Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=[N:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[N:11]=[S:12]=O)=O.O.[Cl:15][S:16](O)(=[O:18])=[O:17]>>[F:10][C:6]1[C:5]2=[N:11][S:12][N:3]=[C:4]2[C:9]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=S=Nc1cccc(F)c1N=S=O
Solvent: O
Product: O=S(=O)(Cl)c1ccc(F)c2nsnc12
Temperature: 25 °C

Procedure:
A solution of N,N′-disulfinyl-3-fluoro-1,2-diaminobenzene 39B (11.5 g, 52.75 mmol) in 80 mL of chlorosulfonic acid was heated at 110° C. for 8 hours. The mixture was cooled to r.t. and poured into water and extracted with EtOAc (50 mL) twice. The combined organic layer was washed with brine and dried over anhy. Na2SO4. The combined organic layer was concentrated in vacuo. Column chromatography (15% Petroleum/EtOAc) afforded 7.1 g of title compound. 1H NMR (CHLOROFORM-d) δ: 8.48 (dd, J=8.4 Hz, 4.4 Hz, 1H), 7.45 (t, J=8.4 Hz, 1H). LC-MS: m/z 253.2 (M+H)+.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+].[S:11](=[O:14])([OH:13])[O-:12].[Na+].S(=O)(O)[O-]>>[S:11]([CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][C:1]([OH:8])=[O:7])([OH:14])(=[O:13])=[O:12]
Reactant: O=S([O-])O
Reactant: CCCC=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCC(CC(=O)O)S(=O)(=O)O

Procedure:
114 g. of 2-hexenoic acid is neutralized with aqueous sodium hydroxide and reacted with 204 g. of a 50% wt. aqueous solution of sodium bisulfite at 25° C. Complete addition of bisulfite to the double bond requires several hours. The product is concentrated to approximately 50% wt. solids and then treated with a strong acid ion exchange resin to obtain an aqueous solution of 3-sulfohexanoic acid. This is dried by vacuum stripping and converted into 3-propyl-1,2-oxathiolane-5-one-2,2-dioxide with refluxing thionyl chloride at 80° C. for 3 hours. Equivalent weight is 93.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([O:32][CH3:33])=[O:31])[CH:18]=[C:17]3[C:34]([O:36][CH3:37])=[O:35])[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([O:32][CH3:33])=[O:31])[CH:18]=[C:17]3[C:34]([O:36][CH3:37])=[O:35])[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)cc(C(=O)OC)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)cc(C(=O)OC)c2c1
Yield: 76.9 %

Procedure:
65.5 mg (0.126 mmol) of methyl 6-[(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]-2-(2-methoxycarbonyl-phenyl)-4-quinolinecarboxylate obtained in Example 7 was dissolved in a mixed solvent of 2 ml of tetrahydrofuran and 2 ml of methanol and the mixture was stirred. After adding 5.24 mg (0.139 mmol) of sodium borohydride, the reaction mixture was allowed to react at room temperature for one hour. Then, the reaction mixture was concentrated under reduced pressure and dichloromethane was added to the residue followed by washing with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 50.6 mg of methyl 6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-2-(2-methoxycarbonyl-phenyl)-4-quinolinecarboxylate. NMR (270 MHz, CDCl3):
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20]C)=[O:19])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([OH:20])=[O:19])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A mixture of methyl 3-(4-(4-chlorophenoxy)piperidine-1-carbonyl)benzoate (301 mg, 0.81 mmol, Step-1), 2M sodium hydroxide aqueous solution (2 mL), tetrahydrofuran (2 mL), and methanol (2 mL) was stirred at 60° C. for 2 hours. The mixture was acidified by 2M aqueous hydrochloric acid solution and extracted with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 270 mg (93% yield) of the title compound as a white solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Si:13]([N:20]1[C@H:23]([CH2:24][C:25]([S:30][CH3:31])([S:28][CH3:29])[S:26][CH3:27])[CH2:22][C:21]1=[O:32])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH:33](=[O:35])[CH3:34]>O1CCCC1>[Si:13]([N:20]1[C@H:23]([CH2:24][C:25]([S:28][CH3:29])([S:26][CH3:27])[S:30][CH3:31])[C@@H:22]([C@H:33]([OH:35])[CH3:34])[C:21]1=[O:32])([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:15])[CH3:14]
Reactant: CC=O
Reactant: CSC(C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSC(C[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1[Si](C)(C)C(C)(C)C)(SC)SC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 50.3 %

