Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C@@H:16]([OH:17])[CH2:15]N(C(OCC3C=CC=CC=3)=O)[CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].N[C@@H]1C[O:32]C[C@H]1O>>[CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[CH2:13][O:32][CH2:15][C@H:16]2[OH:17])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: N[C@@H]1COC[C@H]1O
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Product: CCc1cnc(CC)c(N[C@@H]2COC[C@H]2O)n1

Procedure:
Following the procedure for the preparation of benzyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate but substituting trans-(+/−)-4-aminotetrahydrofuran-3-ol and making non-critical variations provided the title compound as an orange oil. IR (diffuse reflectance) 3356, 3255, 2972, 2938, 1587, 1511, 1464, 1453, 1396, 1337, 1185, 1099, 1064, 965, 888 cm−1; OAMS supporting ions at: ESI+ 238.1; MS (EI) m/z 237 (M+); HRMS (FAB) calcd for C12H19N3O2+H1 238.1555, found 238.1551.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Cl.Cl[CH2:16][C:17]1[CH:18]=[N:19][N:20]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:16][C:17]2[CH:18]=[N:19][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH:21]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: COc1ccc(Cn2cc(CCl)cn2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(Cn3nc(I)c4c([N+](=O)[O-])cccc43)cn2)cc1
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To 3-iodo-4-nitro-1H-indazole (2.13 g, 7.37 mmol) in DMF (20 mL) was added 4-(chloromethyl)-1-(4-methoxybenzyl)-1H-pyrazole hydrochloride (2.21 g, 8.11 mmol) and K2CO3 (3.06 g, 22.1 mmol). The reaction mixture was stirred for 16 hours. The reaction mixture was diluted with EtOAc, washed with H2O, and brine, and the filtrate was concentrated under reduced pressure. Silica gel chromatography (hexanes/EtOAc 5:1) provided the desired product (2.88 g).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:12](OCC)(=O)[CH2:13][CH2:14]C.[O-]CC.[Na+]>O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([CH2:12][CH2:13][CH3:14])=[O:9])[CH:3]=1
Reactant: CCCC(=O)OCC
Reactant: CCOC(=O)c1cccnc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCCC(=O)c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of ethyl nicotinate (15.1 g, 0.1 mole), ethyl butyrate (17.4 g, 0.15 mole) and sodium ethoxide (10.2 g, 0.15 mole) was stirred and heated under nitrogen at 100° C. for five hours. After cooling, the mixture was diluted with water (150 ml), extracted with diethyl ether (50 ml) and the aqueous layer made acidic to pH1 with concentrated hydrochloric acid (50 ml). The aqueous layer was heated at 90° C. for 2 hours, cooled, and made alkaline with solid potassium carbonate and extracted with diethyl ether (3×75 ml). The dried (magnesium sulphate) organic layer was concentrated and distilled to give propyl 3-pyridyl ketone (b.pt. 118°-120° C./14 mm Hg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][CH:7]=1.S(Br)([Br:16])=O>O1CCOCC1.C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Br:16])=[CH:8][CH:7]=1
Reactant: O=S(Br)Br
Reactant: OCc1ccc(OCCCCl)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: ClCCCOc1ccc(CBr)cc1
Reaction time: 0.17 h

