Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B.CSC.[ClH:18]>O1CCCC1.CO>[ClH:18].[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:13])[CH2:11][NH2:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(C)C#N)cc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)c1ccc(C(C)CN)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
In a 100 ml flask, fitted with a condenser, 2-(4-isopropylphenyl) propionitrile 1.90 g (11.0 mmol) was dissolved in tetrahydrofuran (70 ml) under a nitrogen atmosphere. Borane-methyl sulfide complex (10.0-10.2 M in tetrahydrofuran, 1.20 ml, 12.1 mmol) was added to the solution and the mixture heated to reflux for 3 hours. The solution was cooled to ambient temperature and a saturated solution of hydrochloric acid in methanol added slowly until a white precipitate formed. The solvent was removed in vacuo and the resulting white solid triturated (×4) with diethyl ether. Drying under vacuo gave 1.76 g (73%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:20][C:21](=O)[CH3:22])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:20][C:21](=[N:25][OH:26])[CH3:22])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12)=NO
Temperature: 60 °C

Procedure:
The product from Example 24 (0.50 g, 0.0015 mol), hydroxylamine hydrochloride (0.21 g, 0.0031 mol) and 4 Å molecular sieves were suspended in pyridine (10 ml) and heated at 60° C. for 14 h. A further amount of hydroxylamine hydrochloride (0.42 g, 0.0062 mol) was added and the reaction mixture heated under reflux for a further 24 h. The reaction mixture was diluted with ethyl acetate (30 ml) and filtered through hiflo. The mixture was washed with 1N hydrochloric acid (100 ml), the acid layer was back extracted with ethyl acetate (2×20 ml) and the combined organic layers were washed consecutively with water (20 ml), saturated sodium hydrogen carbonate solution (20 ml) and brine (20 ml), then dried (MgSO4), filtered, and concentrated in vacuo to give a white solid. This was recrystallised from ethanol/water to give a white crystalline solid; yield=278 mg. Mp=196°-198° C. Found: C, 62.93; H, 4.37; N, 8.10. C18H15ClN2O3 requires C, 63.07; H, 4.41; N, 8.17. δ (360 MHz, DMSO-d6), 1.60 (3H, s, CH3), 4.06 (2H, s, OCH2), 7.28 (1H, dd, J=8.6 and 2.1 Hz, 6-H), 7.32-7.48 (6H, m, aromatics), 7.78 (1H, d, J=8.7 Hz, 5-H), 10.88 (1H, s, NOH), 11.92 (1H, s, br, NH). MS (CI) m/z=343 [MH]+.
Reaction SMILES: [CH2:1](O)[CH3:2].[C:4](OCC)(=O)C.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11].[OH-].[K+]>C(I)CC.CN(C)C=O.[N+](C1C=CC=CC=1)([O-])=O>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([N:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:4][CH2:1][CH3:2])=[CH:17][CH:18]=1)([O-:12])=[O:11].[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: CCOC(C)=O
Reactant: CCO
Agent: O=[N+]([O-])c1ccc(Nc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCCI
Product: CCCN(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
0.90 g of 2,6-difluorobenzoylisocyanate was added to a solution of 1.27 g of 4-[N-(4-chlorophenyl)-N-propylamino]aniline in 15 ml of dry diethylether while stirring at room temperature. After 1.5 hours at room temperature the formed precipitate was sucked off, washed with acetonitrile and diethylether, and dried. The desired product was obtained in a yield of 1.50 g; melting-point 169°-169.5°C. The starting aniline was obtained from the corresponding nitro compound by reduction with hydrogen under the influence of Raney nickel as a catalyst; a mixture of equal parts by volume of ethanol and ethyl acetate was used as a solvent. 1-Nitro-4-[N-(4-chlorophenyl)-N-propylamino]benzene was prepared by an alkylation of 1-nitro-4-(4-chloroanilino) benzene with propyliodide in dimethylformamide as a solvent under the influence of KOH, 1-Nitro-4-(4-chloroanilino) benzene was formed by a coupling at high temperature of p-chlorobenzeneisocyanate and p-nitrophenyl in nitrobenzene as a solvent. In a corresponding manner, in which, if desired, instead of diethylether acetonitrile was used as a solvent for the urea-formation, the following compounds were prepared; the compound numbers correspond with the numbers given before in the specification:
