Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH2:15][CH3:16])[CH:9]([OH:14])[CH2:10][N+:11]([O-:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>ClCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH2:15][CH3:16])[CH:9]([O:14][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH2:10][N+:11]([O-:13])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NC(=O)OC(C)(C)C)C(C[N+](=O)[O-])O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
To a mixture of (1-ethyl-2-hydroxy-3-nitro-propyl)-carbamic acid tert-butyl ester (1.83 g, 7.37 mmol) and triethylamine (1.49 g, 14.75 mmol) in dry dichloromethane (25 mL) under N2 is added trimethylsilyl chloride (1.20 g, 11.05 mmol). The mixture is stirred at room temperature for 24 h, then diluted with 40 mL of dichloromethane and washed with water (40 mL). The organic layer is dried over magnesium sulfate and concentrated in vacuum. The residue is purified over 110 g silica gel, eluted with ethyl acetate: heptane (1:4) to afford (1-ethyl-3-nitro-2-trimethylsilanyloxy-propyl)-carbamic acid tert-butyl ester (1.505 g, 86%) as an oil.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([C:36]([F:39])([F:38])[F:37])=[O:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:39][C:36]([F:37])([F:38])[S:34]([C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)=[O:35]
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 110 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol/water 1:1 and with diethyl ether. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/n-heptane 3:1) to yield 80 mg (31%) colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][OH:13]>C1COCC1.CCOC(C)=O>[Br:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:7]=[CH:6][CH:5]=1
Reactant: NCCCO
Reactant: Brc1cccc(Br)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCCNc1cccc(Br)n1

Procedure:
A solution of 2,6-dibromopyridine (10 g, 42 mmol) and 3-aminopropanol (3.5 mL, 46 mmol) in THF (60 mL) was stirred at reflux for 48 h. The reaction mixture was diluted with EtOAc and washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to give 3-(6-bromo-pyridin-2-ylamino)-propan-1-ol as a light-yellow oil which crystallized on standing at RT to a white solid. MS m/z: 232.0 (M+H). Calc'd for C8H11BrN2O 231.09.
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH3:11][Si:12]([CH3:21])([CH3:20])[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>O1CCCC1>[CH3:11][Si:12]([CH3:21])([CH3:20])[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:10])[F:1])=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)c1ccc(N)cc1
Reactant: O=C(Cl)CCCC=C(F)F
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(NC(=O)CCCC=C(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With cooling at 10°, 1.0 g of 6,6-difluorohex-5-enoic acid chloride is added to 1.0 g of 4-trimethylsilylaniline, 0.73 g of trithylamine and 10 mg of 4-N-pyrrolidinopyridine in 25 ml of tetrahydrofuran. The mixture is stirred for 2 hours at room temperature and then concentrated by evaporation in vacuo. The residue is taken up in toluene, the toluene phase is washed with water, dried over sodium sulfate and concentrated to dryness by evaporation. The residue is taken up in hexane:ethyl acetate (9:1) and filtered over silica gel. Evaporation of the filtrate yields the title compound having a melting point of 50°-51° (compound no. 1-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]([CH3:28])([C:23]1[O:24][CH:25]=[CH:26][N:27]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:23]1[O:24][CH:25]=[CH:26][N:27]=1)[CH3:28]
Reactant: CC(C)(N)c1ncco1
Reactant: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1)c1ncco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48 e) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=382.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.CC(C)([O-])C.[K+].[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>CN(C=O)C>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][S:26](=[O:28])(=[O:27])[N:25]([CH3:30])[CH3:24])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCC2)c2ccc(OS(=O)(=O)N(C)C)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
