Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=O)[CH:10]([CH2:14][CH:15]=O)[CH2:9][CH2:8]2.[C:17]([NH:20][CH2:21][CH2:22][NH2:23])(=[O:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:11]3[N:23]([CH2:22][CH2:21][NH:20][C:17](=[O:19])[CH3:18])[CH:15]=[CH:14][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(=O)C(CC=O)CC2
Reactant: CC(=O)NCCN
Solvent: Cc1ccccc1
Product: COc1cccc2c1-c1c(ccn1CCNC(C)=O)CC2
Yield: 53.7 %

Procedure:
400 mg of 8-methoxy-2-(2-oxoethyl)-1-tetralone were heated to reflux for 15 minutes under argon with 205 mg of N-acetyl-ethylenediamine in 8 ml of toluene. The solvent was removed in a vacuum and the residue was chromatographed on 40 g of silica gel with hexane/ethyl acetate 1:1 and then with ethyl acetate. 280 mg (54%) of N-[2-(4,5-dihydro-9-methoxy-1H-benz[g]indol-1-yl)ethyl]-acetamide were obtained as yellowish crystals with m.p. 132°-133°.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[H-].[Na+].C([Li])CCC.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:17]1([C:16]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:23][C:1](=[O:6])[CH:2]=[CH:3][CH2:5]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=CCC(c2ccccc2)(c2ccccc2)O1

Procedure:
The title compound was prepared as described in General Method 1 using 20 mmol of methyl acetoacetate, 22 mmol of NaH 60% dispersion in oil, 21 mmol of 1.6M n-butyl lithium in hexane, 20 mmol of benzophenone and 70 mL of tetrahydrofuran. Upon concentrating the reaction a solid precipitated out which was triturated with ether and filtered (m.p. 170.5°-173° C.). 1H NMR (CDCl3) δ 3.18 (s, 2 H), 3.4 (s, 2 H), 7.3-7.5 (m, 10 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:25])[CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:26]([O:30]C)(=[O:29])[CH:27]=[CH2:28]>CO.C(COC)OC>[CH2:12]([C:11]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:10](=[O:25])[CH:9]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:28][CH2:27][C:26]([OH:30])=[O:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CC(=O)OC
Reactant: O=C(C=Cc1ccc(Cl)cc1)C(Cc1ccccc1)c1ccccc1
Solvent: COCCOC
Solvent: CO
Product: O=C(O)CCC(Cc1ccccc1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 96 h

Procedure:
Triton B (2 ml., 40% in MeOH) is added to a stirred solution of 1-(p-chlorophenyl)-4,5-diphenyl-1-penten-3-one (17.33 g., 0.05 mole) in glyme (200 ml.) followed by addition of methyl acrylate (4.73 g., 0.055 mole) in glyme (50 ml.). The solution is stirred for 96 hours and the solvent is removed under reduces pressure. The residue is dissolved in methanol (500 ml.) and a 20% sodium hydroxide solution (25 ml.) is added. After an additional 24 hours, the methanol is evaporated in vacuo and the residue is dissolved in water. Extraction with ether removes unreacted ketone. Acidification produces 16.18 g., m.p. 160°-170°C. when collected and air-dried. Recrystallization from butyl chloride gives material with m.p. 173°-176°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCNCC1

Procedure:
A solution of D6 (10 g, 3.4 mmol) in methanol (150 ml) was hydrogenated at 50 psi in a Parr hydrogenator using 10% Palladium on carbon catalyst (800 mg) for 18 h. Catalyst was filtered off and the filtrate concentrated under reduced pressure to afford the product as a white solid.
Reaction SMILES: [Br:1][C:2]12[CH2:9][CH2:8][C:5]([CH:10]=[CH:11][C:12](Cl)=O)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.COC(C12CCC(Br)(CC1)CC2)=O.CC1(C=O)CCOCC1.[N+:37]([C:40]1[CH:41]=[C:42]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]([F:56])([F:55])[F:54])[CH:43]=[CH:44][C:45]=1[NH2:46])([O-])=O>>[Br:1][C:2]12[CH2:9][CH2:8][C:5](/[CH:10]=[CH:11]/[C:12]3[NH:46][C:45]4[CH:44]=[CH:43][C:42]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=5[C:53]([F:54])([F:55])[F:56])=[CH:41][C:40]=4[N:37]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: O=C(Cl)C=CC12CCC(Br)(CC1)CC2
Reactant: Nc1ccc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: CC1(C=O)CCOCC1
Agent: COC(=O)C12CCC(Br)(CC1)CC2
Product: FC(F)(F)c1ccccc1-c1ccc2[nH]c(/C=C/C34CCC(Br)(CC3)CC4)nc2c1