Procedure:
A solution consisting of 4-(3-chloropropoxy)-benzyl alcohol No. 162 (10.6 g, 52.8 mmol) in dioxane (0.125 l) was cooled to 0° C. and treated with a dropwise addition of thionyl bromide (12.0 g, 58.0 mmol). After 10 minutes the reaction was complete. The dioxane was diluted with ethyl ether and washed with water, brine, and then dried over MgSO4. The material was concentrated down to yield 15 g of an oil: 1H NMR (DMSO) 7.36 (d, 2 H, J=8.8 Hz), 6.92 (d, 2 H, J=8.6 Hz), 4.68 (s, 2 H), 4.08 (t, 2 H, J=5.9 Hz), 3.77 (t, 2 H, J=6.4 Hz); MS (FAB) 266 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:11][CH:12]=2)[CH2:7]1.[N+:24]([C:27]1[CH:37]=[CH:36][C:30](/[CH:31]=[CH:32]/[C:33](Cl)=[O:34])=[CH:29][CH:28]=1)([O-:26])=[O:25].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N+:24]([C:27]1[CH:28]=[CH:29][C:30](/[CH:31]=[CH:32]/[C:33]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][C:10]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:11][CH:12]=3)[CH2:7]2)=[O:34])=[CH:36][CH:37]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)/C=C/c1ccc([N+](=O)[O-])cc1
Reactant: NCCCCN1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc([N+](=O)[O-])cc1)NCCCCN1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
A mixture of 2-(4-aminobutyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline (400 mg, 1.14 mmol), trans-4-nitrocinnamoyl chloride (240 mg, 1.14 mmol) and triethylamine (0.2 ml, 1.37 mmol) in dichloromethane (6 ml) was shaken at room temperature for 18 h. Saturated aqueous potassium carbonate (5 ml) was added and shaking resumed for 15 mins. The organic layer was chromatographed on silica using 10-100% ethyl acetate-hexane gradient elution to afford the title compound as a yellow gum (490 mg, 82%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:44][C:45]([O:47][CH3:48])=[O:46]>CC(C)=O>[CH3:48][O:47][C:45](=[O:46])[CH2:44][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:10]3[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1,3-dibenzyl-2-phenyl-1H-indol-5-yl)-phenol (0.541 g, 1.163 mmol) was reacted with K2CO3 (0.225 g, 1.628 mmol) and methyl bromoacetate (0.249 g, 1.628 mmol) in acetone (10 ml) to give the product (0.525 g, 0.976 mmol, 84%) as a solid. 1H NMR (DMSO-d6) δ 3.66 (s, 3H), 4.03 (s, 2H), 4.77 (s, 2H), 5.30 (s, 2H), 6.84 (d, J=6.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 7.04-7.20 (m, 8H), 7.30 (dd, J=1.7, 8.5 Hz, 1H), 7.35-7.47 (m, 8H), 7.54 (d, J=1.2 Hz, 1H); [ESI(+)], m/z 538 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9](=[O:11])[CH3:10])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[CH:17]([NH2:20])([CH3:19])[CH3:18].C1CCCCC1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:20][CH:17]([CH3:19])[CH3:18])[C:5]([C:9](=[O:11])[CH3:10])=[CH:4][N:3]=1
Reactant: CC(=O)c1cnc(Cl)nc1Cl
Reactant: CC(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(=O)c1cnc(Cl)nc1NC(C)C

Procedure:
1-(2,4-dichloro-pyrimidin-5-yl)-ethanone (10 g, 0.052 mol), sodium hydrogen carbonate (19.35 g, 0.058 mol) and isopropylamine (5 mL, 0.058 mol) are taken up in 35 mL THF and 200 mL cyclohexane and stirred for 2 h at 20° C. The reaction solution is filtered through silica gel, the solvent is eliminated in vacuo and 1-(2-chloro-4-isopropylaminopyrimidin-5-yl)-ethanone (HPLC-MS: tRet.=1.73 min, MS(M+H)+=214/216; method FECB3) is obtained.
Reaction SMILES: CC(=CCCC(C)=CCCC(=[O:13])C)C.O[C:16]1([CH3:32])[CH2:25][CH2:24][CH:23]2[C:18](C)([CH2:19][CH2:20][CH2:21][C:22]2([CH3:27])[CH3:26])[CH:17]1CCO>>[CH3:17][C:16]([CH:25]=[CH:24][CH:23]([CH:22]([CH3:27])[CH3:26])[CH2:18][CH2:19][C:20](=[O:13])[CH3:21])=[CH2:32]
Reactant: CC(=O)CCC=C(C)CCC=C(C)C
Reactant: CC1(C)CCCC2(C)C1CCC(C)(O)C2CCO
Product: C=C(C)C=CC(CCC(C)=O)C(C)C