229.4 mg (1 mmol) of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 2, were suspended under an argon atmosphere in 20 ml of DMF, 0.6 g (1.2 mmol) of molecular sieves (4 nm) were added followed by 138 mg (1.2 mmol) of potassium tert-butoxide, and the mixture was stirred for 1 h at RT. It was then cooled to 0° C., treated with 0.13 ml (1.2 mmol) N,N-dimethylsulfamoyl chloride and stirred for 3 h at 0° C. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted twice with EtOAc, the combined organic layers were washed with water then with saturated NaCl solution, dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with diethyl ether; the viscous oil obtained was filtered off by suction and dried in a high vacuum. Upon further triturating with heptane solid material was obtained which was dried in a high vacuum to give 100 mg (29.3%) of dimethyl-sulfamic acid 2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl ester as an off-white solid. ISP mass spectrum, m/e: 336.2 (M+1 calculated for C16H21N3O3S: 336).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[C:16]([NH:24][NH2:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[C:17]1([C:16]2[N:3]3[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]4[C:11]([C:2]3=[N:25][N:24]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cnc(Cl)c2ccccc12
Reactant: NNC(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cn2c(-c3ccccc3)nnc2c2ccccc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 1-Chloroisoquinoline-4-carboxylate, prepared essentially according to procedures described in Example 1, part 4, (293 mg) and benzoic hydrazide (192 mg) in 8 ml of DMF is stirred at 100° C. overnight. The mixture is cooled and poured into water. The solid is then collected by filtration and dried to give the title compound as a solid (258 mg). LC-MS data for the title compound: HPLC: 2.34 min. MS (ES+) m/e 304 [M+H]+. (The HPLC retention time is obtained by the method of Example 1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]=1>CN(C)C=O.CO>[Cl:25][C:19]1[N:18]=[C:17]2[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:13])=[N:16]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1ccc2ccccc2n1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc2ccccc2n1
Temperature: 4 °C
Yield: 26.8 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 2-quinolinecarboxylic acid (10.4 g), N,N'-carbonyldiimidazole (13 g) and 2-amino-7-chloro-1,8-naphthyridine (7.2 g). After cooling at 4° C., the crystallized solid is separated by filtration, washed with distilled water (5×50 cc) and air-dried. The product obtained (7.4 g; m.p. 260° C.) is dissolved in a mixture of dimethylformamide (200 cc) and methanol (200 cc). After cooling for 3 hours at 4° C., the crystallized solid is separated by filtration, washed with methanol (3×15 cc) and dried at 35° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)quinoline-2-carboxamide (3.6 g), m.p. 275° C., is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[H][H]>O1CCCC1.C(O)C.[C].[Pd]>[NH2:15][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][C:2]=1[OH:1]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N)c(O)c1
Yield: 105.9 %

Procedure:
In 30 ml of tetrahydrofuran and 130 ml of ethanol was dissolved 3.32 g of ethyl 3-hydroxy-4-nitrocinnamate. To the solution was added 100 mg of 10% palladium-carbon. The mixture was stirred under normal pressure in a hydrogen flow until absorption of hydrogen was discontinued. The catalyst was filtered off by suction and the filtrate was concentrated under reduced pressure to obtain 3.10 g of crude ethyl 4-amino-3-hydroxybenzenepropionate as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.[C:47](=[O:59])([O:49][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1Br)[NH2:48]>>[C:20]([O:19][C:18](=[O:24])[NH:17][CH2:16][CH:15]([C:25]1[CH:30]=[CH:29][C:28]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[CH2:51][CH2:50][O:49][C:47]([NH2:48])=[O:59])=[CH:27][C:26]=1[CH3:40])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][C:3]2[C:41]([Cl:46])=[CH:42][C:43]([CH3:45])=[CH:44][C:2]=2[Cl:1])=[CH:9][CH:10]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: NC(=O)OCCc1ccccc1Br
