Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4].O[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1>>[C:14]([C:10]1[C:9]([C:16]([F:19])([F:17])[F:18])=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([C@H:3]([CH3:4])[CH2:2][O:1][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1)[C:6]([CH3:20])=[CH:7]2)#[N:15]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)CO
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(OC[C@@H](C)n2c(C)cc3c(C(F)(F)F)c(C#N)ccc32)cc1

Procedure:
Synthesized as described in Example 139C using 1-[(1R)-2-hydroxy-1-methylethyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 329) and N-(4-hydroxyphenyl)acetamide: 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 7.13 (s, 1H), 6.55 (m, 3H), 4.57 (m, 1H), 4.36 (m, 1H), 4.27 (m, 1H), 2.53 (s, 3H), 2.11 (s, 3H), 1.38 (d, J=6.1 Hz, 3H); MS (ES) m/z 414 (M−1).
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50]Br)=[CH:48][CH:47]=1>CN(C)C=O.O>[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH:2]([OH:1])[CH:3]([NH:18][C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=34)=[O:20])[CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=3)=[CH:33][CH:34]=2)=[CH:48][CH:47]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccc(F)cc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and 4-fluorobenzyl bromide (428 mg, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (381 mg, 79%).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[NH:10][CH2:11][CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:14](Br)(Br)=O>>[S:14]1[C:8]([C:9]2[NH:13][CH2:12][CH2:11][N:10]=2)=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: C(=Cc1ccccc1)C1=NCCN1
Reactant: O=S(Br)Br
Product: c1ccc2sc(C3=NCCN3)cc2c1

Procedure:
The title compound was prepared in the essentially the same manner, from 0.34 g (2 mmol) of 2-(2-phenylethen-1-yl)-4,5-dihydro-1H-imidazole and thionyl bromide, as described in Example 31.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4]1.[Li].C([BH-](C(CC)C)C(CC)C)(CC)C.Cl>C1(C)C=CC=CC=1.CCCCCC.O1CCCC1>[CH3:1][NH:2][CH:3]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4]1
Reactant: CNC1COc2ccccc2C(=O)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNC1COc2ccccc2C(O)C1

