Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][N:12](CC2C=CC=CC=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[OH:10])=[CH:4][C:3]=1[Cl:34]>[Pd]>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[OH:10])=[CH:4][C:3]=1[Cl:34]
Reactant: Nc1c(Cl)cc(C(O)CN(CCCCCOCCc2ccccn2)Cc2ccccc2)cc1Cl
Agent: [Pd]
Product: Nc1c(Cl)cc(C(O)CNCCCCCOCCc2ccccn2)cc1Cl
Yield: 79.4 %

Procedure:
From 4-amino-3,5-dichloro-α-[[(phenylmethyl)[5-[2-(2-pyridinyl)ethoxy]pentyl]amino]methyl]benzenemethanol (2.67 g), using pre-reduced 10% palladium on charcoal (50% aqueous paste, 400 mg) as the catalyst for hydrogenation. FCC eluting with System C (95:5:1) gave the title compound as a pale yellow oil (1.74 g), t.l.c. (System C 95:5:1) Rf 0.07. A solution of the title compound (900 mg) in methanol (5 ml) was treated with fumaric acid (127 mg) in methanol (5 ml) and the solution was concentrated. Trituration of the resultant foam with diethyl ether gave the (E)-butenedioate (salt) (2:1) as a white solid (0.95 g), m.p. 140°-142°.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:15]([C:25]([OH:27])=O)=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl-].[Li+].[NH:30]1[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:36]=[S:33]1(=[O:37])[CH2:34][CH2:35][N:30]([C:25]([C:15]2[N:16]([CH2:20][C:21]([F:22])([F:24])[F:23])[C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:10][CH:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[CH:19][CH:18]=3)=[O:27])[CH2:31][CH2:32]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)O)n3CC(F)(F)F)CC1
Reactant: O=S1(=O)CCNCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
A mixture of 5-(1-isopropyl-piperidin-4-yloxy)-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid, hydrochloric salt with one equivalent of lithium chloride (650 mg, 1.0 eq.), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylurunium tetrafluoroborate (563 mg, 1.2 eq.), thiomorpholine-1,1-dioxide (purchased at Syntec, ref. M1201) and diisopropylethylamine (1.22 mL, 5 eq.) in dimethylformamide was stirred at room temperature for 24 h and then partitioned between an aqueous solution of sodium hydrogenocarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, evaporated in vacuo and purified on silica eluting with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 468 mg (66%) of the desired product as off-white solid. MS (m/e): 502.5 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:8]=[CH:7][C:4]=1[CH:5]=O.Cl.[NH2:75][OH:76].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:8]=[CH:7][C:4]=1[CH:5]=[N:75][OH:76]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(C=O)c(OC)c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(C=NO)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
2-Methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzaldehyde (50 mg, 0.049 mmol) was dissolved in dichloromethane (1 ml), hydroxylamine hydrochloride (18 mg, 0.26 mmol) and triethylamine (51 μl, 0.37 mmol) were added, and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated, and the residue was precipitated with acetonitrile to give 2-methoxy-4-[2,2,2-tris(octadecyloxymethyl)ethoxy]benzaldoxime (43 mg, 0.041 mmol, 85%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([O:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNCCC(O)c1ccccc1
Agent: Cl
Product: CNCCC(Oc1ccccc1)c1ccccc1

Procedure:
Under stirring, while maintaining the temperature between about 15° and about 25° C. with an ice-water bath, 12.3 g of 36 percent aqueous hydrogen chloride are dropped on the filtered organic phase, resulting in the crystallization of D-ATM hydrochloride (mw 277.80). The resulting suspension is stirred at about 20° C. for 1 hour, the solid is collected by filtration, washed twice with 40 ml of n-butyl acetate, and dried for 18 hours under vacuum at about 50° to about 60° C., yielding 32.7 g of product, a 48 percent yield based on the N-methyl-3-hydroxy-3-phenylpropylamine starting material, having a melting point of about 170° to about 174° C. The D-ATM HCl is found by chiral HPLC to be a mixture of enantiomers, with a relative ratio of 69:31.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][NH2:8])[C:3]([O:5][CH3:6])=[O:4].[OH-].[K+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=O)=O)=[CH:14][CH:13]=1>CO.C(Cl)Cl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:8]=[CH:7][C:2]([C:3]([O:5][CH3:6])=[O:4])=[N:1][C:20]=2[C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)C(N)CN
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cnc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1
Temperature: 65 °C