Procedure:
n-Butyllithium (14.8 ml of 2.5 N hexane solution, 37.0 mmol) is added by syringe to a solution of diisopropylamine (3.74 g, 37.0 mmol) in 180 ml of freshly distilled tetrahydrofuran at -78° C. The resulting solution is stirred at -78° C. for 15 min prior to the addition of a solution of (4S)-1-(t-butyldimethylsilyl)-4-[2,2,2-tri(methylthio)ethyl]azetidin-2-one (12.34 g, 35.16 mmol) in 35 ml of tetrahydrofuran. This solution is stirred at -78° C. for 10 min prior to the addition of acetaldehyde (4.62 g, 105 mmol). The solution is stirred for an additional 5 min. at -78° C. and then quenched by addition of saturated aqueous ammonium chloride solution, and allowed to warm to room temperature. The mixture is poured into 250 ml of ether and washed with water (2×100 ml) and brine and dried over magnesium sulfate. Removal of solutions in vacuo gives an oil which is chromatographed on a silica gel column (1:1 ether:petroleum ether) to give (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-[2,2,2-tri(methylthio)ethyl]-azetidin-2-one (7.0 g, 50.4%) at Rf =0.2. The product can be recrystallized from petroleum ether. Alternatively, the trans R product can be isolated from the crude reaction mixture by direct crystallization from a petroleum ether solution.
Reaction SMILES: [C:1]([N:8]([CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[N:32]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=4[F:40])[N:31]=[C:30]([C:41]([C:47]([F:50])([F:49])[F:48])([C:43]([F:46])([F:45])[F:44])[OH:42])[CH2:29]3)=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])C)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[N:32]1[CH:28]([C:25]2[CH:26]=[CH:27][C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([S:13]([CH2:12][CH2:11][CH2:10][NH:8][CH3:1])(=[O:14])=[O:15])[CH:17]=3)=[CH:23][CH:24]=2)[CH2:29][C:30]([C:41]([C:47]([F:48])([F:49])[F:50])([C:43]([F:46])([F:45])[F:44])[OH:42])=[N:31]1
Reactant: CN(CCCS(=O)(=O)c1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCCS(=O)(=O)c1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.7 %

Procedure:
To 5-{3′-[3-(N-BOC-N-methyl-amino)-propane-1-sulfonyl]-biphenyl-4-yl}-1-(2,4-difluoro-phenyl)-3-(di-(trifluoromethyl)-hydroxy-methyl)-4,5-dihydro-1H-pyrazole (23.0 mg, 0.03 mmol) prepared in Example 395, were added dichloromethane (0.5 mL) and trifluoroacetic acid (24.0 uL, 0.31 mmol). The reaction mixture was stirred at room temperature for 72 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 15.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:6]=[C:5]([NH:15][C@@H:16]2[CH2:21][CH2:20][C@H:19]([C:22](O)=[O:23])[CH2:18][CH2:17]2)[N:4]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:6]=[C:5]([NH:15][C@@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]([NH:30][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[C:26]([F:35])([F:36])[F:25])=[O:23])[CH2:20][CH2:21]2)[N:4]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CNc1nc(N[C@H]2CC[C@@H](C(=O)O)CC2)nc(N2CCCCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNc1nc(N[C@H]2CC[C@@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(N2CCCCC2)n1
Yield: 70.8 %

Procedure:
A solution of cis-4-(4-(methylamino)-6-(piperidin-1-yl)-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid (7.6 mg, 0.023 mmol, 1 equivalent), 2-trifluoromethyl benzylamine (4 μL, 0.03 mmol, 1.25 equivalents) and DMAP (0.6 mg, 0.2 equivalents) in dichloromethane (1.5 ml) was cooled with stirring in an ice bath. EDCl (6.6 mg, 0.034 mmol, 1.5 equivalents) was added. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 2-3 hours. The solution was diluted with dichloromethane (1 ml), which was further washed with saturated sodium bicarbonate and water. The organic layer was dried and purified by HPLC (Luna 5μ C8(2), 100×21 mm, 28-70% CH3CN/H2O, 0.1% TFA, 20 min) to afford the final product (8.0 mg, yield 71%). MS (ES+): m/e 492.30 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].[C:7]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[CH:14]=O)([CH3:10])([CH3:9])[CH3:8]>>[C:1]([C:3](=[CH:14][C:13]1[CH:12]=[C:11]([C:7]([CH3:9])([CH3:8])[CH3:10])[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=1)[C:4](=[S:5])[NH2:6])#[N:2]
Reactant: N#CCC(N)=S
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(C=C(C#N)C(N)=S)cc(C(C)(C)C)c1

