Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:12]([NH:22][CH3:23])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl.C(N(C(C)C)C(C)C)C>[CH2:28]([O:27][C:25](=[O:26])[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:12]([NH:22][CH3:23])=[CH:11][N:10]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CNc1cnc(NCc2ccccc2)cc1-c1ccccc1C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cnc(N(Cc2ccccc2)C(=O)OCc2ccccc2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of 2.03 g (6.7 mmol) N2-benzyl-N5-methyl-4-o-tolyl-pyridine-2,5-diamine in 100 ml dichloromethane and 40 ml N-ethyldiisopropylamine was added dropwise at 0° C. a solution of 2.1 ml (14.09 mmol) benzyl chloroformate in 50 ml dichloromethane. After stirring for 2 h at room temperature the reaction mixture was washed with water (2×50 ml), brine (50 ml), dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 2.36 g (80%) of the title compound as light brown crystals. M.p. 110-112° C.
Reaction SMILES: [Br:1]Br.[Br:3][CH:4]([F:35])[C:5]([F:34])([F:33])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([CH3:32])=[C:15]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[N:19]=3)[S:16][CH:17]=2)=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:1][C:17]1[S:16][C:15]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[N:19]=2)=[C:14]([CH3:32])[C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]([F:34])([F:33])[CH:4]([Br:3])[F:35])=[CH:12][CH:11]=1
Reactant: Cc1c(-c2ccc(OC(F)(F)C(F)Br)cc2)csc1-c1nc(-c2c(F)cccc2Cl)nn1C
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)sc(Br)c1-c1ccc(OC(F)(F)C(F)Br)cc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 68.8 %

Procedure:
Bromine (0.03 g, 0.2 mmol) in acetic acid (0.5 mL) was added dropwise to a solution of 5-{4-[4-(2-bromo-1,1,2-trifluoroethoxy)phenyl]-3-methylthien-2-yl}-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (0.1 g, 0.2 mmol) in acetic acid (1 mL) at 0° C. The reaction was allowed to warm to 25° C. and stirred for 50 h. The reaction mixture was made basic with saturated aq NaHCO3 (30 mL) and extracted with ether (3×30 mL). The combined ether extracts were washed with brine, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure to give crude product. Column chromatography gave the product as a clear oil (88 mg, 77%): 1H NMR (CDCl3) δ 2.19 (s, 3H), 4.06 (s, 3H), 6.58 (dt, 1H, J=47.6, 5.1, 4.0, 4.4 Hz), 7.08-7.14 (m, 1H), 7.29-7.40 (m, 6H), EI/MS 636 m/e (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][NH2:14].[CH3:15][CH2:16][O:17][C:18]([CH:20]([C:24]([CH3:26])=O)[C:21]([CH3:23])=O)=[O:19].C(Cl)Cl>C(Cl)Cl.CO>[CH2:16]([O:17][C:18]([C:20]1[C:21]([CH3:23])=[N:14][N:13]([C:4]2[CH:5]=[C:6]([C:9]([F:11])([F:12])[F:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:24]=1[CH3:26])=[O:19])[CH3:15]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: COc1ccc(C(F)(F)F)cc1NN
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1c(C)nn(-c2cc(C(F)(F)F)ccc2OC)c1C
Yield: 58 %

Procedure:
In analogy to the procedure described in Example 38A], (2-methoxy-5-trifluoromethyl-phenyl)-hydrazine and ethyl diacetoacetate gave, after flash column chromatography (CH2Cl2 to CH2Cl2:MeOH 99:1), the title compound in 58% yield as a light green solid. MS: 343.1 (MH+).
Reaction SMILES: [CH:1]([NH2:3])=O.[CH3:4][C:5]1([CH3:12])[C:8](=O)[C:7](C)([CH3:10])[S:6]1.O.O.O.O.O.O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[NH2:3][CH:1]1[C:7]([CH3:10])([CH3:8])[S:6][C:5]1([CH3:12])[CH3:4]
Reactant: CC1(C)SC(C)(C)C1=O
Reactant: NC=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC1(C)SC(C)(C)C1N
Temperature: 170 °C
Yield: 59.6 %