Procedure:
Methyl 2,3-diaminopropionate example 1A (2.4 g, 12.6 mmol) was shaken vigorously for 5 min in a solution of KOH (2.1 g, 37.7 mmol) in 20 mL of MeOH. The resulting milky solution was filtered to remove the solids, and the filtrate was added to a solution of 4,4′-dimethylbenzil (4.48 g, 18.8 mmol) in 20 mL of MeOH. The resulting mixture was heated to 65° C. for 14 h with a reflux condenser open to air. Solvent was evaporated and the residue was dissolved in 300 mL of EtOAc and 200 mL of 1N HCl. The layers were extracted and the organic layer was evaporated to give a thick oil that was redissolved in 5 mL of CH2Cl2 and this solution was loaded onto dry 120 g silica cartridge. The solvent was evaporated with a stream of N2, and the desired product example 1B was eluted with a gradient of 0-40% EtOAc/hexanes to give 1.71 g of a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](I)=[C:9]([C:12]2[C:17](Br)=[CH:16][N:15]=[C:14]([NH2:19])[N:13]=2)[NH:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:5])[CH3:2].[CH:26]([Sn](CCCC)(CCCC)CCCC)=[CH2:27].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:10]2=[CH:26][CH:27]=[C:17]3[C:12]([N:13]=[C:14]([NH2:19])[N:15]=[CH:16]3)=[C:9]2[NH:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2)[nH]c(-c2nc(N)ncc2Br)c1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccccc2)[nH]c2c1ccc1cnc(N)nc12
Temperature: 110 °C
Yield: 30.3 %

Procedure:
To a solution of 5-(2-amino-5-bromo-pyrimidin-4-yl)-4-iodo-2-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (XXVIIA, R2=phenyl, R3=COOEt, 0.099 mmol) in dioxane (4 mL), under argon, vinyltributyltin (0.099 mmol), 2,6-di-tert-butyl-4-methylphenol (0.0045 mmol) and Pd(Ph3P)4 (0.01 mmol) were added. The reaction mixture was heated at 110° C. for 3 h, cooled to rt, the precipitate filtered through a celite pad and the resulting solution evaporated to dryness. The residue was chromatographed on silica gel (eluant: AcOEt/hexane 4:1) affording the title compound (0.03 mmol, 30% yield), ESI (+) MS: m/z 333 (MH+). 1H NMR: 1.20 (t, J=7.03, 3H), 4.19 (q, J=7.03, 2H), 6.55 (bs, 2H), 7.50 (d, J=8.60, 1H), 7.53-7.70 (m., 5H), 7.90 (d, J=8.60, 1H), 9.07 (s, 1H), 12.93 (s, 1H), and 5-amino-8-methylene-2-phenyl-3,8-dihydro-3,4,6-triaza-cyclopenta[a]indene-1-carboxylic acid ethyl ester (0.024 mmol) (XXVIII, R2=phenyl, R3=COOEt), ESI (+) MS: m/z 333 (MH+). 1H NMR: 1.14 (t, J=7.07 Hz, 3H), 4.16 (q, J=7.07 Hz, 2H), 6.02 (d, J=1.32, 1H), 6.43 (d, J=1.32, 1H), 6.57 (bs, 2H), 7.40-7.46 (m, 2H), 7.52-7.66 (m, 3H), 8.44 (s, 1H), 12.74 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:18])=[C:10]([C:14](OC)=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C([NH2:24])=O.C[O-].[Na+].CO.Cl>CN(C=O)C>[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:18])=[C:10]([C:14]([NH2:24])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: NC=O
Reactant: CCCN(CCC)C1Cc2cc(O)c(C(=O)OC)cc2C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2cc(O)c(C(N)=O)cc2C1
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(dipropylamino)-2,3-dihydro-6-hydroxy-1H-indene-5-caboxylate (86, 0.93 g, 2.9 mmol) and formamide (1.2 mL, 29 mmol) in DMF (20 mL) at 100° C. was added 25% sodium methoxide in methanol (1.3 mL, 5.8 mmol) dropwise. The mixture stirred for 4 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer is washed with water, brine dried (MgSO4), filtered and concentrated to give the crude product. Chromatographic purification yielded pure product as an oil that was converted into the HCl salt and crystallized from EtOAc/MeOH to give the title compound 87 as a white solid (m.p. 266-267° C.).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][NH:38][CH3:39])[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:25][C:26]1[C:27]2[C:28](=[O:29])[N:38]([CH3:39])[CH2:37][CH2:36][O:35][C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CNCCOc1cccc(N)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCOc2cccc(N)c2C1=O
Reaction time: 1 h
Yield: 10.2 %