Procedure:
To a boiling solution of 80 g (0.5 mole) rac.-3-methylamino-3,4-dihydro-1-benzoxepin-5-(2H)-one in a mixture of 550 ml toluene and 300 ml hexane, 550 ml of a 1 molar solution of lithium-tri-sec.-butylborohydride in tetrahydrofuran are added in drops, so that the solution is maintained boiling. Following the completion of the addition, the mixture is heated to boiling for another hour. After cooling, the mixture is acidified by the drop-wise addition of methanolic hydrochloric acid. The methanol phase is then separated and the toluene/hexane mixture is again extracted with hydrochloric acid in methanol. The extracts are evaporated, taken up with dichloromethane and a solution (10%) of sodium carbonate, the organic phase washed with saturated sodium chloride, dried over sodium sulfate and evaporated to dryness. 67.6 g (70% of the theoretical yield) of rac.-2,3,4,5-tetrahydro-3-methylamino-1-benzoxepin-5-ol are obtained in the form of an oily residue, wherein rac.-cis-2,3,4,5-tetrahydro-3-methylamino-1-benzoxepin-5-ol predominates with 82 parts for 18 parts of rac.-trans-2,3,4,5 -tetrahydro-3-methylamino-1-benzoxepin-5-ol. The compounds may be separated and identified as described hereinabove.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:13][C:14](=[O:27])[C:15]([CH3:26])([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](OCC)=[O:17])[CH3:12]>C1(C)C=CC=CC=1.ClCCl>[CH2:11]([O:13][C:14](=[O:27])[C:15]([CH:16]=[O:17])([CH3:26])[CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25])[CH3:12]
Reactant: CCOC(=O)C(C)(CCC(C)C)C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C=O)CCC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Diisobutylaluminum hydride (97.5 mL of a 1.0 M solution in toluene, 97.5 mmol) was added over 10 min to a solution of rac-2-methyl-2-(3-methyl-butyl)-malonic acid diethyl ester (11.91 g, 48.7 mmol) in dichloromethane (100 mL) at −78° C. The reaction mixture was stirred at that temperature for 4 h, and then was quenched with saturated aqueous ammonium chloride (100 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (300 mL) and DL-tartaric acid (12 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 2 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford the crude product, rac-2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (8.80 g, 44 mmol, 90%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1.[CH:13]([C@H:16]1[NH:21][CH2:20][CH2:19][N:18]2[C:22]3[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:23]=3[N:24]=[C:17]12)([CH3:15])[CH3:14].O>ClC(Cl)C.C(O)(C)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:8][C:6]1[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]3[C:22]4[CH:28]=[C:27]([S:29]([CH3:32])(=[O:30])=[O:31])[C:26]([C:33]([O:35][CH3:36])=[O:34])=[CH:25][C:23]=4[N:24]=[C:17]3[C@H:16]2[CH:13]([CH3:15])[CH3:14])[N:7]=1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Reactant: COC(=O)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(=O)OC)c(Cl)n1)[C@@H]3C(C)C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A solution of methyl 2,4-dichloropyrimidine-5-carboxylate (27 mg, 0.13 mmol) in dichloroethane/t-butanol (1:1, 2 mL) was cooled to 0° C. ZnCl2 solution (1.0 M in ether, 0.29 mL, 0.29 mmol, 2.2 eq.) was added. After stirring for 1 h, a solution of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (30 mg, 0.09 mmol) in dichloroethane/t-butanol (1:1, 2 mL) was added slowly at 0° C. The mixture was stirred at rt overnight. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-chloro-5-(methoxycarbonyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (34 mg, 77.3% yield) as a solid.
Reaction SMILES: P(OP(O)(O)=O)(O)(O)=O.O.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:16]([C:18](=[CH:23]O)[C:19]([O:21][CH3:22])=[O:20])[CH:17]=1>C(OC)(C)(C)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:16]=2[CH:17]=1
Reactant: COC(=O)C(=CO)c1cc(Cl)ccc1Oc1ccccc1
Agent: O=P(O)(O)OP(=O)(O)O
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)C1=Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
A mixture of 415.23 g (2.33 mol) of pyrophosphoric acid and 22.14 g of water at 0° C. was added over methyl 2-(5-chloro-2-phenoxyphenyl)-3-hydroxyacrylate (compound IXa) as obtained in Example 16. The reaction mixture was stirred at 60° C. for 2 hours. After cooling to 20° C., 500 mL of water and 1.4 L of methyl tert-butyl ether were added. The aqueous layer was extracted and washed with 200 mL of methyl tert-butyl ether. The organic phases were combined, washed with 400 mL of an aqueous saturated solution of sodium bicarbonate and 400 mL of saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was suspended in 400 mL of n-butanol and stirred at room temperature for 1 hour, and at 0° C. for 2 hours. The resulting suspension was filtered, and the solid was dried until constant weight to obtain 161 g of methyl 2-chlorodibenzo[b,f]oxepin-11-carboxylate (compound Xa) as an off-white solid. Yield: 77.7%.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)=[CH:8][C:7]=2[C:23]([F:26])([F:25])[F:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:27].[NH4+]>C(#N)C.[Zn]>[ClH:27].[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)=[CH:8][C:7]=2[C:23]([F:24])([F:25])[F:26])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(C3CCCC3)c(C(F)(F)F)c2)cc1
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC#N
Product: Cl
Product: Nc1ccc(OCc2ccc(C3CCCC3)c(C(F)(F)F)c2)cc1
Temperature: 2.5 °C

