Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[CH2:18])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:21]=1[O:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1C(O)=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>Cl.O1CCOCC1>[Cl:19][C:20]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:21]=1[O:22][C:23]1[C:24]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[CH2:18])[CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)c2ccccc21
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=C1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Yield: 6.6 %

Procedure:
A solution of 4-methylene-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (44.2 mg, 0.18 mmol, 1.2 equiv) in 4 M HCl in dioxane (4 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product redissolved in anhydrous DMF (1 mL). To this solution was added 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1), N-ethyldiisopropylamine (97 mg, 131 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (68 mg, 0.18 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture heated by microwave irradiation to 100° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 4.1 mg (7%) of the title compound. MS (ISP): 410.7 [M+H]+.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6]O)/[CH2:3]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[CH2:20]([N:27]1[CH2:6][CH:5]=[C:2]([CH3:3])[CH2:1]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C/C(=C\CO)CO
Reactant: NCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1=CCN(Cc2ccccc2)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution containing 40.8 g (0.4 mol) of E-2-methyl-2-butene-1,4-diol, 83.8 g (0.8 mol) of triethylamine, and 416.6 g of ethyl acetate in a round flask reactor, methanesulfonyl chloride was added dropwise with stirring for 30 min. at about 5° C. using an ice-bath. After addition, the mixture was allowed to react with stirring for 2 hours at room temperature. To the mixture, 171.7 g (1.6 mol) of benzylamine was added continuously dropwise with stirring for 30 min. at ambient temperature. After 2 hours of stirring, the crystallized solid was removed by filtration; 42.0 g of 35% HCl (aq) was added to the filtrate, and then excess benzylamine hydrochloride was removed by filtration or extraction. After the solvent was evaporated under reduced pressure, 54.2 g of 1-benzyl-3-methyl-3-pyrroline (yield 78.2%) was obtained.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[CH:27]([C@@H:28]([OH:40])[C@@H:29]([NH2:39])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][CH:24]([CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([O:19][C:20]([N:22]1[C@@H:27]([C@@H:28]([OH:40])[C@@H:29]([NH:39][C:8](=[O:10])[CH3:9])[CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[CH2:26][O:25][C@@H:24]([CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC(COc2ccccc2)OCC1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](COc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
Add triethylamine (0.009 mL, 0.066 mmol) and acetic anhydride (0.004 mL, 0.044 mmol) to a solution of (2R,5R)-(5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-phenoxymethyl-morpholine-4-carboxylic acid tert-butyl ester (0.021 g, 0.044 mmol) in tetrahydrofuran (0.44 mL) and stir at room temperature for 1 hour. Concentrate and purify (silica gel chromatography, eluting with 50:50 to 60:40 ethyl acetate:hexanes) to give the title compound as a white foam (0.010 g, 45.5%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][O:18][C:2]2[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ncccc2OCCO)CC1

Procedure:
The title compound was prepared starting from 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 0.67 g, 2.6 mmol) and tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.66 g, 2.9 mmol) according to the procedure in Example 23, Step 1, followed by removing the tetrahydropyranyl protecting group according to the procedure given in Example 23, Step 2. Yield 0.36 g (38%). MS (ESI+) for C18H29N3O5 m/z 368.0 (M+H)+.
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5]([C:8](OC)=O)=[CH:6]O.S(O)(O)(=O)=O.[CH3:19][S:20][C:21](=[NH:23])[NH2:22]>CO.C(OCC)(=O)C>[CH3:19][S:20][C:21]1[N:23]=[CH:8][C:5]([C:4]([O:3][CH3:2])=[O:12])=[CH:6][N:22]=1
Reactant: COC(=O)C(=CO)C(OC)OC
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cnc(SC)nc1
Yield: 76 %

