Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[CH3:16][C:17]1([CH3:37])[O:21][C@H:20]([CH2:22][O:23][C:24]2[C:33]([CH3:34])=[CH:32][C:27]([C:28]([NH:30][OH:31])=[NH:29])=[CH:26][C:25]=2[O:35][CH3:36])[CH2:19][O:18]1.Cl.N>>[CH3:16][C:17]1([CH3:37])[O:21][C@H:20]([CH2:22][O:23][C:24]2[C:33]([CH3:34])=[CH:32][C:27]([C:28]3[N:30]=[C:12]([C:10]4[S:11][C:7]([CH2:6][N:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([CH3:15])[CH:9]=4)[O:14][N:29]=3)=[CH:26][C:25]=2[O:35][CH3:36])[CH2:19][O:18]1.[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:31][N:30]=[C:28]([C:27]3[CH:32]=[C:33]([CH3:34])[C:24]([O:23][CH2:22][C@@H:20]([OH:21])[CH2:19][OH:18])=[C:25]([O:35][CH3:36])[CH:26]=3)[N:29]=2)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2]
Reactant: COc1cc(C(=N)NO)cc(C)c1OC[C@@H]1COC(C)(C)O1
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Agent: Cl
Agent: N
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(OC[C@@H](O)CO)c(OC)c3)no2)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3cc(C)c(OC[C@@H]4COC(C)(C)O4)c(OC)c3)no2)cc1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 114.8 %

Procedure:
(R)-(5-{3-[4-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3-methoxy-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-3-methyl-thiophen-2-ylmethyl)-diethyl-amine is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3-methoxy-5-methyl-benzamidine (36 mg, 117 μmol) according to Method A. After the coupling and cyclisation step, the reaction mixture is acidified by adding 35% aq. HCl and the reaction mixture is stirred at rt for 40 min. The mixture is neutralised by adding 25% aq. NH3 solution before it is separated by prep. HPLC to give the title compound (31 mg) as a resin; LC-MS: tR=0.52 min; [M+1]+=462.21; 1H NMR (D6-DMSO): δ1.03 (t, J=7.0 Hz, 6H), 2.22 (s, 3H), 2.32 (s, 3H), 2.58 (q, J=7.0 Hz, 4H), 3.41-3.50 (m, 2H), 3.73 (s, 2H), 3.74-3.81 (m, 1H), 3.84-3.89 (m, 1H), 3.89 (s, 3H), 4.03 (dd, J=9.8, 4.3 Hz, 1H), 4.59 (t, J=5.8 Hz, 1H), 4.84 (d, J=5.3 Hz, 1H), 7.44-7.47 (m, 1H), 7.49-7.52 (m, 1H), 7.81 (s, 1H).
Reaction SMILES: ClCC1N=NC=CC=1.C(N)CN.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:20][CH2:21][CH2:22][NH2:23])[N:14]=1.[CH3:24][N:25]=[C:26]=[S:27]>>[CH3:24][NH:25][C:26]([NH:23][CH2:22][CH2:21][NH:20][CH2:19][C:15]1[N:14]=[N:13][CH:18]=[CH:17][CH:16]=1)=[S:27]
Reactant: NCCNCc1cccnn1
Reactant: CN=C=S
Agent: ClCc1cccnn1
Solvent: NCCN
Product: CNC(=S)NCCNCc1cccnn1