Procedure:
Formamide (8.0 g, 178 mmol), 2,2,4,4-tetramethyl-3-oxothietane (1.0 g, 6.933 mmol) and aluminum chloride hexahydrate (100 mg) were placed in a Teflon lined Parr bomb and heated at 170° C. for 18 hours. The reaction was then cooled and taken up in water (20 ml). The aqueous solution was extracted with methylene chloride (3×20 ml), the extracts combined and concentrated under reduced pressure. The residue was refluxed with 1N HCl (20 ml) for 4 hours, the reaction cooled and washed with methylene chloride (2×20 ml). It was then brought to pH 14 by addition of 6N sodium hydroxide and extracted with the methylene chloride (3×20 ml). The combined extracts were dried (Na2SO4) and concentrated to give 0.600 g (60%) of title product, verified by its 1H-NMR spectrum.
Reaction SMILES: [OH2:1].NN.C1(=O)N([C:9]2([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:19][CH2:9][CH2:10][CH2:11][O:1][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH2:12][CH2:11][CH2:10][CH:9]2[N:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C1c2ccccc2C(=O)N1C1(N2CCCC2)CCCc2ccccc21
Reactant: O
Agent: NN
Solvent: CCO
Product: NCCCOc1cccc2c1CCCC2N1CCCC1

Procedure:
85% hydrazine hydrate (8.3 ml) is added to a stirred solution of the phthalimido pyrrolidinyl tetrahydronaphthalene obtained in the previous step (about 51 g) dissolved in absolute ethanol (500 ml), and the reaction mixture is heated to reflux for 3 hours and then allowed to cool. A precipitate forms upon cooling, and the reaction mixture is filtered, the precipitate washed with absolute ethanol, and the filtrate evaporated in vacuo, resulting in a solid. The solid is triturated with 5% aqueous HCl, filtered, and the solid washed with additional 5% HCl solution. The acidic filtrate is washed with diethyl ether and made basic with 50% aqueous sodium hydroxide, resulting in the formation of a golden oil. The oil is extracted with diethyl ether, washed with H2O, dried over sodium sulfate, filtered and evaporated in vacuo, resulting in 17 g of a golden oil. NMR analysis indicates that this oil is the desired amino product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:34]([OH:36])=[O:35])[C@@H:6]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[C:7]=1[C:8]([O:10][CH2:11]CNC(=O)C1C=CC=CC=1C(O)=O)=[O:9].C[O-].[Na+]>O>[CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:34]([OH:36])=[O:35])[C@@H:6]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC1=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCCNC(=O)c2ccccc2C(=O)O)=C(C)N1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To 50 mg of the (4R)-1,4-dihydro-2,6-dimethyl-3-[2(2-carboxybenzoyl) aminoethyl]oxycarbonyl-4-(3-nitrophenyl)pyridine-5-carboxylic acid obtained in Example 8 was added 5 ml of sodium methoxide (28% methanol solution) and the mixture was stirred at 50° C. for 2 hours. After it was diluted with 10 ml of water, the reaction mixture was washed with 5 ml of ethyl acetate and the aqueous layer was adjusted to pH 3 before it was extracted 3 times with 10 ml each of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and evaporated to dryness. The yellow substance thus obtained was purified on a column packed with 120 ml of Sephadex LH-20 (solvent: methanol) to obtain 22 mg of (4R)-1,4-dihydro-2,6-dimethyl-3-methyloxycarbonyl-4-(3-nitrophenyl) pyridine-5-carboxylic acid. The optical purity of this substance was analyzed by HPLC (mobile phase: hexane:ethanol:acetic acid=90:10:0.1, flow rate: 1.0 ml/minute, detection UV 254 nm) using an otical resolution column: CHIRALPAK AS (4.6 mm ×250 mm) manufactured by Daicel Chemical Industries Ltd. As a result, it revealed that the optical purity of the substance was 100% and the retention time was 12.5 minutes. 1 H-NMR(CD3OD): δ 8.09(1 H,s), 7.99(1 H,d,J=9.5 Hz), 7.65(1 H,d,J=7.7 Hz), 7.44(1 H,t,j=8.1 Hz), 5.09(1 H,s), 3.62(3 H,S), 2.34(3 H, s), 2.33(3 H,s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C@@H:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][C:35]([NH:19][C@H:11]([C:7]1[N:6]([CH2:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=2[O:2][CH3:1])[CH:10]=[CH:9][N:8]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:36]
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Reactant: COc1ccccc1Cn1ccnc1[C@@H](N)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1Cn1ccnc1[C@H](Cc1ccccc1)NC(=O)Cc1c[nH]c2ccc(O)cc12
Reaction time: 0.5 h