Procedure:
(E)-2-[2-(4-Bromo-bicyclo[2.2.2]oct-1-yl)-vinyl]-5-(2-trifluoromethyl-phenyl)-1H-benzoimidazole was prepared from 3-(4-bromo-bicyclo[2.2.2]oct-1-yl)-acryloyl chloride (prepared from 4-bromo-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester utilizing a procedure analogues to the preparation of 4-methyl-tetrahydro-pyran-4-carbaldehyde in Example 9) and 3-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (prepared as described in Example 3, STEP A) according to the procedure as described in Example 9, STEPS A-C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH2:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N:16]1[S:20][N:19]=[C:18]2[C:21]([S:25]([NH:28][C:29]3[CH:37]=[C:36]([Cl:38])[C:35]([Cl:39])=[CH:34][C:30]=3[C:31](O)=[O:32])(=[O:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:17]=12>>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:14][C:31](=[O:32])[C:30]1[CH:34]=[C:35]([Cl:39])[C:36]([Cl:38])=[CH:37][C:29]=1[NH:28][S:25]([C:21]1[C:18]2=[N:19][S:20][N:16]=[C:17]2[CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)cc1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-4-chloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-(4-chloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled to 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=11.61 min. MS (ESI−): mass calcd. for C23H17Cl3N4O5S2, 597.97; m/z found, 597/599 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.20 (s, 1H), 8.36 (d, J=6.3, 1H), 8.23 (d, J=8.7, 1H), 7.87 (s, 1H), 7.74-7.71 (m, 1H), 7.27-7.25 (m, 3H), 6.98 (d, J=8.3, 2H), 6.38 (d, J=7.3, 1H), 4.96-4.92 (m, 1H), 3.82 (s, 3H), 3.23-3.14 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:27][CH:28]([CH3:32])[CH:29]([NH2:31])[CH3:30].C(N(CC)CC)C>C(#N)C>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:4]=1)=[N:31][CH:29]([CH3:30])[CH:28]([CH3:32])[CH3:27])#[N:24]
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: CC(C)C(C)N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)C(C)N=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 48.8 %

Procedure:
A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.8 mmol, 300 mg), 3-methyl-2-butylamine (0.88 mmol, 0.101 ml) and triethylamine (0.88 mmol, 0.123 ml) in acetonitrile (2 ml) was stirred for 7 h at 75° C. After concentration the residue was dissolved in ethyl acetate, washed with water, dried (Na2SO4) and concentrated. The residue was purified by column chromatography (heptane:ethyl acetate 4:1) to give the title compound (143 mg, 59%) as white crystals. Mp 134-136° C.; EI SP/MS: 366 (M+); 1H-NMR (CDCl3): δ 0.92 (d, 6H),1.15 (d, 3H), 1.78 (m, 1H), 3.78 (m, 1H), 4.85 (br, 1H), 7.73 (br s, 3H), 8.0 ppm (br, 1H); MA calc for C15H16F6N4 :C, 49.18%; H, 4.40%; N, 15.29%. Found: C, 48.95%; H, 4.38%; N 15.08%.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH:7]([CH3:8])[CH:6]1[C:9]1[N:14]=[C:13]2[N:15]([CH3:24])[C:16](=[O:23])[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]2=[CH:11][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[N-]=[N+]=[N-]>C1COCC1>[NH2:1][CH2:4][CH:5]1[CH:7]([CH3:8])[CH:6]1[C:9]1[N:14]=[C:13]2[N:15]([CH3:24])[C:16](=[O:23])[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:12]2=[CH:11][CH:10]=1
Reactant: CC1C(CN=[N+]=[N-])C1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: [N-]=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1C(CN)C1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 55 °C
Reaction time: 1 h