Procedure:
2,6-dimethyl-2,6-undecadiene-10-one; 2-methyl-5-isopropyl acetophenone; 2-hydroxy-2,5,5,8a-tetramethyl-1-(2-hydroxyethyl)-decahydronaphthalene;
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6]3.[CH3:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([NH:36][CH2:37][CH2:38][NH2:39])[CH:27]=1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:39][CH2:38][CH2:37][NH:36][C:28]2[CH:27]=[C:26]([CH3:25])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[C:9]2[O:14][CH2:15][C:16]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6]3
Reactant: Cc1cc(NCCN)nc2ccccc12
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3C1(CCCC1)CO2
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(NCCNc2c(F)c(N)c3c(=O)c(C(=O)O)cn4c3c2OCC42CCCC2)nc2ccccc12
Yield: 3.9 %

Procedure:
A solution of 8-amino-9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]-quinoline-3,1′-cyclopentane]-6-carboxylic acid (13 mg, 0.04 mmol) and N1-(4-methylquinolin-2-yl)ethane-1,2-diamine (10 mg, 0.05 mmol) and 11 μL triethylamine in DMSO (0.3 mL) was stirred at 90° C. for 72 h. The reaction mixture was cooled and freeze-dried overnight. The crude product was taken up in CH2Cl2 and purified by preparative TLC to yield 8-amino-9-fluoro-10-(2-(4-methylquinolin-2-ylamino)ethylamino)-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopentane]-6-carboxylic acid (0.8 mg, 4%) as a yellow solid. MS (EP) m/z: 518 (M++1). (Calcd. for C28H28FN5O4, 517.21).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]([CH3:25])[CH:6]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14].N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([CH:6]([C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[F:14])[CH:5]([CH3:25])[CH2:4][CH2:3][N:2]([CH3:1])[S:33]([CH3:32])(=[O:35])=[O:34])(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNCCC(C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(CCN(C)S(C)(=O)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
To the amine from Step (b) (0.116 g, 0.3 mmol) in dry dichloromethane (5 ml) was added pyridine (0.060 ml, 0.75 mmol), followed by methanesulfonyl chloride (0.035 ml, 0.45 mmol), and the mixture was stirred at room temperature for 48 hours. After dilution with water (20 ml) and extraction with ethyl acetate (3×20 ml), the combined organic fractions were washed with brine, dried (MgSO4 and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with 10% to 30% ethyl acetate in iso-hexane to give as a mixture of diastereoisomers the title compound as a colourless oil (35 mg, 25%).
Reaction SMILES: [CH3:1][C:2]1[C:30]([CH3:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:30]([CH3:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[N:13]=3)[C:4]=2[CH:3]=1
Reactant: CCCN(CCC)CC(=O)N1c2cc(C)c(C)cc2-n2c(n[nH]c2=O)-c2cccnc21
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CCCN(CCC)CC(=O)N1c2cc(C)c(C)cc2-n2c(nn(CCCN(C)C)c2=O)-c2cccnc21
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 6,7-dimethyl-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling 3-(dimethylamino)propylchloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 21 to give 6,7-dimethyl-2,9-dihydro-2-[3-(dimethylamino)-propyl]-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepine-3-one.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([CH2:23][CH2:24][S:25]([CH3:27])=[O:26])[C:20](=[O:28])[C@H:19]([NH:29]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:29][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]([CH2:23][CH2:24][S:25]([CH3:27])=[O:26])[C:20]1=[O:28]
Reactant: CS(=O)CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylsulfinyl)ethyl]-2-oxoazepan-3-ylcarbamate (23 mg, 0.053 mmol) in dichloromethane (2 mL). After 3 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 331 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)=[CH:2]1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[K+]>C(O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:20][OH:21])=[CH:2]1
Reactant: O=C(Cc1c[nH]c2ccccc12)c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: ON=C(Cc1c[nH]c2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
2-(1H-indol-3-yl)-1-phenylethanone (0.97 g, 4.12 mmol) dissolved in absolute ethanol (20 ml) was added to a solution of hydroxylamine hydrochloride (0.97 g, 13.95 mmol) and potassium acetate (1.54 g, 15.74 mmol) in absolute ethanol (20 ml). This reaction mixture was stirred for 24 h at room temperature. The batch was then boiled for 3 h with reflux. The batch was then dissolved in water (20 ml) at 70° C. The batch was then left to stand for 5 h at 4° C. Since no solid separated out, the volatile constituents were removed completely in a vacuum. The residue was mixed with water (10 ml) and the pH value of the solution adjusted to pH 11 with 5N sodium hydroxide solution. The mixture was then extracted with ethyl acetate (5×30 ml). The combined organic phases were dried with sodium sulphate, filtered and all the volatile constituents removed in a vacuum. Yield: 90% (990 mg) yellow-brown oil
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:31](O)=O>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[C:25]=3[N:24]=[N:23]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CO
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3c2CCCN3)cc1
Product: CN1CCCc2c1nnn2-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 100 °C