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH:38][C:25](=[O:26])[CH:24]=[CH:23][C:20]2[CH:21]=[CH:22][C:17]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][CH3:10])=[CH:18][CH:19]=2)(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 4-chlorobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (22%); 1H NMR (d6-DMSO) δ 12.31 (br s, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.39-7.07 (m, 13H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.4 Hz, 2H), 0.82 (t, J=7.4 Hz, 3H); APcI m/z: 527 (M−H−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[S:13](=[O:16])(=[O:15])[NH2:14].N[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>>[CH2:6]([OH:7])[CH2:5][CH2:4][CH2:3][CH3:2].[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[N:8]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[CH2:20][CH2:19]3)[C:9]2=[O:10])=[CH:11][C:12]=1[S:13]([NH2:14])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Reactant: COc1ccc(CN2CCC(N)CC2)cc1
Product: CCCCCO
Product: COc1ccc(CN2CCC(N3C(=O)c4cc(Cl)c(S(N)(=O)=O)cc4C3=O)CC2)cc1

Procedure:
Reaction of 4-chloro-5-sulfamoylphthalimide (5.21 g., 0.02 mole) and 4-amino-1-(4-methoxybenzyl)piperidine (4.5 g., 0.02 mole) in 80 ml. of n-pentanol according to the procedure of Example 1(a) afforded the crude 1,3-dioxoisoindole product purified by chromatography (silica gel, ethyl acetate-n-hexane) to yield 2.88 g. (31%) of 6-chloro-2,3-dihydro-2-[1-[(4-methoxyphenyl)methyl]-4-piperidinyl]-1,3-dioxo-1H-isoindole-5-sulfonamide. The NMR spectral data was consistent for the compound used without further purification below.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([CH2:14][CH3:15])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([C:11]([CH2:14][CH3:15])([CH3:12])[CH3:13])=[CH:17][CH:18]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 96.9 %

Procedure:
Following procedure A, 2-chloro-5-nitropyridine (303 mg, 1.91 mmol, 1.00 eq) and 4-tert-pentylphenol (397 mg, 2.42 mmol, 1.27 eq) were dissolved in DMSO (6 mL). Anhydrous K2CO3 (403 mg, 2.92 mmol, 1.53 eq) was added and the reaction mixture was stirred at room temperature for 7 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100) to afford the title compound as colourless solid (530 mg, 1.85 mmol, 97% yield). Rf=0.31 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C16H19N2O3+ [M+H]+ 287.1390. found: 287.1381. 1H NMR (400 MHz, CDCl3) δ 9.07-9.05 (m, 1H, aromatic H), 8.45 (dd, J=9.4, 2.4 Hz, 1H, aromatic H), 7.40 (d, J=8.6 Hz, 2H, aromatic H), 7.09 (d, J=8.6 Hz, 2H, aromatic H), 6.99 (d, J=9.2 Hz, 1H, aromatic H), 1.67 (q, J=7.4 Hz, 2H, Ar—C(CH3)2CH2CH3), 1.31 (s, 6H, Ar—C(CH3)2CH2CH3), 0.73 (t, J=7.4 Hz, 3H, Ar—C(CH3)2CH2CH3). 13C NMR (101 MHz, CDCl3) δ 167.17, 150.46, 147.34, 145.20, 140.27, 134.90, 127.56, 120.72, 111.28, 37.89, 37.06, 28.55, 9.26.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].CO[C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Br)[CH:15]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]2[C@:32]3([C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:34][C:33]3=[O:41])[CH2:31]2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C@@H:30]2[C@:32]3([C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]([CH2:20][C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([N:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]5)=[O:22])[CH:15]=4)[C:33]3=[O:41])[CH2:31]2)=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: CS(=O)(=O)N1CCN(C(=O)c2cccc(CN3C(=O)[C@]4(C[C@@H]4c4ccc(Cl)cc4)c4ccccc43)c2)CC1

Procedure:
The title compound was prepared in analogy to Example 60 starting from 1-(methylsulfonyl)piperazine, 3-bromomethyl-benzoic acid methyl ester (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C29H28ClN3O4S: 549, observed (M+H)+: 550.21H NMR (400 MHz, MeOD-d4) δppm 8.19-8.05 (m, 2 H) 7.49 (s, 3 H) 7.25 (br. s., 4 H) 7.09-7.05 (m, 1H) 6.88 (br. s., 2 H) 6.50 (br. s., 2 H) 5.29-5.12 (m, 2 H) 4.23 (d, J=7.58 Hz, 1 H) 3.64-3.56 (m, 1H) 3.41 (d, J=7.58 Hz, 1 H) 3.29-3.19 (m, 1 H) 3.11 (d, J=8.08 Hz, 2 H) 3.07-2.99 (m, 2 H) 2.98-2.91 (m, 2 H) 2.88-2.75 (m, 2 H).