Procedure:
Reacting 3-chloromethylpyridazine with ethylenediamine by the procedure of Example 34 and reacting the resulting N-(3-pyridazinylmethyl)ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b), then chromatographing gives N-methyl-N'-[2-(3pyridazinylmethylamino)ethyl]thiourea. This intermediate is reacted with lead cyanamide by the procedure of Example 3(b) to give N-cyano-N'-methyl-N"-[2-(3-pyridazinylmethylamino)-ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N'-[2-(3-pyridazinylmethylamino)ethyl]guanidine dihydrochloride.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH3:1][N:2]([CH2:3][C:4]([OH:6])=[O:5])[C:16]([NH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: O=C=Nc1ccccc1
Reactant: CNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(CC(=O)O)C(=O)Nc1ccccc1
Temperature: 24 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 70 g. of N-methylaminoacetic acid and 70 g. of sodium hydroxide in 500 ml. of water were added portion-wise over twenty minutes 100 g. of phenyl isocyanate. Following complete addition, the aqueous reaction mixture was stirred at 24° C. for two hours. The mixture was then filtered and the filtrate was acidified to pH 2 by the addition of corc. hydrochloric acid. The precipitate which formed was collected by filtration to provide N-methyl-N-carboxymethyl-N'-phenylurea.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:11])=[C:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:29])[N:26]([CH3:27])[C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:18][C:17]=1[S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C.O>C(OCC)(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:29])[N:26]([CH3:27])[C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:18][C:17]=1[S:30](=[O:32])(=[O:31])[NH:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]([OH:11])=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:7]=1
Reactant: CN1C(=O)CCC1(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CC(C)c1cc(N)cc(C(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1cc(NS(=O)(=O)c2cc(C3(O)CCC(=O)N3C)ccc2Cl)cc(C(C)C)c1O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A suspension of 29.1 g of 4-amino-2,6-diisopropylphenol in 450 ml of ethyl acetate is added in portions to a solution of 17.5 g of 5-(4-chloro-3-chlorosulfonylphenyl)-5-hydroxy-1-methyl-2-pyrrolidone and 22.7 g of triethylamine in 200 ml of ethyl acetate. The mixture is stirred at 50° C. for 3 hours, cooled, water is added, the organic phase is separated off, and the aqueous phase is extracted several times with ethyl acetate. The combined organic phases are washed with water and dried over sodium sulfate, and the solvent is distilled off. After addition of about 250 ml of methylene chloride to the amorphous red residue it is refluxed and crystallization is induced by scratching. The mixture is stirred at room temperature for 30 min, and the precipitate is filtered off and recrystallized from acetonitrile without prolonged standing. Colorless crystals of melting point 198°-200° C.
Reaction SMILES: [OH-:1].[K+].Cl.[NH2:4]O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]([C@@H:17]1[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:20]([OH:21])[C@H:18]1[OH:19])[C:11]([Br:29])=[C:10]2[C:30]#[N:31].CO.C(Cl)(Cl)Cl>CO.NO.CO.O>[NH2:4][OH:1].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]([C@@H:17]1[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]1[OH:19])[C:11]([Br:29])=[C:10]2[C:30](=[N:31][OH:1])[NH2:4]
Reactant: [OH-]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Br)c(C#N)c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=NO)c1c(Br)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
A solution of hydroxylamine in absolute MeOH was prepared by adding potassium hydroxide (1.83 g, 33 mmol) to hydroxylamine hydrochloride (2.50 g, 36 mmol) dissolved in absolute MeOH (20 mL) and stirring for 10 min. The resulting solids were filtered and rinsed with cold absolute MeOH (10 mL), and the filtrate used without further purification. 5,6-Dichloro-2-bromo-3-cyano-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.139, 133 mg, 0.29 mmol) was dissolved in the crude solution of hydroxylamine in MeOH and stirred at room temperature for 4 days. The solvent was then removed under vacuum, and the residual solid dissolved in brine (40 mL). The aqueous suspension was extracted with EtOAc (2×50 mL), and the combined organic extracts dried over MgSO4, filtered and evaporated to yield a pale yellow solid. The solid was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 20% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a pale yellow solid. The solid was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a pale yellow solid which was recrystallized from MeOH/H2O to yield 54 mg (41%) of 4.140 as a pale yellow powder: mp slow dec >170 □C; Rf 0.5 (20% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 9.66 (s, 1H, D2O exch.), 8.48 (s, 1H), 7.89 (s, 1H), 5.99 (d, 1H), 5.76 (s, 2H, D2O exch.), 5.35 (t, 1H, D2O exch.), 5.31 (d, 1H, D2O exch.), 5.22 (d, 1H, D2O exch.), 4.45 (q, 1H), 4.15 (t, 1H), 3.96 (d, 1H), 3.72 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 146.18, 133.16, 127.04, 124.88, 123.77, 120.74, 115.72, 114.86, 110.61, 90.17, 85.68, 71.21, 69.55, 61.07. HRMS (ES) m/z calcd. for C14H14BrCl2N3O5+H 453.9572, found 453.9570. Anal calcd for C14H14BrCl2N3O5·¼MeOH: C, 36.96; H, 3.26; N, 9.07. Found: C, 37.11; H, 3.22; N, 8.85.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([F:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C)C(=O)C>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:8]([F:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Solvent: CC(=O)N(C)C
Product: CCS(=O)(=O)c1ccc(N2CCNCC2)c(F)c1
Temperature: 80 °C