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-[4-chloro-2-(4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide (synthesized according to general procedure M, 11 mg, 0.025 mmol), H2CO (37% in H2O, 3 mg, 0.037 mmol), and HCO2H (100 L). The vial was sealed and heated to 100° C. for 1 hour. The solvent was subsequently removed in vacuo and the residue purified by preparative TLC to afford 4-tert-butyl-N-[4-chloro-2-(4-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide: MS (ES) M+H expected 460.2, found 460.0.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]([N:17](CC)C(C)C)(C)C.N#CBr>ClCCl.O>[C:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)#[N:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: N#CBr
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.1 %

Procedure:
To a cooled (0° C.) solution of tert-butyl piperazine-1-carboxylate (1.517 g, 8.14 mmol) in dichloromethane (10 mL) were added N,N-diisopropylethylamine (1.54 mL, 9.00 mmol) and cyanogen bromide (911 mg, 8.60 mmol) and the reaction was stirred for 45 min at 0° C. The reaction mixture was warmed to room temperature, poured in water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was washed twice with heptane and dried in vacuo, yielding 1.24 g (5.87 mmol, 72%) of a white solid that was used directly in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11](=[NH:13])[NH2:12].[Na].[C:15](OCC)(=[O:22])[CH2:16][C:17](OCC)=[O:18]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11]1[N:12]=[C:17]([OH:18])[CH:16]=[C:15]([OH:22])[N:13]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)Cc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Oc1cc(O)nc(Cc2c(Cl)cccc2Cl)n1
Yield: 76.4 %

Procedure:
To the stirred solution of 2,6-dichlorobenzeneethanimidamide HCl (1:1), (0.0042 mol) in ethanol (20 ml), a solution of sodium (0.013 mol) in ethanol (10 ml) was added dropwise first and then propanedioic acid, diethyl ester (0.0109 mol) was added. The reaction mixture was stirred and refluxed for 4 hours and then stirred at room temperature overnight. After adding another equivalent of propanedioic acid, diethyl ester (stirring and refluxing it overnight), the solvent was evaporated and the residue was dissolved in water and acidified with 1 N HCl. The solid was filtered off, washed with water and dried, yielding 0.87 g (76.4%) of 2-[(2,6-dichloro-phenyl)methyl]-4,6-pyrimidinediol (interm. 8).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.O.[H-].[Na+].C[O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](Br)[N:20]=1)=[O:18]>CC(N(C)C)=O.[Cu](I)I>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]([OH:18])=[O:16])=[N:20][C:21]=1[O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(OC)c(Br)n1
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(C(=O)O)nc1Oc1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
3-(trifluoromethyl) phenol (1.317 g, 0.0081 mol) was dissolved in 10 ml of dried dimethyl acetamide. While cooling the obtained solution with water, sodium hydride (0.39 g (ca. 60% in mineral oil), 0.0081×1.2 mol) was added to the solution. After completion of the foaming, a solution obtained by dissolving 6-bromo-5-methoxy-2-pyridine carboxylic acid methyl ester (2.0 g, 0.0081 mol) in 10 ml of dried dimethyl acetamide, and then copper iodide (1.55 g, 0.081 mol) were successively added to the solution. The obtained mixture was heated and stirred at 120° C. for 10 hours. Thereafter, the obtained reaction solution was cooled, mixed with 50 ml of water and then with 50 ml of ethyl acetate, and filtered through a glass filter provided with Hyflo Super-Cell. The obtained filtrate was extracted with ethyl acetate to obtain an aimed product. An organic phase was separated from the product, washed with water and then dried with anhydrous sodium sulfate. The dried product was concentrated, and the obtained residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[N:7][S:8][C:9]=1[NH:10]C(OC(C)(C)C)=O)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[N:7][S:8][C:9]=1[NH2:10])=[O:4]
Reactant: COC(=O)c1c(SCc2ccc(Cl)cc2)nsc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(SCc2ccc(Cl)cc2)nsc1N
Reaction time: 16 h
Yield: 82.3 %