Procedure:
Sodium hydride (8.81 g, 220.38 mmol) was added portionwise to 2-(methylamino)ethanol (16.55 g, 220.38 mmol) in THF (500 mL) at 0° C. over a period of 10 minutes under an atmosphere of argon. The resulting solution was stirred at 0° C. for 1 hour and then 2-amino-6-fluorobenzonitrile (20 g, 146.92 mmol) was added in one portion and the mixture heated at 85° C. for 2 hours. The mixture was quenched with water and then evaporated. The residue was dissolved in EtOAc (300 mL), and the mixture washed sequentially with water (2×300 mL), and then with a saturated solution of NaCl (300 mL). The organic layer was dried over MgSO4, and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-10%, of a 7M solution of NH3 in MeOH, in CH2Cl2. Fractions containing product were evaporated to afford 2-amino-6-(2-methylaminoethoxy)benzonitrile (12.08 g, 43% yield); Mass spectrum: m/z (ESI+) (M+H)+=192.43. b) Potassium hydroxide (32 g, 570.35 mmol) was added in one portion to 2-amino-6-(2-methylaminoethoxy)benzonitrile (16 g, 83.67 mmol) in ethanol (160 mL). The resulting mixture was heated at 90° C. for 2 days. The mixture was then diluted with water (1000 mL) and acidified to ˜pH1 with 2M HCl. The mixture was loaded onto an SCX column and the product was eluted first using MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford 2-amino-6-(2-methylaminoethoxy)benzoic acid which was used without further purification. c) HATU (35.0 g, 92.04 mmol) was added in one portion to 2-amino-6-(2-methylaminoethoxy)benzoic acid (17.59 g, 83.67 mmol) and DIPEA (15.92 mL, 92.04 mmol) in DMF (200 mL) and the resulting solution was stirred for 1 hour. The mixture was evaporated and the residue dissolved in EtOAc (500 mL). The mixture was washed sequentially with a saturated solution of Na2CO3 (500 mL), water (500 mL), and finally with a saturated solution of NaCl (500 mL). The organic layer was dried over MgSO4, and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford 6-amino-4-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (1.635 g, 10% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.09 (s, 3H), 3.44 (t, 2H), 4.20 (t, 2H), 5.74 (br s, 2H), 6.22 (dd, 1H), 6.52 (dd, 1H), 7.08 (appt t, 1H); Mass spectrum: m/z (ESI+) (M+H)+=193.41.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]([NH:26][CH2:27][C:28]1[N:32]([CH3:33])[N:31]=[N:30][N:29]=1)([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:23]([N:26]([CH2:27][C:28]1[N:32]([CH3:33])[N:31]=[N:30][N:29]=1)[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:25])([CH3:24])[CH3:22]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: Cn1nnnc1CNC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnnc1CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2-methyl-N-((1-methyl-1H-tetrazol-5-yl)methyl)propan-2-amine hydrochloride in the presence of TBTU and DIEA to obtain the title compound as yellow solid; MS (EI): m/e=436.5 [MH+].
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=CC=1.[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:47]=[CH:48][CH:49]=1)[CH2:37][S:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=O.CO>C(COC)OC>[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][O:33][C:34]1[CH:35]=[C:36]([CH:47]=[CH:48][CH:49]=1)[CH2:37][S:38][C:39]1[CH:40]=[C:41]([CH2:42][C:16]#[N:17])[CH:44]=[CH:45][CH:46]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2cccc(C=O)c2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2cccc(CC#N)c2)c1
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
To a mixture of potassium t-butoxide (0.38 g) and dimethoxyethane (10 mL) was added a solution of toluenesulfonylmethylisocyanide (0.33 g) in dimethoxyethane (5 mL) at −78° C. and the mixture was stirred for 10 min. A solution (10 mL) of 3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzaldehyde (0.70 g) in dimethoxyethane was added to the reaction mixture and the mixture was stirred for 30 min at −78° C. Methanol (25 mL) was added to the reaction mixture at room temperature and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]acetonitrile as an oil (0.295 g, yield 41%) from a fraction eluted with acetone-hexane (1:5, v/v).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].O>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([CH3:16])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(-n2c(C)ccc2C)nc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution containing 1.18 g (5.50 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-hydroxy-4,6-dimethylpyridine (15) in 20 mL of anhydrous THF were added 1.20 mL (10.10 mmol) of benzyl bromide followed by 440 mg (11.00 mmol) of 60% sodium hydride suspension in mineral oil. The reaction mixture was stirred at room temperature under argon atmosphere overnight. The reaction mixture was poured into 150 mL of water and extracted with two portions of 100 mL of ethyl acetate. The combined organic solution was washed with a portion of 100 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 4:1 gave the expected product as light yellow oil: yield 1.42 g (84%). 1H-NMR (CDCl3) δ 6.98 (s, 1H), 5.91 (s, 2H), 4.94 (s, 2H), 2.58 (s, 3H), 2.37 (s, 3H), 2.17 (s, 6H); 13C-NMR (CDCl3) δ 152.02, 151.03, 146.64, 141.95, 136.73, 128.60, 128.33, 127.89, 121.94, 106.44, 74.59, 19.48, 16.18, 13.08.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([C:14]1[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=1)[OH:13].OC1C2C(=CC=CC=2)[NH:26]C1=O.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.S(Cl)(Cl)(=O)=O>>[NH2:26][C:5]1([C:14]2[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:4]2[C:8](=[CH:9][C:10]([F:11])=[C:2]([Cl:1])[CH:3]=2)[N:7]([S:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:42])=[O:41])[C:6]1=[O:12].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([C:14]1[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=1)[OH:13]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1Nc2ccccc2C1O
Agent: CCOc1ncccc1C1(O)C(=O)Nc2cc(F)c(Cl)cc21
Solvent: O=S(=O)(Cl)Cl
Product: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccccc2)c2cc(F)c(Cl)cc21