Procedure:
To 2.0 mmol 4-ethanesulfonyl-1,2-difluoro-benzene in 5 ml N,N-dimethylacetamide was added 5.6 mmol piperazine and the mixture was heated at 80° C. for 45 min. The mixture was then concentrated in vacuo to afford the title compound. MS (m/e): 273.0 (M+H+, 100%)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[Cl:33].Cl.CCO>>[Cl:25][C:26]1[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=1[O:17][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH2:15][CH3:16]
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CCC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCC[C@H](Oc1cccc(Cl)c1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((S)-1-Hydroxybutyl)pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 0.2 mmol) was dissolved in DMF (1.0 mL, 13 mmol). NaH (5.9 mg, 246 μmmol) was slowly added and the mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3-fluorobenzene (67.8 mg, 411 μmmol) was added. The mixture was stirred at 70° C. for 3 hours, then concentrated. 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (19 mg, 100% purity). MS m/z: [M+H]+ calcd for C14H19Cl2NO, 288.08; found 288.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][C:2]=1[CH3:10].[C:11]([C:13]1([NH:16][C:17]([C@@H:19]2[CH2:23][C@@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@H:20]2[O:38][CH3:39])=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@@H:19]2[CH2:23][C@@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:4]4[CH:5]=[CH:6][N:1]=[C:2]([CH3:10])[CH:3]=4)=[CH:29][C:28]=3[C:34]([F:35])([F:36])[F:37])(=[O:25])=[O:26])[CH2:21][C@H:20]2[O:38][CH3:39])=[O:18])[CH2:14][CH2:15]1)#[N:12]
Reactant: CO[C@@H]1C[C@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1
Reactant: Cc1cc(B(O)O)ccn1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: CO[C@@H]1C[C@H](S(=O)(=O)c2ccc(-c3ccnc(C)c3)cc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared in analogy to example 62 using 2-picoline-4-boronic acid instead of 2.4-difluorophenylboronic acid and (1R,2R,4R)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 137) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. Pink solid. MS (EI): 508.1 (M+H)+.
Reaction SMILES: C(Cl)(=O)C.[Cl:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Cl:46])[C:11]=1[C@H:12]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20](C1CCCCO1)[N:19]=[C:18]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][N:35]([CH2:37][CH2:38][O:39]C2CCCCO2)[CH:36]=1)[CH3:13]>CO>[Cl:46][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:5])[C:11]=1[C@H:12]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][N:35]([CH2:37][CH2:38][OH:39])[CH:36]=1)[CH3:13]
Reactant: C[C@@H](Oc1ccc2c(c1)c(/C=C/c1cnn(CCOC3CCCCO3)c1)nn2C1CCCCO1)c1c(Cl)cncc1Cl
Solvent: CC(=O)Cl
Solvent: CO
Product: C[C@@H](Oc1ccc2[nH]nc(/C=C/c3cnn(CCO)c3)c2c1)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Charge a 3-neck, 250 mL round bottom flask equipped with an addition funnel, nitrogen inlet, internal temperature probe and magnetic stirrer with methanol (57 mL) and cool in an ice bath. To the resulting solution, add acetyl chloride (20 mL, 281.03 mmol) slowly through an addition funnel To the solution, add 5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-3-((E)-2-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)vinyl)-1H-indazole (7.1 g, 11.59 mmol) dissolved in methanol (40 mL) via addition funnel. After addition is complete, remove the ice bath, warm to RT and stir the mixture for 4 hours. Concentrate the reaction mixture in vacuo to a yellow foam. Dissolve the yellow foam in methanol (10 mL) and add slowly to a saturated aqueous sodium bicarbonate solution (120 mL). Stir the mixture at RT for 30 minutes. Filter the mixture, wash the solid with water (100 mL), and dry under vacuum. Recrystallize the solid from hot EA/methanol/hexanes to give the title compound as a white solid. Yield: 2.1 g (41%). MS (ES) m/z 444 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:27][O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH2:31]>CCCCCC.C(OCC)(=O)C>[CH3:27][O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH:31][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1-c1ccccc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(OCc2ccccc2)cc1-c1ccccc1
Yield: 82 %