Procedure:
Compound 19 (6.5 g, 15.67 mmol) is dissolved in methylene chloride (65 mL) and TFA is added (65 mL). After 16 hrs., the reaction is filtered and the solids are washed with ethyl ether. The solids are further dried in vacuo to provide 20 (4.06 g, 82%). 1H NMR (d6 DMSO): δ 7.88 (2H, br. s), 7.38 (2H, d, J=8.6 Hz), 7.32 (2H, d, J=8.6 Hz), 4.24 (2H, s), 3.69 (3H, s).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>ClCCl>[Cl:13][C:11]1[CH:10]=[C:9]([Cl:14])[CH:8]=[C:7]2[C:12]=1[C@@H:3]([NH:2][C:26]([CH2:27][CH2:28][CH3:29])=[O:30])[CH2:4][C@H:5]([C:15]([O:17][CH3:18])=[O:16])[NH:6]2
Reactant: CCCC(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N[C@H]1C[C@H](C(=O)OC)Nc2cc(Cl)cc(Cl)c21
Yield: 84.4 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (example 9a) (0.200 g, 0.642 mmol) in anhydrous dichloromethane (15 ml) under an atmosphere of nitrogen was added dry triethylamine (0.197 ml, 1.41 mmol) and the mixture was stirred until dissolution was complete. To this solution was then added butyryl chloride (0.073 ml, 0.706 mmol) and the reaction was stirred at room temperature for 4 h. The mixture was then evaporated to dryness in vacuo and the residue was partitioned between ethyl acetate (50 ml) and 0.5M aqueous citric acid (30 ml). The organic layer was separated, washed successively with saturated sodium bicarbonate solution (1×30 ml) and brine (1×30 ml), then dried (MgSO4) and evaporated to give a solid which was triturated with diethyl ether. The solid was collected by filtration to give the pure title compound as colourless crystals (0.187 g), m.p. 205°-206° C. δ (CDCl3, 360 MHz) 0.96 (3H, t, J=7.4 Hz, COCH2CH2CH3). 1.64-1.72 (3H, m, CHACHBHCCHD and COCH2CH2CH3), 2.17 (2H, t, J=7.4 Hz, COCH2CH2CH3), 2.68 (1H, dm, J=14.0 Hz, CHACHBHCCHD), 3.81 (3H, s, CO2CH3), 3.94 (1H, dd, J= 12.6 and 2.9 Hz, CHACHBHCCHD), 4.85 (1H, br.s, ArNH), 5.26 (1H, m, CHACHBHCCHDNHCO), 5.37 (1H, br.d, J=18 7 Hz, CHDNHCO), 6.56 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.73 (1H, d, J=2.0 Hz, 6-H or 8-H). m/e (CI+) 345 (100%, (M+I)+).
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>>[C:20]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[CH2:7][O:6][C:5]1[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:4]=1[C:2]#[N:3])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Product: CC(C)(C)C(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared as in Example 176b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride and pivaloyl chloride in 99%. 1H NMR (400 MHz, DMSO-d6) δ 1.16 (s, 9H), 1.91 (m, 3H), 2.13 (m, 1H), 3.70 (m, 2H), 4.35 (m, 3H), 7.81 (dd, J=7.5, 2.1 Hz, 1H), 7.92 (m, 2H).