Procedure:
(S)-1-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethanamine (75 mg, 0.2 mmol), 2-(5-hydroxy-1H-indol-3-yl)acetic acid (47 mg, 0.25 mmol) and HATU (97 mg, 0.26 mmol) were combined in DMF (2 mL) and treated with diisopropylethylamine (70 μL). The reaction was stirred for 30 min and the purified by RP HPLC to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ 10.53 (d, 1H), 8.67 (d, 1H), 7.58 (s, 1H), 7.38-7.28 (m, 2H), 7.20-7.12 (m, 3H), 7.12-6.98 (m, 4H), 6.91-6.79 (m, 3H), 6.72 (d, 1H), 6.57 (dd, 1H), 5.38-5.31 (m, 1H), 5.17 (d, 2H), 3.71 (s, 3H), 3.40-3.22 (m, 3H), 3.16 (dd, 1H). MS (m/z) 481.2 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH:8]1[C:16]2[C:11](=[C:12]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[CH3:34][CH:32]([CH3:33])[C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:11]=3[CH:10]=[CH:9][N:8]4[C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[CH2:19][CH2:20]2)[CH:25]=1)=[O:35]
Reactant: Ic1ccncc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccncc3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 4-iodopyridine and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 453.2 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([F:13])[CH:4]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[F:14][CH:2]([F:1])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:13])[CH:4]=1
Reactant: COC(=O)c1ccc(C(F)F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(F)F)cc1F
Reaction time: 3.5 h

Procedure:
To a solution of methyl 4-(difluoromethyl)-2-fluorobenzoate (61 mg, 0.27 mmol) in THF (2.7 mL), was added a solution of lithium hydroxide, monohydrate (170 mg, 4.0 mmol) in water (0.90 mL). The mixture was stirred for 3.5 hours. Hydrochloric acid (1 N) was added to adjust the pH to 2, and the product was extracted with ethyl acetate. The extracts were washed twice with water, once with brine, dried over sodium sulfate and concentrated to afford crude acid, used directly in the next step (51 mg, 99%). 1H NMR (300 MHz, d6-dmso): δ 13.56 (br s, 1H), 8.00 (t, 1H), 7.53 (t, 2H), 7.11 (t, 1H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:13]1([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:14]=1>O1CCCC1>[C:1]([NH:5][S:23]([C:13]1[CH:14]=[C:15]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
A solution of 1.46 grams (20 mmole) of t-butylamine and 2.02 grams (20 mmole) of triethylamine in tetrahydrofuran was added dropwise to a solution of 5.5 grams (20 mmole) of 1,3-benzenedisulfonyl chloride in tetrahydrofuran. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo. The residue was purified on silica gel eluting with methylene chloride to give 3.86 grams of the titled compound as an oil.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14](=[O:38])[NH:15][C@H:16]([C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]1[NH:31][C:30]2[CH:32]=[C:33]([C:36]#[CH:37])[CH:34]=[CH:35][C:29]=2[N:28]=1)=[O:21])[CH:17]([CH3:19])[CH3:18].[CH3:39][O:40][C:41](=[O:66])[NH:42][C@H:43]([C:47]([N:49]1[CH2:53][CH2:52][CH2:51][C@H:50]1[C:54]1[NH:58][C:57]2[CH:59]=[C:60]([N:63]=[N+:64]=[N-:65])[CH:61]=[CH:62][C:56]=2[N:55]=1)=[O:48])[CH:44]([CH3:46])[CH3:45]>C1(C)C=CC=CC=1.[Cu]I>[CH3:12][O:13][C:14](=[O:38])[NH:15][C@H:16]([C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]1[NH:31][C:30]2[CH:32]=[C:33]([C:36]3[N:65]=[N:64][N:63]([C:60]4[CH:61]=[CH:62][C:56]5[N:55]=[C:54]([C@@H:50]6[CH2:51][CH2:52][CH2:53][N:49]6[C:47](=[O:48])[C@@H:43]([NH:42][C:41]([O:40][CH3:39])=[O:66])[CH:44]([CH3:46])[CH3:45])[NH:58][C:57]=5[CH:59]=4)[CH:37]=3)[CH:34]=[CH:35][C:29]=2[N:28]=1)=[O:21])[CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(N=[N+]=[N-])cc2[nH]1)C(C)C
Reactant: C#Cc1ccc2nc([C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c2c1
Agent: [Cu]I
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3cn(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c5c4)nn3)cc2[nH]1)C(C)C
Reaction time: 0.5 h