Procedure:
The compound prepared in Example 975A was hydrolyzed with 1N aqueous NaOH and the carboxylic acid was coupled with (L)-methionine methyl ester by using coupling reagents. After flash column chromatography (1.5:1 =hexane/ethyl acetate), the desired compound was obtained (82% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:13]=[C:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C@@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:40](=[O:41])[C:39]2[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=2)[CH2:7][CH2:6]1
Reactant: O=C1CCCN1[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](N2CCCC2=O)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: -5 °C
Yield: 62.1 %

Procedure:
Dissolve 1-(trans-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (144 g, 0.79 mol) in dry tetrahydrofuran (5 L) and cool to −5° C. under nitrogen. Add triphenylphosphine (310 g, 1.185 mol) and 4-nitrobenzoic acid (198 g, 1.185 mol). Add diisopropyl azodicarboxylate (230 mL, 1.185 mol) drop-wise and stir at room temperature overnight. Add saturated aqueous sodium bicarbonate (IL) and extract into dichloromethane (2×2.5 L) in a 20 L separating funnel. Dry the combined organic layers over magnesium sulfate, filter and concentrate. Purify over silica gel (iso-hexane/ethyl acetate 50-100% then 10% methanol in ethyl acetate) to afford 163 g (62%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:18]([CH3:20])[CH3:19])[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])=[O:12])=[CH:6][CH:5]=1)[CH3:2].S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[Cl:23][C:5]1[CH:6]=[C:7]([CH:10]([CH:18]([CH3:19])[CH3:20])[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])=[O:12])[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CC#CCOC(=O)C(c1ccc(OCC)cc1)C(C)C
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC#CCOC(=O)C(c1ccc(OCC)c(Cl)c1)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
Into a solution of 0.15 g (0.55 mM) of Compound No. 2 (2-butynyl 2-(4-ethoxyphenyl)isovalerate) in 5 ml of chloroform, 0.76 g (5.5 mM) of thionyl chloride was added, and the mixture was stirred for 16 hours at room temperature. After condensing the reaction mixture, the condensate was subjected to silica gel column chromatography while using a 1:30 mixture of ethyl acetate and n-hexane as an eluent, thereby 0.14 g of the colourless and only compound No. 24 was obtained (yield: 80%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:11]1([CH2:10][N:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2[nH]nnc2c1
Reactant: ClCc1ccccc1
Product: c1ccc(Cn2nc3ccccc3n2)cc1
Product: c1ccc(Cn2nnc3ccccc32)cc1

Procedure:
(Phenylmethyl)-1H-benzotriazole was prepared from 1H-benzotriazole (11.91 g, 0.100 mol) and benzyl chloride as in Example 1 for 1 hour to give the title compound and (phenylmethyl)-2H- benzotriazole in a ratio of 75:25. Workup and two recrystallization gives the pure 1H-isomer: mp 117°-119° C. (CH3CN); (lit.1 mp 114°-117° C.; lit.2,3 mp 115°-116° C.)
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)NC(=O)[O:4][C:2]2=O.C(=O)([O-])[O-].[Na+].[Na+].[N+:19]([CH3:22])([O-:21])=[O:20].O.C[N:25](C)P(=O)(N(C)C)N(C)C>>[N+:19]([CH:22]([NH2:25])[C:2]([C:1]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4])([O-:21])=[O:20]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: NC(C(=O)c1ccccc1)[N+](=O)[O-]
Reaction time: 12 h

