.0769, found 243.0764.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>CC(O)C.ClCCl>[Cl:9][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:7]=1[NH2:8]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: NC1CCOCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Cl)c(N)c(NC2CCOCC2)n1
Temperature: 25 °C

Procedure:
Heat a solution of 4,6-Dichloro-2-methyl-pyrimidin-5-ylamine (0.008 mol, 1.5 g, 1.0 equiv.), 4-amino tetrahydropyran (0.012 mol, 1.27 g, 1.5 equiv.), and N,N-diisopropylethylamine (0.0092 mol, 1.1 g, 1.1 equiv.) in 2-propanol (80 mL) at 150° C. in a sealed tube for 16 hours. Cool the reaction mixture to room temperature and remove the 2-propanol under reduced pressure to give the residue. Dissolve the residue in dichloromethane and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue on silica gel column eluting with dichloromethane: methanol 96:4 to give the title compound. MS (m/z): 243.41 (M+1).
Reaction SMILES: Cl([O-])=O.[Na+].[OH:5][C:6]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][C:7]=1[CH:8]=[O:9].C[O-:20].[Na+].Cl>CO.CS(C)=O.O>[OH:5][C:6]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][C:7]=1[C:8]([OH:20])=[O:9]
Reactant: C[O-]
Reactant: COCCOc1ccc(O)c(C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: COCCOc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium chlorite (8.08 g) was added over a period of 30 seconds to a stirred solution 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde (see Example 41) and sodium methoxide in methanol (25% by weight solution, 9.68 ml) in dimethylsulphoxide (350 ml) at 15° C. After warming to room temperature and stirring for 3 hours the mixture was added to water (600 mls), acidified with 2M aqueous hydrochloric acid, and extracted with diethyl ether (4×250 mls). The ethereal extracts were combined, washed with water (2×100 ml), dried (MgSO4) and evaporated. The residue was crystallised from toluene to give 2-hydroxy-5-(2-methoxyethoxy)benzoic acid (4.1 g) as solid m.p. 115-116° C.; NMR 3.3(3H,s), 3.65(2H,m), 4.05(2H,m), 6.9(1H,d), 7.15(1H, d of d), 7.25(1H,d); m/z 213(M+H).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:1])[CH2:32][CH2:31]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC(O)CC3)C[C@@H]12
Reactant: OC1CCNCC1
Product: C[C@]12C[C@H](N3CCC(O)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC(O)CC3)C[C@@H]12
Yield: 85.4 %

Procedure:
2α,3α-Epoxy-16β-(4-hydroxy-1-piperidinyl)-5α-androstane-17β-ol is reacted with 4-hydroxypiperidine as described in Example 3 to obtain the title compound in a yield of 85.4%, m.p.: 248°-250° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4[CH2:27][C:28]3([NH:36]C(=O)OC(C)(C)C)[CH2:33][O:32]C(C)(C)[O:30][CH2:29]3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].CC1(C)OCC(NC(=O)OCCCC)(CNC2C=CC(CCCCCCCC)=CC=2)CO1>>[NH2:36][C:28]([CH2:27][N:22]1[C:23]2[C:19](=[C:18]([C:15]3[N:14]=[C:13]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)[O:17][N:16]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]1)([CH2:29][OH:30])[CH2:33][OH:32]
Reactant: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Agent: CCCCCCCCc1ccc(NCC2(NC(=O)OCCCC)COC(C)(C)OC2)cc1
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC(N)(CO)CO)no2)cc1OCC
Yield: 71 %

Procedure:
When the product of Step D was substituted for tea-butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan-5-ylcarbamate in Example 1, Step B, the identical process afforded the title compound in 71% yield, as a creamy solid. 1H-NMR (CDCl3) 1.5 (m, 6H); 1.82 (broad s, 4H+H2O); 3.16 (m, 2H); 3.41-3.59 (m, 8H); 4.13-4.3 (m, 4H); 6.96 (d, 1H, J=7.9 Hz); 7.2 (tr, 1H, J=7.9 Hz); 7.5 (d, 1H, 7.8 Hz); 7.67 (d, 1H, J=1.9 Hz); 7.7 (dd, 1H, J=1.9, 8.4 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C.O>C(#N)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:24])(=[O:23])[NH2:25])=[CH:20][CH:21]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: NS(=O)(=O)c1ccc(CNC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.5 %

Procedure:
A solution of 4-nitrobenzoylchloride (1.85 g, 1 eq.) in acetonitrile (20 ml) was added to a solution of 4-aminomethyl-benzenesulfonamide hydrochloride (4.44 g, 2 eq.) and triethylamine (2.78 ml, 2 eq.) in acetonitrile (40 ml) at 0° C. under inert atmosphere. After the addition was completed, the mixture was warmed to rt and stirred for 3 d. Water was added and the mixture was concentrated under reduced pressure. The resulting precipitate was filtered off and washed with water and methanol to yield 2.86 g (85%) of 4-nitro-N-(4-sulfamoylbenzyl)-benzamide.
Reaction SMILES: Cl[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:9]2[C:8](=[O:18])[NH:7][C:6](=[O:19])[N:5]([CH3:20])[C:4]=2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(OCC)(=O)C>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:9]3[C:8](=[O:18])[NH:7][C:6](=[O:19])[N:5]([CH3:20])[C:4]=3[N:3]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Cl)n2-c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Temperature: 150 °C
Reaction time: 4 h
Yield: 51.2 %

Procedure:
8-Chloro-7-(2-chlorophenyl)-3-methyl-3,7-dihydropurine-2,6-dione (58 mg) and 1-(tert-butoxycarbonyl)piperazine (150 mg) were mixed. The reaction solution was stirred at 150° C. for 4 hours, then diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 44 mg of the title compound from a fraction eluted with ethyl acetate.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][CH:21]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[CH3:22]>>[CH3:22][CH:21]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:30][CH:31]=1)[CH3:20]
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CC(C)Oc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-propan-2-yloxybenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-propan-2-yloxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.