Procedure:
DBU (154 μL, 1.03 mmol) is diluted in 0.5 mL of anhydrous toluene. Copper(I) iodide (5.9 mg, 0.031 mmol) is added followed by a solution of {(S)-1-[(S)-2-(6-Ethynyl-1H-benzoimidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester intermediate 14 (38 mg, 0.10 mmol) in 0.5 mL of toluene and a solution of {(S)-1-[(S)-2-(6-Azido-1H-benzoimidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester intermediate 20 (50 mg, 0.13 mmol) in 1.0 mL of toluene. The resulting mixture is submitted to microwave for 30 minutes at normal power. The final mixture is filtrated through a pad of celite using DCM. The filtrate is concentrated and purified by flash chromatography on silica gel (MeOH/CH2Cl2, 0% to 15%) The compound is further purified by reverse phase HPLC to give title compound (6.5 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[Br:11].N1C=CC=CC=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=O>O>[Br:11][C:3]1[C:2]2[N:1]=[C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=3)[O:9][C:8](=[O:10])[C:7]=2[CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1c(Br)cncc1C(=O)O
Solvent: O
Solvent: c1ccncc1
Product: O=c1oc(-c2cccc(C(F)(F)F)c2)nc2c(Br)cncc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
A mixture of 5-bromo-4-aminonicotinic acid 46 (10.5 g, 48.4 mmol) and pyridine (60 mL) was heated at 60° C. until homogeneous. 3-(trifluoromethyl)benzoyl chloride 2 (8.0 mL, 53.0 mmol) was added and stirring continued for 2 h. H2O (200 mL) was added and the mixture cooled to 0° C. The resulting yellow precipitate was collected by filtration, rinsed with H2O (100 mL) then pentane (100 mL), and dried under vacuum to give the 47 (8.50 g, 47% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[C:19]=3[O:21][CH3:22])[N:14]([CH2:25][C:26]3[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[C:13]2=[O:35])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][CH:16]=[C:15]2[C:20]=1[C:12]1([C:3]3[C:2](=[CH:11][C:6]4[O:7][CH2:8][CH2:9][O:10][C:5]=4[CH:4]=3)[O:1][CH2:36]1)[C:13](=[O:35])[N:14]2[CH2:25][C:26]1[O:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: COc1ccc2c(c1OC)C(c1cc3c(cc1O)OCCO3)C(=O)N2Cc1ccc(C(F)(F)F)o1
Product: COc1ccc2c(c1OC)C1(COc3cc4c(cc31)OCCO4)C(=O)N2Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 4′,5′-dimethoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (77%): mp 62-65° C.; 1H NMR (300 MHz, CDCl3) δ6.80 (d, J=8.4 Hz, 1H), 6.74-6.69 (m, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.45 (s, 1H), 6.38-6.32 (m, 1H), 6.20 (s, 1H), 4.90 (ABq, 2H), 4.85-4.81 (m, 2H), 4.18-4.05 (m, 4H), 3.78 (s, 3H), 3.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.0, 155.6, 152.3, 152.2, 149.9, 146.6, 144.6, 137.9, 135.1, 125.0, 120.3, 112.7, 111.1, 109.2, 103.7, 99.1, 78.2, 64.5, 63.9, 60.4, 57.7, 56.3, 37.1; MS (ES+) m/z 503.9 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:33][CH:34]([CH3:36])[CH3:35])[CH3:32]>>[CH2:31]([N:33]([CH:34]([CH3:36])[CH3:35])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:32]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: CCNC(C)C
Product: CCN(CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1)C(C)C