Procedure:
The title compound was prepared in analogy to example 1.1 to 1.3 using 5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-one as 3-hydroxy-1,3-dihydroindol-2-one IV and phenylsulfonyl chloride as sulfonyl chloride VII. 5-Chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-1,3-dihydroindol-2-one was prepared in analogy to example a.1.
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C@H:4]1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17]>CCOCC>[CH3:2][C@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17]
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N1CCCC1
Agent: Cl
Solvent: CCOCC
Product: C[C@H]1CCNC[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Saturated ethereal hydrogen chloride (40 mL) was added to a solution of cis-tert-butyl 4-methyl-3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (2.6 g, 8.78 mmol) in ether (20 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to afford cis-(4-methylpiperidin-3-yl)(pyrrolidin-1-yl)methanone (1.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([N:13]1[C:18]2[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH2:26][C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:29]([F:38])[CH:28]=1>>[CH2:34]([O:33][C:31](=[O:32])[C:30]1[CH:36]=[CH:37][C:27]([NH:26][C:23]([C:20]2[CH:21]=[CH:22][C:17]3[O:16][CH2:15][CH2:14][N:13]([S:10]([C:4]4[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])(=[O:12])=[O:11])[C:18]=3[CH:19]=2)=[O:24])=[CH:28][C:29]=1[F:38])[CH3:35]
Reactant: CCOC(=O)c1ccc(N)cc1F
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCOc2ccc(C(=O)O)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCO3)cc1F

Procedure:
The title compound, MS (ISP)=501.1 (M+H)+, was produced as described in example 1, steps 1-6. Step 3 was performed using 2-methoxy-5-methylbenzenesulfonyl chloride, furnishing 4-(2-methoxy-5-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 4, leading to 4-(2-methoxy-5-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-amino-2-fluorobenzoate in step 5 and yielded 2-fluoro-4-{[4-(2-methoxy-5-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[N:9]([CH3:19])[N:10]=[CH:11][C:12]=1[C:13]([N:15]1[CH2:18][CH2:17][CH2:16]1)=[O:14])=[O:7])C.Cl.[Na+].[Cl-]>C1COCC1>[N:15]1([C:13]([C:12]2[CH:11]=[N:10][N:9]([CH3:19])[C:8]=2[C:6]([OH:7])=[O:5])=[O:14])[CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1c(C(=O)N2CCC2)cnn1C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
NaOH (1N, 10 ml) was added to a solution of 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.32 g, 5.0 mmol) in THF (50 ml), and the mixture was stirred at r.t. (3.5 h). The mixture was neutralized by addition of HCl (1N, 10 ml). The mixture was evaporated under vacuum and the title compound, containing theoretically 2 equiv. of NaCl, (1.72 g, 99%) was used in Step 6 without further purification. MS (m/e)=210.2 [M+H+].