Procedure:
A solution of the sodium salt of 3,3-dimethoxy-2-methoxycarbonylpropen-1-ol (5.0 g, 25 mmol), 2-methyl-2-thiopseudourea sulfate (3.5 g, 25 mmol) in anhydrous methanol (25 mL) was refluxed for 3 hours under anhydrous conditions. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was filtered and the residue was washed with ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel) using 25% ethyl acetate in hexane to afford the desired product (3.5 g, 75%) as a white powder. 1H-NMR (d6-DMSO, 400 MHz) δ 9.0 (s, 2H), 3.92 (s, 3H), 2.58 (s, 3H); ES-HRMS m/z 185.041 (M+H C7H8N2O2S requires 185.0379).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:17][CH2:16]1)=[O:14]>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:17][CH2:16]1)=[O:14]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: COC(=O)C1CCC(COS(=O)(=O)c2ccc(C)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(Cn2ccc([N+](=O)[O-])n2)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
The 3-Nitro-1H-pyrazole (prepared in example 3, 130 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (4 mL) and a 60% suspension of sodium hydride in mineral oil (50 mg, 1.25 mmol) was added. After the effervescence ceased and the reaction stirred for an additional 10 min, the 4-(toluene-4-sulfonyloxymethyl)-cyclohexanecarboxylic acid methyl ester (380 mg, 1.16 mmol) was added and the reaction was heated to 80° C. while stirring for 4 h. The reaction continued to stir under nitrogen for 2 h. The solution was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (35 mL), 1.0 M aqueous hydrochloric acid solution (35 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 4-(3-nitro-pyrazol-1-ylmethyl)-cyclohexanecarboxylic acid methyl ester (114 mg, 37%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ 1.00-1.12 (2H, m), 1.36-1.50 (2H, m), 1.68-1.78 (2H, m), 1.90-2.08 (3H, m), 2.20-2.30 (1H, m), 3.66 (3H, s), 4.03 (2H, d, J=7.2 Hz), 6.88 (2H, d, J=2.4 Hz), 7.40 (2H, d, J=8.4 Hz).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([Cl:12])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(C1N(CC2C=CC(C3C=CC=CC=3C(OC(C)(C)C)=O)=CC=2)C(Cl)=C(CO)N=1)CCC>>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:7]([Cl:12])=[C:8]([CH:10]=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO)c(Cl)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCc1nc(CO)c(Cl)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCCc1nc(C=O)c(Cl)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
This Step A compound can be prepared as described in Example 3, Step A, except that 2-butyl-1-[(2'-{N-triphenylmethyltetrazol-5-yl}biphen-4-yl)methyl]-5-chloro-1H-imidazole-4-methanol (European Patent Applications 253,310 and 291,969) can be used as the starting material for the oxidation instead of 2-butyl-1-[(2'-t-butoxycarbonylbiphen-4-yl)methyl]-5-chloro-1H-imidazole-4-methanol.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:15])(=O)[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[C:5]([Cl:3])(=[O:15])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
The title substance was synthesized as follows: 300 ml of thionyl chloride was dropped into a mixture of 358 g of commercially available terephthalaldehydic acid with 700 ml of toluene and 2 g of pyridine, and the solution was heated under reflux slowly until a homogeneous reaction solution was obtained. After the solution was cooled to room temperature, unreacted thionyl chloride and toluene as a solvent were distilled off in vacuum. Terephthalaldehydic acid chloride (b.p. 133°-135° C./15 Torr) was obtained by the vacuum distillation of the remaining reaction product.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.N1C=CC(CCCO)=CC=1>>[ClH:28].[N:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[CH:33][CH:34]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Reactant: ClCCCc1ccncc1
Agent: Cl
Agent: OCCCc1ccncc1
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCCc3ccncc3)cc12