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:26][C:27]1[N:32]=[CH:31][C:30]([CH2:33][OH:34])=[C:29]([CH:35]=O)[C:28]=1[OH:37].C(N(CC)CC)C>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])[CH:6]=[CH:35][C:29]1[C:30]([CH2:33][OH:34])=[CH:31][N:32]=[C:27]([CH3:26])[C:28]=1[OH:37])[CH3:5]
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1c(CO)cnc(C)c1O
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A clear solution of (carbethoxymethylene)triphenylphosphorane (22.3 g, 64.02 mmol) in THF was added to pyridoxal (13.01 g, 64.0 mmol) in THF at room temperature. The mixture was stirred for one hour, then triethylamine (10 mL) was added and the mixture was stirred until the solution turned to a yellow suspension. The solvent was evaporated, and the crude product purified by column chromatography on silica gel using a mixture of dichloromethane:methyl alcohol (20:1) as eluant to give 3-(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-yl)-acrylic acid ethyl ester (34) (15.2 g, quantitative yield) as a yellow solid.
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1.Br[C:45]1[CH:46]=[N:47][N:48]([CH2:51][CH2:52][CH2:53][OH:54])[C:49]=1[Cl:50]>>[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28]([C:45]2[CH:46]=[N:47][N:48]([CH2:51][CH2:52][CH2:53][OH:54])[C:49]=2[Cl:50])=[CH:29][CH:30]=1
Reactant: CNC(=O)c1nc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: OCCCn1ncc(Br)c1Cl
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cnn(CCCO)c2Cl)ccc1N
Yield: 47.3 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Compound 48D, 284 mg, 1.03 mmol) and 3-(4-bromo-5-chloro-1H-pyrazol-1-yl)propan-1-ol (Compound 49D, 270 mg, 1.1 mmol) to afford 151 mg of the title compound (48%). 1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.20 (d, J=8.6 Hz, 1H), 4.32 (t, J=7.1 Hz, 2H), 3.60 (t, J=6.1 Hz, 2H), 2.94 (s, 3H), 2.06 (quin, J=6.6 Hz, 2H). MS (ESI): m/z=310.20/312.18 [M+H]+. UPLC: tR=0.77 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([N:8]([CH3:24])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]=[C:21]=[CH:22][CH3:23])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6]C)=[O:5].[OH-].[Li+].O>O1CCCC1.CO>[CH3:24][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]=[C:21]=[CH:22][CH3:23])=[CH:16][CH:17]=1)(=[O:10])=[O:11])[C@H:3]([C:4]([OH:6])=[O:5])[CH:2]([CH3:25])[CH3:1]
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC=C=CCOc1ccc(S(=O)(=O)N(C)[C@H](C(=O)O)C(C)C)cc1
Yield: 87.1 %

Procedure:
The procedure of Example 12 was followed using the product from Example 20 (240 mg, 0.65 mmol), and lithium hydroxide (31 mg, 1.31 mmol) in tetrahydrofuran (2 ml), methanol (2 ml), and water (1 ml) to give 200 mg (87%) of the product.