Procedure:
In a 2 L flask equipped with stirrer and thermocouple, was placed 1-cyclopentyl-4-((4-nitrophenoxy)methyl)-2-(trifluoromethyl)benzene (40 g, 109 mmol) in ACN (520 mL). Ammonium chloride (3M, 520 mL) was added and the mixture was stirred and cooled to 2.5° C. Zinc (35.8 g, 547 mmol) was added in portions keeping temperature below 5° C. After addition was completed, the reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered through a bed of celite (50 g) and the filter bed was washed with ACN (150 mL). The aqueous layer of the filtrate was separated and back extracted with isopropyl acetate (200 mL). The combined organic layers were dried over sodium sulfate (50 g), filtered and concentrated. The residue was dissolved in ethanol (120 mL), added HCl (1.25 M in EtOH, 140 mL), and stirred at ambient for 2.5 hours. After removal of the solvent, the residual solids was triturated with ACN (120 mL), filtered, washed with ACN (2×50 mL), and dried under vacuum to give the title compound (29.8 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH:6]([CH3:10])[C:7](Cl)=[O:8].[NH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:12]1=[O:21]>C(=S)=S>[Cl:5][CH:6]([CH3:10])[C:7]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[NH:11][C:12](=[O:21])[CH2:13][CH2:14]2)=[O:8]
Reactant: O=C1CCc2ccccc2N1
Reactant: CC(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Cl)C(=O)c1ccc2c(c1)CCC(=O)N2

Procedure:
Aluminum chloride (109 g, 817 mmol) was slurried in carbon disulfide (600 mL) and 2-chloropropionyl chloride (16.8 mL, 173.07 mmol) was added. To this mixture was added 3,4-dihydro-2(1H)-quinolone (20.0 g, 135.89 mmol, J. Amer. Chem. Soc., 1944, 66, 1442). The mixture was refluxed for 4 hours, cooled, and the carbon disulfide poured off and discarded. The reddish residue was carefully quenched with ice water which caused the product to solidify. The solids were collected, rinsed well with water, and suctioned dry followed by drying in vacuo. The product weighed 31.37 g (97%) and had mp 205°-206° C. Analysis calculated for C12H12CINO2 : C, 60.64; H, 5.09; N, 5.89. Found: C, 60.20; H, 4.89; N, 5.78.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][N:30]([C:34](=[O:42])[CH2:35][CH:36]5[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]5)[CH2:31]4)=[CH:26][CH:25]=3)[N:21]=[C:20]([NH2:43])[N:19]=2)[CH2:14][CH2:13]1>>[C:1]([N:39]1[CH2:38][CH2:37][CH:36]([CH2:35][C:34]([N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][C:24]([C:22]4[CH:23]=[C:18]([N:15]5[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]5)[N:19]=[C:20]([NH2:43])[N:21]=4)=[CH:25][CH:26]=3)[CH2:31]2)=[O:42])[CH2:41][CH2:40]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCNCC3)CC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCN(C(=O)c5ccccc5)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 71, Step 4 starting from benzoyl chloride (Alfa Aesar, Cat. #A14107) and 4-(4-methylpiperazin-1-yl)-6-[2-(piperidin-4-ylacetyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=554.3.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:13]>[Cl-].[Zn+2].[Cl-].Cl>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([CH2:12][CH3:13])=[CH:15][C:16]=1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CCc1ccc(N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CCc1ccc(N)c(C(=O)c2ccc(F)cc2F)c1
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 30.6 %