Procedure:
6-(3-Pyridin-4-yl-propoxy)-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 7% overall yield using the method described in example 127, starting from 6-hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl oxime (example 127A) and 4-(3-Chloro-propyl)-pyridine hydrochloride, prepared from 4-pyridine propanol (U.S. Pat. No. 6,362,336).
Reaction SMILES: [CH:1](O)=[O:2].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[F:28][C:29]1[C:41]([F:42])=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:30]=1[O:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)(O)[O-].[Na+]>C(OCC)C.O>[CH:1]([N:35]1[CH2:36][CH2:37][CH:32]([O:31][C:30]2[C:38]([F:45])=[C:39]([F:44])[C:40]([F:43])=[C:41]([F:42])[C:29]=2[F:28])[CH2:33][CH2:34]1)=[O:2]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: O=CO
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 1.5 ml of formic acid and 3.5 ml of acetic anydride was stirred at 55° C. for one hour, cooled, and treated with a solution of 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine in 50 ml of diethyl ether. The reaction mixture was then stirred at ambient temperature for three hours. Thereafter, the mixture was poured into 100 ml of water, adjusted to pH 10 by the addition of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. Filtration, followed by evaporation of the solvent afforded an oil which was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate) to yield 4.0 g (91%) of 1-formyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine, m.p. 32°-34° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(C1[CH:15]=[CH:14][C:13]([S:16]([N:19]=[N+:20]=[N-:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(O)=O>CN(C)C=O>[N:19]([S:16]([C:13]1[CH:14]=[CH:15][C:1]([C:2]([Cl:4])=[O:3])=[CH:11][CH:12]=1)(=[O:17])=[O:18])=[N+:20]=[N-:21]
Reactant: O=C(Cl)C(=O)Cl
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under Argon at 0° C. and while stiffing, 0.7 ml oxalylchloride were added dropwise to a suspension of 908 mg (4 mmol) 4-carboxybenzene sulfonyl azide (Aldrich). The mixture was allowed to warm to room temperature. Then, 10 μl DMF (dimethylformamide) were added. After stirring for 1 h at room temp. a clear solution was formed. The solvent was removed using a rotary evaporator.
Reaction SMILES: C(O)(C(F)(F)F)C(F)(F)F.[O:11]=[C:12]1[O:18][C@H:17]([C@H:19]([CH2:21][OH:22])[OH:20])[C:15]([OH:16])=[C:13]1[OH:14].[O:23]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]12>C(#N)C>[OH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:16][C:15]1[C@@H:17]([C@H:19]([CH2:21][OH:22])[OH:20])[O:18][C:12](=[O:11])[C:13]=1[OH:14]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: C1CCC2OC2C1
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: O=C1O[C@H]([C@@H](O)CO)C(OC2CCCCC2O)=C1O
Temperature: 70 °C
Reaction time: 36 h

Procedure:
Under an argon atmosphere, 4 ml of 1,1,1,3,3,3-hexafluoro isopropanol and 12 ml of acetonitrile were added to L-ascorbic acid (1.00 g), and further, 1,2-epoxycyclohexane (1.42 g) was added. The mixture was heated up to 70° C. and stirred for 36 hours, then, concentrated under reduced pressure, and 3.65 g of the resultant residue was subjected to silica gel column chromatography. Thereafter, it was eluted with chloroform/methanol/water(volume ratio:20/3/0.3) to obtain two elution fractions (first eluted fraction: 244 mg, later eluted fraction: 217 mg). Based on the measurement results of high resolution mass analysis, infrared absorption spectrum, 1H-NMR, 13C-NMR and specific optical rotation on the resultant elution fractions, it was confirmed that these are two 3-O-(2-hydroxycyclohexyl) ascorbic acids which are in mutual stereoisomerism and both of them are represented by the following structural formula.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13](I)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH2:25][CH2:26][O:27][CH:28]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:23]3[O:24][CH2:25][CH2:26][O:27][CH:28]=3)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=COCCO1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nc2c(OC)ccc(C3=COCCO3)c2s1
Temperature: 100 °C
Yield: 45.2 %

Procedure:
To a stirred solution of 13.0 g (35.7 mmol) (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 200 ml dioxane were added 20.1 g (53.6 mmol) tributyl-(5,6-dihydro-[1,4]dioxin-2-yl)-stannane, 616 mg (1.07 mmol) bis(dibenzylideneacetone)palladium, 1.33 g (5.71 mmol) trifurylphosphine and 7.46 ml (53.6 mmol) triethylamine. The mixture was heated at 100° C. for 16 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/4-1/2 acetone/hexane) followed by trituration in ether afforded 5.20 g (45%) [7-(5,6-dihydro-[1,4]dioxin-2-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester as a white solid. ES-MS m/e (%): 323 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:15]1[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=1)([CH2:11][CH2:12][CH2:13]I)[CH2:6][CH2:5]2.[CH3:29][NH2:30]>O1CCCC1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:15]1[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=1)([CH2:11][CH2:12][CH2:13][NH:30][CH3:29])[CH2:6][CH2:5]2
Reactant: CS(=O)(=O)Nc1cccc2c(C3(CCCI)CCc4cc(F)ccc43)c[nH]c12
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCCCC1(c2c[nH]c3c(NS(C)(=O)=O)cccc23)CCc2cc(F)ccc21
Yield: 49 %