Procedure:
Following the procedure as set forth in Example 11 above, cyanothioacetamide was condensed with 3,5-di-tert butylbenzaldehyde to yield the title compound, m.p. 172°-174° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([CH:7]([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1ccc(Br)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(O)c1ccc(Br)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of ethyl 2-(5-bromothiophen-2-yl)-2-oxoacetate (2.5 g, 9.5 mmol) in tetrahydrofuran (50 mL) was added sodium triacetoxy borohydride (2.5 g, 11.8 mmol, 1.2 eq). After stirring for 1 hour at 60° C., the reaction mixture was diluted with ethyl acetate, washed (brine), dried (Na2SO4), filtered and concentrated to provide ethyl 2-(5-bromothiophen-2-yl)-2-hydroxyacetate (2.5 g, 99.24%). 1H NMR (400 MHz, DMSO-d6): δ 1.19 (t, J=7.0 Hz, 3H), 4.11-4.16 (m, 2H), 5.34 (d, J=5.6 Hz, 1H), 6.50 (d, J=6.0 Hz, 1H), 6.91 (d, J=4.0 Hz, 1H), 7.09 (d, J=4.0 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1.[O-]CC.[Na+].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[C:6]([C:4]1[N:3]=[CH:2][N:1]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=1)#[N:7]
Reactant: N#Cc1c[nH]cn1
Reactant: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cn1cnc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.3 g (35.3 mmol) of 1H-imidazole-4-carbonitrile [Matthews et al., J. Org. Chem. 1986, 51, 3228-3231] are initially charged in 13.2 ml (11.5 g, 35.3 mmol) of 21% strength sodium ethoxide solution in ethanol, and 4.3 ml (6.5 g, 38.9 mmol) of ethyl bromoacetate are added. The reaction mixture is stirred at RT for 16 h. For work-up, the precipitated solid is filtered off, the filter residue is washed with ethanol and the filtrate is concentrated under reduced pressure. Diisopropyl ether is added to the residue, the mixture is filtered again, the filtrate is once more concentrated on a rotary evaporator and the residue is dried under reduced pressure. Yield: 3.8 g (60% of theory)
Reaction SMILES: [CH2:1]([C:4]([P:10]([OH:13])([OH:12])=[O:11])([P:6]([OH:9])([OH:8])=[O:7])[OH:5])[CH2:2][NH2:3].[OH-].[Na+:15]>>[CH2:1]([C:4]([P:10]([O-:13])([OH:12])=[O:11])([P:6]([O-:8])([OH:9])=[O:7])[OH:5])[CH2:2][NH2:3].[Na+:15].[Na+:15]
Reactant: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NCCC(O)(P(=O)([O-])O)P(=O)([O-])O
Temperature: 0 °C
Yield: 94 %

Procedure:
Pamidronic acid (50 g) is dissolved in hot sodium hydroxide solution (150 ml) of 12.5% p/v (parts/volume) at 90° C. and the mixture was adjusted to pH 7.5˜8.5. By filtering the solution, the insoluble material is removed. The filtrate is added to isopropanol (400 ml) which is stirring. After the mixture is cooled to 0° C. filtered and dried in oven at 90° C. white disodium pamidronate (55.8 g. yield 94%) is obtained.
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.[CH:21]1([CH2:24][C@H:25]([NH2:32])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C@H:25]([NH:32][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e) as starting materials, MS (EI): m/e=434.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[C:30]12([NH2:40])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:40][C:30]34[CH2:31][CH:32]5[CH2:38][CH:36]([CH2:35][CH:34]([CH2:33]5)[CH2:39]3)[CH2:37]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NC34CC5CC(CC(C5)C3)C4)n2)cc1
Yield: 8 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 27 mg, 0.078 mmol) in 1.5 mL of ethanol was added 10 μL of triethylamine and 1-Adamantanamine (12 mg, 0.078 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (3 mg, 8% yield.) MS/ES+: m/z=465.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[S:5][CH:6]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([C:2]2[N:3]=[C:4]([C:7]3[CH:12]=[C:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[CH:10]=[C:9]([CH3:23])[N:8]=3)[S:5][CH:6]=2)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(Br)cs2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)cs2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-thiazol-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.80) (0.5 g, 1.253 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.354 g, 1.378 mmol) according to the general procedure VI. Obtained as a white solid (0.10 g, 15%) and additional off-white solid (0.40 g, 60%). MS (ISP) 532.1 [(M+H)+]; mp 196° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[N:18]1[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=1>>[N:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:25])=[CH:20][CH:19]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(O)c1ccncc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccncc4)cc3c2C1
Yield: 37.4 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 12.5 mg (0.101 mMol) 4-pyridinecarboxylic acid, 5.0 mg (37%) of the title compound were recovered as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].IC1C=C2C(=CC=1)N=C(C(O[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=O)C=N2>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:6]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cnc2cc(I)ccc2n1
Reactant: O=C(O)c1ccnc(F)c1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccnc(F)c1
Yield: 61 %