Procedure:
Zinc chloride (7.2 g) was added portionwise to a stirred mixture of 2,4-difluorobenzoyl chloride (17 g) and 4-ethylaniline (5.3 g) at 180° C. The mixture was stirred for 2.5 hours at 200° C. and cooled to 120° C. To the mixture was added 3N hydrochloric acid (50 ml) and the resulting mixture was refluxed for 1.5 hours, then the supernatant was decanted out. The above procedure was repeated three times. 75% Sulfuric acid (40 ml) was added and the reaction mixture was stirred and heated at 140° C. for 2 hours. The reaction mixture was poured into ice (500 ml) and extracted with dichloromethane. The organic layer was washed with 3N hydrochloric acid (200 ml), 3N sodium hydroxide (200 ml) and water, dried, and evaporated. The oily residue (5.7 g) was purified by column chromatography on silica gel (170 g) eluting with toluene to give crystals of 2-amino-5-ethyl-2',4'-difluorobenzophenone (3.5 g).
Reaction SMILES: [CH3:1][C:2]([S@@:5](/[N:7]=[CH:8]/[C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:6])([CH3:4])[CH3:3].[Cl:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[Cl:26].[NH4+].[Cl-].O>C1COCC1.CCOC(C)=O>[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:8]([C:9]2[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:7][S@:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1C(F)(F)F
Reactant: Clc1ccc([Mg]Br)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(Cl)c(Cl)c1)c1ncccc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
(S,E)-2-Methyl-N-((3-(trifluoromethyl)pyridin-2-yl)methylene)propane-2-sulfinamide (0.493 g, 1.772 mmol) was dissolved in dry THF (10 mL) and cooled in an ice bath. 3,4-Dichlorophenylmagnesium bromide (Aldrich, 0.5 M solution in THF, 4.0 mL, 2.0 mmol) was added, and the reaction mixture was stirred for 5 minutes. Saturated aqueous NH4Cl (10 mL), H2O (100 mL) and EtOAc (100 mL) were added, and the phases were mixed and separated. The organic layer was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave (S)—N—((S)-(3,4-dichlorophenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][CH:19](SC)SC)[CH:15]=[N:14]1.BrN1C(=O)CCC1=O.O.[NH2:33]/[C:34](/[C:39]#[N:40])=[C:35](\[NH2:38])/[C:36]#[N:37]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][CH:19]=[N:33][C:34]([C:39]#[N:40])=[C:35]([NH2:38])[C:36]#[N:37])[CH:15]=[N:14]1
Reactant: CSC(Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)SC
Reactant: N#C/C(N)=C(/N)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: N#CC(N)=C(C#N)N=CCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-4-[2,2-di(methylthio)ethyl]-2H-1,2,3-triazole was treated with N-bromosuccinimide in aqueous acetonitrile., After 10 minutes the mixture was added to water and extracted with diethyl ether. The extract was worked up to give crude 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-acetaldehyde. This was then treated with diaminomaleonitrile in a similar manner to Example 1, to give 2-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-[2-(2-amino-1,2-dicyanoethenylimino)ethyl]-2H-1,2,3-triazole, which was cyclised in a similar manner to Example 1a, to give 2-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-[(4,5-dicyano-1H-imidazol-2-yl)methyl]-2H-1,2,3-triazole (Compound 30).
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[O-:14]CC.[Ge+2:17].[O-]CC.CN1CCCN(C)CCN(C)CCCN(C)CC1>O>[CH3:7][CH2:6][O:5][Si:4]([O:3][CH2:1][CH3:2])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13].[Ge:17]=[O:14]
Reactant: CC[O-]
Reactant: [Ge+2]
Agent: CCO[Si](OCC)(OCC)OCC
Agent: CN1CCCN(C)CCN(C)CCCN(C)CC1
Solvent: O
Product: O=[Ge]
Reaction time: 48 h