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(-c4ccccc4CCOC(N)=O)cc3C)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and 2-(2-bromophenyl)ethyl carbamate (V.7) as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[S:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[CH:15]=1)=[O:13].[NH2:23][C:24]1[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:28][CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:8])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[S:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[CH:15]=1)=[O:13]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1cc2nccnc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cc2nccnc2s1
Yield: 52 %

Procedure:
A solution of 4-methyl-3-(thieno[2,3-b]pyrazine-6-carboxamido)benzoic acid 50 (25 mg, 0.080 mmol), 3-aminobenzotrifluoride (9.87 μl, 12.86 mg, 0.080 mmol), TBTU (38.4 mg, 0.120 mmol) and DIPEA (0.039 mL, 0.239 mmol) in DMF (1 mL) under a nitrogen atmosphere was stirred overnight at 40° C. The reaction mixture was poured into 3% citric acid solution. The resulting precipitation was collected and washed with water to give the title compound N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 51 (19 mg, 53%). NMR (400 MHz, DMSO-d6) 2.38 (s, 3H), 7.46 (d, J=7.4 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.90 (dd, J=7.8 and 1.6 Hz, 1H), 8.04 (d, J=1.6 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 8.25 (s, 1H), 8.57 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.90 (d, J=2.3 Hz, 1H), 10.55 (s, 1H), 10.66 (s, 1H). (m/z)=457 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[N+](C1C=CC([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:35]([C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:27]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][CH:8]=3)[CH2:5][CH2:6]2)=[O:26])=[CH:30][CH:31]=1)([CH3:37])[CH3:36]
Reactant: c1ccc2c(C3CCNCC3)ccnc2c1
Reactant: CC(C)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(NC(=O)N2CCC(c3ccnc4ccccc34)CC2)cc1
Temperature: 100 °C
Reaction time: 14 h
Yield: 32.3 %

Procedure:
A solution of 4-piperidin-4-yl-quinoline (21.1 mg, 99.5 μmol), as prepared in the previous step, (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (33.2 mg, 111 μmol), as prepared in Example 4a, and DIEA (18 μL, 109 μmol) in DMSO (100 μL) was stirred at 100° C. for 14 h. The reaction was then allowed to cool to rt, shaken with 2 M K2CO3 (aq) (2 mL), and extracted with DCM (2×2 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography of the residue (3:4 hex/acetone) provided the title compound (12 mg, 32%). 1H-NMR (300 MHz, CDCl3) δ 8.88 (d, 1H), 8.14 (m, 2H), 7.74 (m, 1H), 7.61 (m, 1H), 7.30 (m, 2H), 7.28 (d, 1H), 7.17 (m, 2H), 6.38 (br s, 1H), 4.36-4.26 (m, 2H), 3.58 (m, 1H), 3.16 (td, 2H), 2.87 (heptet, 1H), 2.13-2.03 (m, 2H), 1.95-1.79 (m, 2H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 373.2, found 374.2 (MH)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[N:7]([CH:8]([CH3:11])[CH2:9]O)[C:6]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:5]=2[N:4]=1.N1C=CC=CC=1.S(Cl)([Cl:40])=O>C(OCC)C>[CH3:28][N:19]1[C:20]([C:24]([F:26])([F:27])[F:25])=[CH:21][C:22](=[O:23])[N:17]([C:13]2[C:14]([F:16])=[CH:15][C:5]3[N:4]=[C:3]([C:2]([F:31])([F:30])[F:1])[N:7]([CH:8]([CH3:11])[CH2:9][Cl:40])[C:6]=3[CH:12]=2)[C:18]1=[O:29]
Reactant: O=S(Cl)Cl
Reactant: CC(CO)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(CCl)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.4 gram (0.0009 mole) of 2-[2-trifluoromethyl-5-fluoro-6-(1-methyl-6-trifluoromethyluracil-3-yl)benzimidazol-1-yl]propan-1-ol (Compound 7--prepared as in Step A of Example 8) in 10 mL of diethyl ether was cooled in an ice-water bath, and 0.07 mL (0.0009 mole) of pyridine was added at a rate to maintain the reaction mixture temperature below 5° C. Upon completion of the addition, 0.1 mL (0.0013 mole) of thionyl chloride was added dropwise from a syringe. Upon completion of the addition, the reaction mixture stirred at about 0° C. for 30 minutes. After this time, the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 18 hours. Analysis of the reaction mixture by thin layer chromatography (TLC) indicated the reaction was not complete. The reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride, and 0.1 mL of thionyl chloride and 0.07 mL of pyridine were added. The mixture was warmed to reflux, where it stirred for about 24 hours. Analysis of the reaction mixture using TLC indicated the reaction was still not complete. Additional equivalents of thionyl chloride and pyridine were were added to the reaction mixture each day for a period of five days, as the reaction mixture stirred at reflux. At the end of five days the reaction mixture was allowed to cool to ambient temperature, where it stirred for two days. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with sodium chloride and dried with sodium sulfate. The mixture was filtered, and the filtrate concentrated under reduced pressure, yielding about 0.3 gram of 1-methyl-3-[1-(1-methyl-2-chloroethyl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil, mp 93°-95° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CS(C)=O.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([Cl:15])[CH:21]=1
Reactant: Nc1cccc(O)c1
Reactant: Clc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cccc(Oc2ccnc(Cl)c2)c1
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
To a mixture of 3-aminophenol (3.7 g, 34.09 mmol) in DMSO (50 mL) was added Cs2CO3 (30.7 g, 94.46 mmol). The mixture stirred for 10 minutes and then 2,4-dichloropyridine (5.0 g, 33.79 mmol) was added. The mixture was stirred at 120° C. for 1.5 h. The mixture was cooled and diluted with water. The aqueous solution was extracted with EtOAc (3×100 mL). The organic extracts were combined, dried over MgSO4 and concentrated to afford a dark oil. The oil was purified via column chromatography, eluting with 30-40% EtOAc/hexanes, to afford 4-(3-Aminophenoxy)-2-chloropyridine (6.63 g, 89%) as a brown solid.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[CH3:27][O:28][C:29](=[O:50])[CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=2[OH:48])(O)[C:32]1=[O:49]>>[CH3:27][O:28][C:29](=[O:50])[CH2:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=2[OH:48])[C:32]1=[O:49]
Reactant: COC(=O)CN1C(=O)C(O)(c2ccc(Cl)cc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: COC(=O)CN1C(=O)C(c2ccc(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with methyl[3-(4-chloro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (83%) as a semi-solid; 1H NMR (300 MHz, CDCl3) δ 7.36 (t, 1H), 7.29 (bd, 1H), 7.18 (t, 1H), 6.95 (br, 1H), 6.86-6.78 (m, 3H), 5.13 (br, 1H), 4.55 (d, 1H), 4.45 (d, 1H), 3.75 (s, 3H); MS (ES+) m/z 332.5 (M+1), 334.5 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccsc2)SCC(N)C1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccsc2)CN(CC(=O)OC(C)(C)C)C1=O
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of 0.47 g of t-butyl α-[6-amino-5-oxo-2-(3-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (d) above] and 0.8 g of ethyl 2-bromo-4-phenylbutyrate in 7 ml of dimethylformamide was added 1.0 g of sodium carbonate. The reaction mixture was stirred at 70° C. for 18 hours and then dissolved in ethyl acetate and an aqueous solution of sodium chloride. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated off. The residue was subjected to silica gel column chromatography using a 1:20 by volume mixture of ethyl acetate and methylene chloride to give two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached). The first eluted isomer A was an oily compound in a yield of 0.27 g.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][C@H:5]1[CH3:18])=[N+:2]=[N-:3].[ClH:19].C(OC)(C)(C)C>C1COCC1>[ClH:19].[N:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([NH2:10])[CH2:6][C@H:5]1[CH3:18])=[N+:2]=[N-:3]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@H]1N=[N+]=[N-]
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C[C@@H]1C[C@H](N)CC[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Yield: 94.4 %

Procedure:
tert-Butyl [(1R*,3R*,4R*)-4-azido-3-methylcyclohexyl]carbamate (example C10; 2.5 g; 10.0 mmol) is dissolved in THF (25.0 mL). After addition of HCl (4M solution in dioxane; 10.0 mL; 40.0 mmol) the reaction mixture is stirred at ambient temperature over night and gently refluxed for additional 6 hours. tert-BuOMe is added at ambient temperature, the precipitated product is collected by suction filtration, washed with several small portions of tert-BuOMe and dried under reduced pressure to yield 1.8 g of the title compound as colourless solid.