Procedure:
The product from Example 44E and ethyl(isopropyl)amine were processed as described in Example 1D to provide the titled compound. 1HNMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.25 (d, J=1.8 Hz, 1H), 7.98 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.3-3.8 (m, 15H), 1.4 (m, 9H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:22]([N:10]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:17]2[C:12]([C:13]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=[CH:16]2)=[N:11]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)cc1
Temperature: 120 °C
Yield: 79.8 %

Procedure:
To a solution of 3-(4-methoxy-phenyl)-7-trifluoromethyl-1H-indazole (59 mg, 0.2 mmol) in 0.5 ml DMF were added 72 μl of benzyl bromide (0.6 mmol). The reaction mixture was heated overnight at 120° C. After cooling to room temperature, ethyl acetate was added and the solution was washed three times with brine. The organic layer was dried over MgSO4 and concentrated. Column chromatography (n-heptane/ethyl acetate, 70:30 as eluent) afforded 61 mg of pure product.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[CH:15]=[C:14]([CH2:16]O)[NH:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C)C=O.ClCCl>[Cl:3][CH2:16][C:14]1[NH:13][N:12]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:15]=1
Reactant: OCc1cc(-c2ccccc2)n[nH]1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cc(-c2ccccc2)n[nH]1

Procedure:
At 20° C., 6.1 ml of thionyl chloride and 10 drops of dimethylformamide are added to a solution of 7.3 g (42.0 mmol) of (3-phenyl-1H-pyrazol-5-yl)methanol in 220 ml of dichloromethane. The mixture is then boiled under reflux for 12 h. The solvent is then removed from the reaction mixture. The residue is taken up in 100 ml of dichloromethane, and a saturated sodium bicarbonate solution is added to the mixture until a pH of from 6 to 7 is established. The mixture is then freed from the solvent under reduced pressure and dried. This gives 5.65 g of the desired product which is reacted further without further purification; log P(HCOOH): 2.05 with MS (ESI): 193.1/195.1 ([M+H]+).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C(C1C=NC(C2C=CC(O)=CC=2)=NC=1)CCCCCC>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:45])([F:46])[O:33][C:34]([F:43])([F:44])[C:35]([F:41])([F:42])[O:36][C:37]([F:38])([F:40])[F:39])([F:29])[F:28])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Agent: CCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl chloride (4.0 g, 8.4 mmol, Example 24) with 5-heptyl-2-(4-hydroxyphenyl)pyrimidine (2.3 g, 8.4 mmol). The resulting crude product was isolated essentially as described in Example 3 and purified by chromatography on silica gel, eluting with 10 vol. % ethyl acetate in hexane, followed by Kugelrohr distillation (215° C. at 0.3 torr) to provide a yield of 5 g.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:22][CH2:23][C:24](Br)=[O:25].C1COCC1>C(Cl)(Cl)Cl.O.CCCCCC>[Br:22][CH2:23][C:24]([N:15]=[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]1[CH:8]=[CH:7][C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][CH:6]=1)=[O:25]
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)N=C1C=CC=CC1C=Cc1ccccc1
Yield: 116 %

Procedure:
A solution of 6.0 g (0.03 mole) of iminostilbene in 250 mL of chloroform was added to a solution of 10 g (0.09 mole) of sodium carbonate in 100 mL of water and the mixture was stirred rapidly. To this rapidly stirring solution 6.2 g (0.03 mole) of bromoacetyl bromide was added dropwise through an additional funnel, at which time thin layer chromatography analysis using 2:1 THF:hexane indicated the reaction was incomplete. An additional 1.0 g (0.005 mole) of bromoacetyl bromide was added. Thin layer chromatography indicated that the starting material had been totally consumed. The chloroform layer was separated, dried over Na2SO4 and concentrated to yield 11.0 g of N-bromoacetyliminostilbene (38) as a light yellow oil. This material was used in the following reaction.