Reaction SMILES: C=C(C([O:19][C:20](/[CH:22]=[CH:23]/[C:24]1[CH:25]=[CH:26][C:27]([OH:31])=[C:28]([OH:30])[CH:29]=1)=[O:21])C[O:7][C@@H:8]1[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]([OH:17])[C@H:9]1[OH:18])CO>O>[C:20]([OH:21])(=[O:19])/[CH:22]=[CH:23]/[C:24]1[CH:25]=[CH:26][C:27]([OH:31])=[C:28]([OH:30])[CH:29]=1.[O:7]=[CH:8][C@@H:9]([C@H:10]([C@@H:11]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:16])[OH:17])[OH:18]
Reactant: C=C(CO)C(CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)OC(=O)/C=C/c1ccc(O)c(O)c1
Solvent: O
Product: O=C(O)/C=C/c1ccc(O)c(O)c1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Acid hydrolysis of pubescenoside B: Compound 2 (15 mg) was hydrolyzed in a manner similar to that described for compound 1, yielding caffeic acid, D-(+)-glucose {[α]D21=+33.1° (c=0.1, H2O), determined after being dissolved in H2O for 24 hours} and compound 1a which was identified by comparing its 1H-NMR data with those described in the reference13.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:43]1[CH2:44][CH2:45][N:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([Br:33])[CH:35]=2)[CH2:41][CH2:42]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2cccc(Br)c2)CC1
Yield: 16 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3-bromo-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (12.6 mg, 16%) as light yellow oil. MS m/e=569.3 [M+H]+.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[CH3:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([NH:23][S:2]([C:16]1[S:15][C:14]([CH3:13])=[CH:18][CH:17]=1)(=[O:5])=[O:3])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cccs1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(C)(C)C)s1
Temperature: 0 °C
Yield: 78 %

Procedure:
291 gm (2.5 mol) of chlorosulfonic acid were added in portions to 208 gm (1.0 mol) of phosphorus pentachloride while stirring and cooling. After the evolution of hydrogen chloride had subsided, 98 gm (1.0 mol) of 2-methyl-thiophene were added dropwise while stirring at a temperature of 10° C. When the addition was finished, the mixture was stirred for another 10 minutes. After pouring the reaction mixture over 2.5 kg of ice, the obtained sulfochloride was separated by extracting 5 times with 500 ml of ether. The organic phase was washed twice with 200 ml of water, dried and evaporated in vacuo. The residual oil was taken up in 200 ml of tetrahydrofuran and added, while stirring, dropwise, to a solution of 183 gm (2.5 mol) of tert. butylamine in 100 ml of tetrahydrofuran at a temperature of 20° C. The mixture was stirred for 1 hour at room temperature and for 20 minutes at 70° C. bath temperature. The crystals of tert. butylamine hydrochloride which separated out were filtered off and washed with ether. The combined filtrates were evaporated, and the residue was taken up in ether. After washing with 2 N hydrochloric acid and water, the residue was dried over sodium sulfate and again evaporated. The obtained crude product was recrystallized from cyclohexane, yielding 182 gm (78% of theory) of N-tert.-butyl-5-methyl-thiophene-2-sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH:16]=O)[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C.CO.CC(O)=O>[ClH:1].[ClH:1].[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH2:16][N:30]3[CH2:31][C@H:32]4[C@:28]([C:25]5[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=5)([CH2:33]4)[CH2:29]3)[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: O=CCCn1cc(-c2cccnc2Cl)c(=O)[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cl
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of 3-[5-(2-chloro-pyridin-3-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionaldehyde (Prep97, 128 mg, 0.46 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 104 mg, 0.46 mmol), and AcOH (32 μl) in dichloroethane-MeOH (10-01, 4 ml) was cooled to 0° C. NaBH(AcO)3 (102 mg, 0.48 mmol) was added portionwise. The mixture was stirred at 0° C. for further 1 hour and then basified with 1N NaOH. The product was extracted with DCM. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98:2:0.2) to give 77 mg of the free base of title compound (34% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+:14].[Cl:15][O-].[Na+]>>[Na:14][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[C:8]([Cl:15])=[N:9]1