Procedure:
1.01 g tetraethylorthosilicate, 2.0 g deionized water, and 0.41 g germanium ethoxide were mixed together in a tared 23 mL Teflon liner. Then 0.42 g of 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane (Strem Chemicals) was dissolved in the mixture. The Teflon container was then capped, sealed, and placed within an 23-mL steel Parr autoclave. The autoclave was allowed to remain at room temperature for 2 days during which time the TEOS and germanium ethoxide were allowed to hydrolyze. The Teflon cup was then removed from the autoclave and 0.13 g 50% HF was added and mixed to create a white viscous gel. The ethanol (formed from the hydrolysis of the TEOS and germanium oxide) and water were allowed to evaporate within a vented hood with flowing air over the course of 3-4 days. Sufficient water was added and mixed into the gel to bring the molar ratio H2O/(Si+Ge) to 7. The liner was then capped and placed within a Parr Steel autoclave reactor. The autoclave was then fixed in a rotating spit within an oven heated at 160° C. for 10 days. The solid products were recovered from the cooled reactor by vacuum filtration and washed with copious quantities of water.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]([C:33](OC(C)(C)C)=O)[NH:25]C(OC(C)(C)C)=O.[C:40]([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:33]([CH3:40])=[N:24][N:25]=3)[C:11]=2[CH:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: Clc1ccc2c(cc(-c3ccccn3)n2Cc2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1nnc2ccc3c(cc(-c4ccccn4)n3Cc3ccccc3)n12
Temperature: 110 °C
Yield: 49.1 %

Procedure:
1-Benzyl-5-chloro-2-pyridin-2-yl-1H-pyrrolo[3,2-b]pyridine (38 mg, 0.12 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (41 mg, 0.18 mmol) and Cs2CO3 (58 mg, 0.18 mmol) were combined in toluene (4.1 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (9.3 mg, 0.012 mmol) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was heated to 110° C. overnight. The mixture was diluted with DCM, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes afforded 20 mg of intermediate di-tert-butyl 1-(1-benzyl-2-pyridin-2-yl-1H-pyrrolo[3,2-b]pyridin-5-yl)hydrazine-1,2-dicarboxylate, which was then dissolved in AcOH (2.4 mL) and heated in the microwave to a temperature of 180° C. for 6 minutes. The resulting product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (4.0 mg, 10%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[N:25]1([CH2:30][C:31](O)=[O:32])[CH:29]=[N:28][N:27]=[N:26]1>>[ClH:16].[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:31](=[O:32])[CH2:30][N:25]2[CH:29]=[N:28][N:27]=[N:26]2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: O=C(O)Cn1cnnn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Product: Cl
Product: O=C(Cn1cnnn1)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate and 2-(1H-tetrazol-1-yl)acetic acid, and by a method similar to that in Example 39, steps A and B, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH2:23][CH2:22][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14]1>[N+]([O-])([O-])=O.[Ag+]>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:13]2[CH2:23][CH2:22][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14]2)=[C:3]([C:4]#[N:5])[CH:6]=1)([O-:12])=[O:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)C1CCNCC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Temperature: 25 °C
Yield: 102.9 %

Procedure:
2-Chloro-5-nitrobenzonitrile (10 g), ethyl isonipecotate (60 g) and silver nitrate (11.1 g) were stirred at 120° C. for 3 h. The reaction mixture was cooled to room temperature and the solid was filtered off. To the filtrate was added dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous diisopropyl ether to give ethyl 1-(4-nitro-2-cyanophenyl)piperidin-4-ylcarboxylate (17.1 g).
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[C:21]([OH:26])[C:22]([OH:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[Br:27]Br>>[Br:27][C:23]1[CH:24]=[C:19]([C:9]2[C:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[S:13][C:14]=3[C:2]([Br:1])=[C:3]3[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]3)[CH:20]=[C:21]([OH:26])[C:22]=1[OH:25]
Reactant: BrBr
Reactant: Oc1ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1O
Product: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1O

Procedure:
Prepared from 4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-benzene-1, 2-diol (Example 43) according to the procedure of Example 58. White solid: mp 212-213° C.: MS (EI): [M+], 2 bromine isotope pattern, 498, 500, 502; Anal. Calc. for C22H12Br2O2S:C, 52.83, H, 2.42, N, 0.00. Found: C, 52.08, H, 2.55, N, 0.01.