Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21]([N:26]3[CH2:31][CH2:30][S:29][CH2:28][CH2:27]3)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)O)c2)=C(C)C1=O
Reactant: C1CSCCN1
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)N3CCSCC3)c2)=C(C)C1=O
Yield: 32.1 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (65 mg, 0.19 mmol) obtained in Example 31 and thiomorpholine (0.022 ml, 0.21 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (26 mg, 0.061 mmol, yield 32%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[CH2:13][C:14]1[C:15]([CH3:20])=[N:16][O:17][C:18]=1[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:20][C:15]1[C:14]([CH2:13][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=2)=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Cc1ccc(OCc2c(C)noc2C)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A mixture of 4-hydroxyphenyl acetone (1.5 g), 4-chloromethyl-3,5-dimethylisoxazole (1.6 g) and potassium carbonate (1.5 g) in dimethylformamide (10 ml) was heated and stirred at 60° C. for 18 h. After cooling, the mixture was poured into water and extracted twice with ethyl acetate. The combined solvent phase was washed twice with brine, dried (magnesium sulphate) and then evaporated. The resultant oil was chromatographed on silica using isohexane to 20% ethyl acetate in isohexane mixtures to give the title compound (2.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]#[N:12])[N:8]=[CH:7]1)[CH3:2].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH2:1]([O:3][C:4](=[O:13])[C:5]([N:6]1[CH:10]=[C:9]([C:11]#[N:12])[N:8]=[CH:7]1)=[CH:17][N:18]([CH3:20])[CH3:19])[CH3:2]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cn1cnc(C#N)c1
Product: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1

Procedure:
3.8 g (21.4 mmol) of the compound from Example 33A and 7.4 ml (6.3 g, 42.8 mmol) dimethylformamide diethyl acetal are stirred at a bath temperature of 100° C. for 16 h. For working up, the cooled reaction solution is concentrated on a rotary evaporator and the residue is dried in vacuo.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>O1CCOCC1>[CH3:24][N:23]([CH3:25])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:40]2[CH2:39][CH:38]=[C:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([Cl:27])[CH:29]=4)[NH:33][CH:32]=3)[CH2:42][CH2:41]2)=[O:7])[CH2:12][CH2:13]1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CC=C(c3c[nH]c4ccc(Cl)cc34)CC2)CC1
Yield: 8.7 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (705 mg, 2 mmole) was added to a solution of 5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (465.4 mg, 2 mmole) in dioxane (12 ml). The reaction mixture was then boiled under reflux for 20 hours. The reaction mixture was a suspension at RT. The solid was filtered off, washed with cold dioxane (3×2 ml) and dried. The solid was the polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (259 mg, m.p. 120°-130° C., 26%). The reaction solution (filtrate and wash phases) was concentrated by evaporation and water (10 ml) was added to the residue. The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The combined EE extracts were washed with 1M NaOH (1×5 ml) and dried with Na2SO4. The solvent was distilled off in vacuo. The residue contained phenol and mainly the non-polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (80 g). Ethanol (1000 ml) was used as eluent. The non-polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (304 mg, m.p. 216°-222° C., 31%) and a further part of the polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (85 mg, m.p. 108°-111° C., 9%) were thereby isolated.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1)=O.[CH3:38][NH2:39].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:38][NH:39][CH2:1][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:27])=[O:28])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: CN
Reactant: NC(=O)c1cc(-c2ccc(C=O)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)c[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCCN5CCOCC5)CC4)c3c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of 5-(5-formyl-2-thienyl)-3-(1-{[3-(4-morpholinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (20 mg, 0.04 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added methyl amine (0.11 mL, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4 (10.5 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (13.4 mg, 65%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[N:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[C:23]=[S:24]>C(#N)C.CCN(C(C)C)C(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:23](=[S:24])[NH:22][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:27][CH:26]=1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Reactant: NCCCCCN(Cc1ccccn1)Cc1ccccn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(NC(=S)NCCCCCN(Cc2ccccn2)Cc2ccccn2)cc1
Yield: 19 %