Procedure:
Stir N-{3-[5-fluoro-1-(3-iodo-propyl)-indan-1-yl]-1H-indol-7-yl}-methane sulfonamide (88 mg, 0.17 mmol) and methylamine (40% in water, 2 ml) in tetrahydrofuran (1 ml) at room temperature under nitrogen for 30 minutes. Dilute with dichloromethane and 10% aqueous potassium carbonate. Filter the white solids that crush out and dry under high vacuum to obtain the title compound (35 mg, 49%). LC-MS m/z 416.1 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[C:16](O)(=[O:20])[C:17]([CH3:19])=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClC(Cl)(Cl)C.C(C1CC(=CN(C)C)C=C(C(C)(C)C)C=1O)(C)(C)C>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: O=C(O)c1ccc(OCCCCO)cc1
Reactant: C=C(C)C(=O)O
Agent: CN(C)C=C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(Cl)(Cl)Cl
Product: C=C(C)C(=O)OCCCCOc1ccc(C(=O)O)cc1
Yield: 60 %

Procedure:
A solution of 282 g of 4-(4′-hydroxybutoxy)benzoic acid (1.34 mol), 325 ml of freshly distilled methacrylic acid (3.35 mol), 0.3 g of 2,6 di-tert-butyl-4-(dimethylaminomethylene)phenol (Ethanox® 703) and 23.7 g of p-toluenesulfonic acid in 1.1 l of 1,1,1-trichloroethane was refluxed for 10 hours on a water separator. The reaction mixture was cooled to 60° C.-70° C. and stirred into 2.51 of petroleum ether, and the precipitate was filtered off. After washing with petroleum ether, the precipitate was dried under reduced pressure at room temperature for 24 hours, giving 223.7 g of 4-(4′-methacryloxybutoxy)benzoic acid (yield 60%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH:5]=[CH:6][CH:7]=[N:8][NH:9][C:10]([NH2:12])=[S:11].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=O>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:12]=[C:10]([NH:9][N:8]=[CH:7]/[CH:6]=[CH:5]/[C:4]3[CH:3]=[C:2]([OH:1])[CH:15]=[CH:14][CH:13]=3)[S:11][CH:17]=2)=[CH:21][CH:22]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: NC(=S)NN=CC=Cc1cccc(O)c1
Product: Oc1cccc(/C=C/C=NNc2nc(-c3ccc(Cl)cc3)cs2)c1
Yield: 39 %

Procedure:
The compound is prepared according to the method described in example 1B from 3-hydroxycinnamaldehyde thiosemicarbazone (0.5 mmoles) prepared in step 15A and from 2-bromo-4′-chloroacetophenone (0.5 mmoles). Yield 39%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:12]=[CH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)C>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C=CC(=O)OC(C)(C)C)cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1[nH]c(CCC(=O)OC(C)(C)C)cc1C
Yield: 99.7 %

Procedure:
A solution of 5-(2-tert-butoxycarbonyl-vinyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.48 g) in ethyl acetate (60(mL) and ethanol (30 mL) was hydrogenated using 1% palladium on carbon at room temperature for overnight to give 2.49 g (100%) of 5-(2-tert-butoxycarbonyl-ethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.12 (br s, 1H, NH), 5.74 (d, J=2.3 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H, OCH2), 2.71 (t, J=7.5 Hz, 2H, CH2), 2.47 (t, J=7.5 Hz, 2H, CH2), 2.18 (s, 3H, CH3), 1.36 (s, 9H, 3×CH3), 1.28 (t, J=7.1 Hz, 3H, OCH2CH3). MS 282 [M++1].
Reaction SMILES: NC[C@@H]1[C@H](C)CCCN1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[C:30]([CH:34]=1)[C:31]([OH:33])=O.[F:40][C:41]1([F:59])[CH2:46][CH2:45][NH:44][CH:43]([CH2:47][N:48]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:42]1>>[NH2:48][CH2:47][CH:43]1[CH2:42][C:41]([F:59])([F:40])[CH2:46][CH2:45][N:44]1[C:31]([C:30]1[CH:34]=[C:26]([CH3:25])[CH:27]=[CH:28][C:29]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:33]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: O=C1c2ccccc2C(=O)N1CC1CC(F)(F)CCN1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC(F)(F)CC2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid and 2-((4,4-difluoropiperidin-2-yl)methyl)isoindoline-1,3-dione. MS (ESI) 336 (M+H).