Reactant: [Na+]
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: [O-]Cl
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(Cl)nn([Na])c2c1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a mixture of 6-nitroindazole (1.63 g) and 6N sodium hydroxide (2.08 ml) was added 5.25% w/v sodium hypochlorite (17.86 ml). After stirring for 30 minutes, filtration, and washing with 1N sodium hydroxide, 1-sodio-3-chloro-6-nitroindazole (2.08 g, 95%) was obtained as a solid; mp >270° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=[CH:18][C:7]=2[C:8]=1[CH2:9][CH2:10][O:11]C1CCCCO1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>C1COCC1>[C:34]([O:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=[CH:18][C:7]=2[C:8]=1[CH2:9][CH2:10][OH:11])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)COc1cccc2c(CCOC3CCCCO3)c(CCO)oc12
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)COc1cccc2c(CCO)c(CCOC(C)=O)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
Methyl (2-(2-hydroxyethyl)-3-(2-tetrahydropyranyloxyethyl)benzofuran-7-yloxy)acetate (403 mg), pyridine (0.13 ml) and acetic anhydride (0.3 ml) were dissolved in THF (5 ml) and the solution was stirred at room temperature for 16 hours. The reaction solution was poured into water (50 ml) and the organic layer was separated, followed by extraction twice with ethyl acetate (20 ml). The organic layers were combined and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was dissolved in methanol (4 ml). To this solution, 1N hydrochloric acid (1 ml) was added and the solution was stirred at room temperature for 2 hours. The reaction solution was poured into water (50 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=1/2) using silica gel to obtain the desired compound (412 mg, yield: 42%).
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)C.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[OH:24][CH2:25][C@@H:26]1[N:30]([CH3:31])[C:29](=[O:32])[CH2:28][CH2:27]1>C(Cl)(Cl)Cl.O>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:24][CH2:25][C@H:26]2[CH2:27][CH2:28][C:29](=[O:32])[N:30]2[CH3:31])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CN1C(=O)CC[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC(=O)N2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (5.26 mL), trimethylamine hydrochloride (1.07 g) and 4-methylbenzenesulfonyl chloride (5.6 g) were sequentially added to a solution of (R)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one (2.93 g, 48.3 g, described in J. Med. Chem., 34(3), 1991, 887-900) in chloroform (40 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure to give (R)-(1-methyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate as a yellow amorphous (6.6 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8]C(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)[CH2:4][CH:5]([CH3:7])[CH3:6].[CH:26]1([CH2:31][O:32][C:33]2[N:38]=[C:37]([C:39]([OH:41])=O)[CH:36]=[N:35][C:34]=2[N:42]2[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44][CH2:43]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.N[C@H](CO)CC(C)C>>[OH:1][CH2:2][C@@H:3]([NH:8][C:39]([C:37]1[CH:36]=[N:35][C:34]([N:42]2[CH2:43][CH2:44][C:45]([F:48])([F:49])[CH2:46][CH2:47]2)=[C:33]([O:32][CH2:31][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[N:38]=1)=[O:41])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Reactant: O=C(O)c1cnc(N2CCC(F)(F)CC2)c(OCC2CCCC2)n1
Agent: CC(C)C[C@H](N)CO
Product: CC(C)C[C@@H](CO)NC(=O)c1cnc(N2CCC(F)(F)CC2)c(OCC2CCCC2)n1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-cyclopentylmethoxy-5-(4,4-difluoro-piperidin-1-yl)-pyrazine-2-carboxylic acid and (S)-leucinol (commercially available). m/z (ES+): 441.3 (M+H).