Procedure:
This compound was prepared starting from compound 27 (1.00 g, 7.09 mmol), according to the procedure developed for compound 24. Reaction time at reflux: 3.5 h, reaction time at 50° C.: 12 h to give compound 35 (1.14 g, 4.35 mmol) as a white solid. Yield 61%; mp 148-150° C.; IR (KBr) ν 1220, 1283, 1406, 1525, 1742 cm−1; 1H NMR (200 MHz, CDCl3) δ 7.44 (d, 2H, J=9.3 Hz), 7.66 (m, 1H), 7.91 (td, 1H, 5JH-F=1.5 Hz, J=1.5, 5.1 Hz), 8.36 (d, 2H, J=9.3 Hz), 8.50 (d, 1H, J=5.1 Hz); MS m/z 262 (M+, 4), 124 (100), 96 (59), 76 (18), 69 (16), 63 (12), 51 (10).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:10][C:11]1[C:14](=O)[C:13](=[O:16])[C:12]=1[O:17]CCCC)[CH2:7][CH2:8][CH3:9]>CO>[CH2:6]([O:10][C:11]1[C:12](=[O:17])[C:13](=[O:16])[C:14]=1[NH:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:7][CH2:8][CH3:9]
Reactant: NCCCBr
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Solvent: CO
Product: CCCCOc1c(NCCCBr)c(=O)c1=O
Temperature: 22 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
Solid 3-bromopropylamine hydrobromide (41.52 g, 0.1897 mole) was added with stirring to a solution of sodium hydroxide (7.73 g, contains 0.187 mole) in methanol (150 mL) at 22° C., stirred for 15 minutes, then cooled to 0° C. to give a hazy solution of bromopropylamine base. The solution of bromopropylamine base was added slowly (over 20 minutes) with vigorous stirring to the product of Step A in methanol at 0° C. The mixture was stirred at 22° C. for 1.5 hours, polish filtered through diatomaceous earth (washed through with 50 mL of methanol) and added with vigorous stirring to water (1060 mL). The stirred mixture was cooled to -10° C. over several hours. The solid was collected by filtration, washed well with water (0° C., 440 mL) and dried in vacuo to give 50.0 g (91.8% yield) of the title compound as an off-white solid; m.p.=66°-68° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8]/[C:9](=[CH:24]\[C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]([CH3:14])[CH:16]=3)/[C:10](=[O:11])/[C:12](=[CH:24]/[C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:15]([CH3:14])[CH:16]=3)/[O:13][C:4]=2[CH:3]=1
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Product: Cc1ccc2c(c1)O/C(=C\c1cn(C)c3ccccc13)C(=O)/C(=C/c1cn(C)c3ccccc13)O2

Procedure:
Calone is reacted with 1-methylindole-3-carbaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-2,4-bis[1-(1-methyl-1H-indol-3-yl)meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[CH:17][C:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:11]2=[O:16]>[Ni].O.C(O)C>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([CH2:17][C:18]1([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[C:11]2=[O:16]
Reactant: CC1(C=C2Cc3c(cccc3-c3ccccc3-c3ccccc3)C2=O)CCCCC1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CC1(CC2Cc3c(cccc3-c3ccccc3-c3ccccc3)C2=O)CCCCC1
Yield: 88.2 %

Procedure:
A mixture of Raney nickel (a slurry in water, 4.4 g), compound 20 (4.4 g, 11.21 mmol, 1 equiv) in ethanol (450 mL) was hydrogenated @ 50 psi at room temperature overnight. The mixture was filtered through Celite and the filter cake was washed with ethanol (200 mL). The filtrate was concentrated under reduced pressure to give crude compound 21 (3.9 g, 88% yield) as a pale-yellow oil. This material was used subsequently.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].OCCCCNC(=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([N:4]([CH:31]1[CH2:32][CH2:33][C:34]2[N:9]=[CH:10][S:11][C:35]=2[CH2:36]1)[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([CH2:14][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]2[CH2:13][CH2:12][C:8]3[N:9]=[CH:10][S:11][C:7]=3[CH2:6]2)=[CH:16][CH:17]=1)[CH2:2][CH3:3]
Reactant: CCCN(Cc1ccc(C(=O)Cl)cc1)C1CCc2ncsc2C1
Reactant: O=C(NCCCCO)c1ccccc1
Product: CCCN(Cc1ccc(C(=O)N(CCC)C2CCc3ncsc3C2)cc1)C1CCc2ncsc2C1
Yield: 74 %

Procedure:
Compound 42 is prepared from 42C and IC-CORRECT? as described for 1D.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[CH:46]=[N:45][CH:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:41]2[CH:46]=[N:45][CH:44]=[CH:43][N:42]=2)=[O:40])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1cnccn1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3cnccn3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N-methylpyrazine-2-carboxamide.