Procedure:
A solution of tert-butyl 5-(bis(pyridin-2-ylmethyl)amino)pentylcarbamate (0.63 g, 1.64 mmol) in DCM (10 mL) and TFA (1.0 mL) was stirred at room temperature for 3 h. Upon completion the solvent was evaporated and the reaction mixture was diluted with DCM, washed with saturated aqueous potassium carbonate and concentrated under vacuum to afford N,N-bis(pyridin-2-ylmethyl)pentane-1,5-diamine. A solution of the above product N,N-bis(pyridin-2-ylmethyl)pentane-1,5-diamine, 4-isothiocyanatobenzenesulfonamide (0.35 g, 1.64 mmol) in acetonitrile (10 mL) and DIPEA (0.40 mL) was stirred at 50° C. under nitrogen for 3 h. The solvent was evaporated under reduced pressure to give a crude product, which was purified by flash chromatography eluting utilizing 5% MeOH in DCM followed by 15% MeOH in DCM to give 4-(3-(5-(bis(pyridin-2-ylmethyl)amino)pentyl)thioureido) benzenesulfonamide (0.145 g, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.48 (d, 2H), 7.98 (s, 1H), 7.78-7.69 (m, 4H), 7.63 (d, 2H), 7.53 (d, 2H), 7.29-7.21 (m, 4H), 3.55 (s, 4H), 3.46-3.44 (m, 2H), 2.49-2.47 (m, 2H), 1.56-1.42 (m, 2H), 1.32-1.28 (m, 2H); ESMS m/z: 499.5 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH2:25])[CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][C:8]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH3:10])[CH3:9])=[O:26])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(Oc2cc(Cl)ccc2N)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 49.2 %

Procedure:
A mixture of tert-butyl[1-[3-(2-amino-5-chlorophenoxy)phenyl]-1-methylethyl]carbamate (2.5 g, 6.62 mmols), ethyl 4-bromobutyrate (9.0 g, 46 mmols), potassium carbonate (2.7 g, 20 mmols) and N,N-dimethylformamide (20 ml) was stirred at 80° C. for 24 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[N-[2-[3-(1-tert-butoxycarbonylamino-1-methylethyl)phenoxy]-4-chlorophenyl]]aminobutyrate (1.6 g, 49%).
Reaction SMILES: O1CCCC1.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[I:40]I.[I-]>C1C=CC=CC=1>[CH2:6]([I:40])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][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][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: II
Reactant: CCCCCCCCCCCCCCCCC=CCCCCCCCCCCCCCCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCI
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 44.8 g. (0.15 mole) of Cp2ZrCl2 in 800 ml. tetrahydrofuran under Argon was added 24.7 g. (0.086 mole) of NaAlH2 (OCH2CH2OCH3)2 in benzene via syringe. After stirring 2 hours at room temperature, 36.8 g. (0.077 mole) of the olefin, 17-tetratriacontene, was added and the mixture kept at 40° C. for 7 days. After cooling in an ice bath, solid iodine (34.0 g., 0.134 mole) was added. The mixture was filtered and the solvent removed in vacuum. NMR analysis indicated an olefin:iodide ratio of 25:75. The residue was dissolved in hexane and percolated through dry silica gel to remove impurities. Recrystallization from hexane gave 13.0 g. pure iodide, m.p. 75°-6° C. and 14.4 g. of a 58:42 olefin:iodide mixture.
Reaction SMILES: C[Al](C)C.Cl.[CH3:6][NH:7][CH3:8].[Br:9][C:10]1[C:23]([CH3:24])=[C:22]([C:25]#[N:26])[C:13]2[N:14]=[C:15]([C:17]([O:19]CC)=O)[O:16][C:12]=2[C:11]=1[F:27].Cl>ClCCl>[Br:9][C:10]1[C:23]([CH3:24])=[C:22]([C:25]#[N:26])[C:13]2[N:14]=[C:15]([C:17]([N:7]([CH3:8])[CH3:6])=[O:19])[O:16][C:12]=2[C:11]=1[F:27]
Reactant: CNC
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(Br)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(Br)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 57.9 ml, 59.6 mmol) was dropwise added to a dichloromethane (100 ml) solution of dimethylamine hydrochloride (4.86 g, 59.6 mmol) with cooling in a water bath, taking 30 minutes, and stirred for 65 minutes at room temperature. Subsequently, a dichloromethane (30 ml) solution of ethyl 6-bromo-4-cyano-7-fluoro-5-methyl-1,3-benzoxazole-2-carboxylate (I-126) (6.50 g, 19.9 mmol) was dropwise added and stirred for 30 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, and the reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (100:1, v/v) gave the entitled compound (3.10 g, 48%) as a pale yellow solid. The fraction containing impurities was recovered and purified twice in the same manner to obtain the entitled compound (362 mg, 591 mg), and 4.05 g (62%) of the entitled compound was obtained in total.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[C:44]1[CH:45]=[CH:46][C:47]([CH:50]=[C:51]2[NH:56][C:55](=[O:57])[C:54](=[CH:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62]C=3)[NH:53][C:52]2=[O:66])=[N:48][CH:49]=1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][C:44]1[CH:49]=[N:48][C:47](/[CH:50]=[C:51]2\[NH:56][C:55](=[O:57])/[C:54](=[CH:58]/[C:59]3[CH:60]=[CH:65][CH:64]=[CH:63][CH:62]=3)/[NH:53][C:52]\2=[O:66])=[CH:46][CH:45]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1[nH]c(=Cc2ccc(O)cn2)c(=O)[nH]c1=CCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C(=O)Oc1ccc(/C=c2\[nH]c(=O)/c(=C/c3ccccc3)[nH]c2=O)nc1)c1ccccc1