Procedure:
A mixture of 16.3 g of isatoic anhydride (100 mmol) and 26.5 g (250 mmol) of anhydrous sodium carbonate is heated in 140 ml of hexamethylphosphoric triamide to 75°-80° C. and a solution of 10.8 ml of nitromethane (d=1.134; 200 mmol) in 50 ml of hexamethylphosphoric triamide is added dropwise in the course of one hour. The reaction mixture is stirred for 12 hours at the given temperature, allowed to cool, then poured into 400 ml of water and the resultant solution is extracted with four 200 ml portions of chloroform (in order to recover the solvent). Thereafter the aqueous layer is adjusted to a pH of 2 by adding concentrated hydrochloric acid and the product is extracted with methylene chloride (4 extracts of 150 ml). The combined extracts are washed with an aqueous solution of sodium chloride, dried over sodium sulphate, concentrated to approx. 50 ml and passed through a column of 160 g of silica gel (silica gel 60, Merck, granular size 0.063 to 0.200 mm). The eluate is concentrated and yields 6.8 g of ω-nitro-amino-acetophenone with a melting point of 110°-111° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH:18]1([CH2:21][CH2:22][NH2:23])[CH2:20][CH2:19]1>C(O)CO.C(OCC)(=O)C>[CH:18]1([CH2:21][CH2:22][NH:23][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)=[C:4]([NH2:17])[N:3]=2)[CH2:20][CH2:19]1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: NCCC1CC1
Solvent: CCOC(C)=O
Solvent: OCCO
Product: Nc1nc(NCCC2CC2)nc2c1ncn2C1CCCCO1
Temperature: 120 °C
Yield: 100.2 %

Procedure:
To a suspension of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (3.49 g) in ethylene glycol (17 ml) at room temperature was added cyclopropylethylamine (4.69 g). The reaction mixture was heated to 120° C. with reflux condenser overnight, resulting in a yellow/brown solution. The reaction was allowed to cool, taken up in ethyl acetate (100 ml) and washed with water (2×100 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark brown gum (4.17 g)
Reaction SMILES: [NH2:1][S:2]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]([CH3:15])[C:5]=1[C:16]([O:18][CH3:19])=[O:17])=[O:3].[Mn]([O-])(=O)(=O)=[O:21].[K+]>CC(C)=O.O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH3:15])[C:5]([C:16]([O:18][CH3:19])=[O:17])=[C:4]2[S:2](=[O:21])(=[O:3])[NH2:1].[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH3:15])[C:5]3[C:16](=[O:18])[NH:1][S:2](=[O:3])(=[O:21])[C:4]=3[C:12]=2[CH:11]=1
Reactant: COC(=O)c1c(S(N)=O)c2cc(OC)ccc2n1C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1c(S(N)(=O)=O)c2cc(OC)ccc2n1C
Product: COc1ccc2c(c1)c1c(n2C)C(=O)NS1(=O)=O
Yield: 78 %
Yield: 19 %

Procedure:
A suspension of 40.8 gm (0.145 mol) of methyl 3-aminosulfinyl-5-methoxy-1-methyl-indole-2-carboxylate in 3 liters of acetone was reacted with 17.4 gm (0.11 mol) of potassiumpermanganate in 350 ml of water and processed analogous to Example 18(c). 33.7 gm (78% of theory) of methyl 5-methoxy-1-methyl-3-sulfamoyl-indole-2-carboxylate, M.p.: 190° C., and 7.4 gm (19% of theory) of 7-methoxy-4-methyl-2H-isothiazolo[4,5-b]indole-3(4H)-one-1,1-dioxide, M.p.: above 290° C. (decomposition), were obtained.
Reaction SMILES: [CH2:1]([N:3]([CH3:25])[C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([OH:23])=O)=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([N:3]([CH3:25])[C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:23])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2]
Reactant: CCN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Reactant: C1COCCN1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCOCC4)cnn3C)ccn2n1
Yield: 81.6 %

Procedure:
A mixture of 5-(2-(ethyl(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (144 mg, 419 μmol), morpholine (365 mg, 4.19 mmol), propylphosphonic anhydride (50% in ethyl acetate, 618 μl, 1.05 mmol) and N,N-diisopropylethylamine (214 μL, 1.26 mmol) in tetrahydrofuran (7.00 ml) was refluxed for 2.5 days (weekend). The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(ethyl-methyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (141 mg, 81.5%) as a white solid. mp: 167-169° C., MS: m/z=413.4 (M+H+)