Procedure:
2-(Tert-butoxycarbonylamino)-2-phenylacetic acid was dissolved in DMF and treated with HBTU. Compound C were then added into the mixture and stirred. After the completion of reaction, the reaction mixture was partitioned by K2CO3(aq) and CH2Cl2. The organic layer was collected, dried over MgSO4(s), and dried by rotary evaporator. The solid residues were then purified by column chromatography to get Compound 8. mp 198° C.; 1H-NMR (400 MHz, CDCl3): δ 1.50 (s, 9H), 5.48 (s, 1H), 5.58-5.59 (m, 1H), 6.78 (s, 1H), 7.11 (s, 1H), 7.37-7.50 (m, 13H), 8.22 (s, 1H), 8.42 (s, 1H), 12.46 (s, 1H).
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:13]=2)=[CH:7][CH:6]=1)C.[CH2:28]([O:30][C:31](=[O:42])C1C=CC=C(CC(O)=O)C=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:42])[C:6]1[CH:5]=[CH:10][CH:9]=[C:8]([CH2:11][C:12]2[O:16][N:15]=[C:14]([CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:13]=2)[CH:7]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc(Cc2nc(COc3ccc(OC)cc3)no2)cc1
Reactant: CCOC(=O)c1cccc(CC(=O)O)c1
Product: CCOC(=O)c1cccc(Cc2nc(COc3ccc(OC)cc3)no2)c1

Procedure:
The title compound is prepared essentially as described for 4-[3-(4-methoxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester, employing 3-carboxymethyl-benzoic acid ethyl ester (45%). LC-MS (m/e): 369 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:18]([CH2:17][CH2:16][NH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCBr
Reactant: COc1ccc(OC)c(C(C)=O)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1c(OC)ccc(OC)c1C(C)=O
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Triethylamine (19.4 g, 192 mM) was added to a mixture of 2'-amino-3',6'-dimethoxyacetophenone (2.5 g, 128 mM) and ethyl 3-bromopropionate (139 g, 770 mM) in a 250 mL flask. The pale solid complex so formed was stirred at 135° for 2 hours with a large and heavy stirring bar. During this time the complex became a homogeneous brown oil. This oil was cooled to 10° C. and 200 mL of 2% NaHCO3 was added to the reaction mixture. The solution was then extracted with CHCl3 (3×100 mL) and the organic layer washed with H2O (100 mL) and then dried over MgSO4. After filtration, the CHCl3 and most of the bromopropionate were removed under reduced pressure. The oily residue was put on a 10×60 cm, SilicAR CC-7 column (500 g) and eluted with 5-20% ethyl acetate/hexane, collecting 1 L fractions. Evaporation of fractions 5 and 6 gave purified 2'-(N-2-carbethoxyethylamino)-3',6'-dimethoxyacetophenone (9.97 g, 26%); IR (neat) μ: 3.3, 5.78, 5.8, 6.25.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=1)/[C:5]([O:7][CH3:8])=[O:6].[Cr](O)(O)(=O)=[O:25].O>CC(C)=O>[CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:25])=[O:23])[CH:17]=1)/[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=[Cr](=O)(O)O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(CO)c1
Solvent: CC(C)=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(C(=O)O)c1
Yield: 98.3 %

Procedure:
To (E)-methyl 3-methoxy-2-(2-[3-hydroxymethylphenoxy]phenyl)propenoate (2.43 g, prepared as described in Example 17) stirred in acetone (100 ml) at 5°-10° C., was added chromic acid [made by dissolving chromium trioxide (6.5 g) in 18.5 ml water containing 5.5 ml of concentrated sulphuric acid]until a reddish brown colour persisted, and GC indicated the disappearance of all the starting alcohol. The mixture was then poured into water and extracted with ether. The ether extracts were washed with water, dried and evaporated to give (E)-methyl 3-methoxy-2-(2-[3-carboxyphenoxy]phenyl)propenoate as a pale yellow oil (2.495 g).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:28])[CH2:27][CH2:26][N:25]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[N:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:24][CH2:23]1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Reactant: FC1(F)CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCC(F)(F)CC2)ncn1

Procedure:
250 mg (0.8 mmol) of the compound from Example 12A, 158 mg (1.0 mmol) of 4,4-difluoropiperidine hydrochloride and 435 μl (323 mg, 2.5 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 5 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 30 min. After pre-purification by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient), the product is additionally purified by column chromatography on silica gel (mobile phase dichloromethane/methanol, 10/1). Yield: 29 mg (10% of theory)
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1OC)[C:5]([NH:7]C1C=CC(F)=C(F)C=1)=[O:6].ClS(N=C=O)(=O)=O.C(N(CC)CC)C.CNC.Cl>C(Cl)Cl>[C:5]([NH2:7])(=[O:6])[C:4]1[CH:16]=[CH:17][CH:18]=[CH:2][CH:3]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Agent: CNC
Agent: Cl
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
3-Amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (2.0 g, 7.2 mmol) was dissolved in 50 mL of methylene chloride and cooled to 0° C. Chlorosulfonyl isocyanate (0.85 mL, 9.8 mmol) dissolved in 20 mL of methylene chloride was added dropwise. The mixture was stirred overnight. The resulting solid was collected by filtration and dried under vacuum. The dried solid (1.0 g, 2.4 mmol) was sited in 50 mL of methylene chloride with triethylamine (0.7 mL, 4.8 mmol) for 1 hour. Dimethylamine (1.2 mL of a 2N solution, 2.4 mmol) was added, and the solution stirred for 48 hours. The resulting mixture was washed with water (2×50 mL) and the organic phase dried over magnesium sulfate. The solvents were evaporated under reduced pressure to give a foam. The foam was redissolved in a small amount of fresh methylene chloride and treated with 1N hydrochloric acid (20 mL). Vigorous shaking produced a precipitate, which was collected via filtration. The resulting powder was sequentially triturated with water, methylene chloride, and ether. The triturated solid was dried under vacuum to give 0.64 g of benzamide, N-(3,4-difluorophenyl)-3-[[[[(dimethylamino)sulfonyl]-amino]carbonyl]amino]-4-methoxy-. Microanalysis: C17H18F2N4O5S-0.86 H2O; calculated: C=46.00; H=4.31; N=12.69. found: C=46.00; H=4.31; N=12.69. MS:M++1=349 Da. Mp 253-255° C. 1HNMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 10.25 (s, 1H), 9.26 (s, 1H), 7.94-7.89 (m, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.64 (s, 1H), 7.49-7.39 (m, 2H), 7.27 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 2.95 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:27](O)CC>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH2:23][CH3:27])=[O:20])=[CH:25][CH:26]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCO
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1
Agent: O=S(=O)(O)O
Product: CCCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1
Reaction time: 72 h

Procedure:
A mixture of ethyl 2-[4-(7-chloroquinolin-3-yloxy)phenoxy]propionate (500 mg), concentrated sulphuric acid (2 drops) and n-propanol (50 ml) was heated under reflux with stirring for 72 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulphate and evaporated to give n-propyl 2-[4-(7-chloroquinolin-3-yloxy)phenoxy]propionate as a pale brown oil which was characterised by its proton magnetic resonance spectrum (Table 3).