Procedure:
1-(2,2-Dimethylpropyl)-5-[2-(hydroxymethyl)-3-methylcyclopropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (35-1, 61.6 mg, 0.20 mmol, 1.0 equiv) was added to anhydrous DCM (2.0 mL) and cooled to −10° C. Triethylamine (54.9 μL, 0.42 mmol, 2.1 equiv) and methanesulfonyl chloride (17.4 μL, 0.22 mmol, 1.1 equiv) were added sequentially and the resulting reaction mixture was stirred for 1 min. Following this duration, TLC showed complete consumption of 35-1. The reaction mixture was partitioned between ethyl acetate (5 mL) and saturated NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a clear, yellow oil. The yellow oil (77 mg, 0.20 mmol, 1 equiv) and sodium azide (32.8 mg, 0.50 mmol, 2.5 equiv) were dissolved in DMF, cooled to 0° C. and added with sodium hydride (12.1 mg, 0.50 mmol, 2.5 equiv). The reaction mixture was stirred for 18 h. Following this duration, TLC showed complete consumption of the mesylate. Azide intermediate (5-(2-(azidomethyl)-3-methylcyclopropyl)-3-methyl-1-neopentyl-1H-imidazo[4,5-b]pyridin-2(3H)-one) was isolated by normal-phase HPLC (0-40% EtOAc:hexanes). 5-(2-(azidomethyl)-3-methylcyclopropyl)-3-methyl-1-neopentyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (65 mg, 0.19 mmol, 1 equiv), triphenylphosphine (156 mg, 0.59 mmol, 3 equiv) and water (35.1 μL, 1.9 mmol, 9.8 equiv) were added with THF. The reaction mixture was stirred at 55° C. for 1 h. Following this duration, UPLC showed trace of the azide intermediate. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 35-2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][C:13]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:14]=1[O:15][CH:16]([CH3:20])[C:17](O)=[O:18].[OH-].[Na+]>O>[CH3:12][C:13]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:14]=1[O:15][CH:16]([CH3:20])[CH2:17][OH:18]
Reactant: Cc1ccc(C)c(OC(C)C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C)c(OC(C)CO)c1

Procedure:
To a stirred and refluxing mixture of 56 parts of lithium aluminum hydride in 1000 parts of tetrahydrofuran was added dropwise a solution of 359 parts of 2-(2,5-dimethylphenoxy)propanoic acid in 1000 parts of tetrahydrofuran. Upon completion, stirring was continued at reflux temperature for 1.50 hours. The reaction mixture was cooled and decomposed by the successive additions of 55 parts of water, 45 parts of a 15% sodium hydroxide solution and 190 parts of water and the whole was stirred for 30 minutes. The inorganic material was filtered off after acidification with hydrochloric acid solution. The filtrate was dried, filtered and evaporated. The residue was distilled, yielding 73 parts of 2-(2,5-dimethylphenoxy)-1-propanol; bp. 150° C. at 11 mm. pressure (131).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:28])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([CH:25]([CH3:27])[CH3:26])[CH:18]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].B(Br)(Br)Br>ClCCl>[Cl:28][C:14]1[CH:13]=[C:4]([CH:3]=[C:2]([Cl:1])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:25]([CH3:26])[CH3:27])[CH:18]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: COc1ccc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a solution of the title compound from Step C (26 mg, 0.060 mmol) in dichloromethane (1 ml) at room temperature was added boron tribromide (1M in dichloromethane, 0.12 ml, 0.12 mmol). After the addition, a brown solution was obtained which was stirred at room temperature for about three hours. An additional 4 equivalents of boron tribromide was added and the mixture was stirred for 15 minutes at room temperature. A brown precipitation formed. The reaction was quenched with water (5 ml) and extracted with dichloromethane (3×10ml). The combined extracts were dried, filtered, and concentrated, and the residue was purified by preparative TLC (7% methanol in dichloromethane) to give the title compound (13 mg) as an off-white solid. MS (APCl−) Calc: 423.0, Found: 422.0 (M−1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([O:19][CH3:20])[C:17]=1[F:18])[N:14]=[CH:13][C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:11]2[OH:26].[N+:27](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:27][N:14]1[C:15]2[C:10](=[CH:9][C:8]([F:7])=[C:17]([F:18])[C:16]=2[O:19][CH3:20])[C:11](=[O:26])[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13]1
Reactant: CCOC(=O)c1cnc2c(OC)c(F)c(F)cc2c1O
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c2c(OC)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
1.10 g (0.008 mole) of potassium carbonate was added to a solution of 1.13 g (0.004 mole) of ethyl 6,7-difluoro-4-hydroxy-8-methoxyquinoline-3-carboxylate (IX) [prepared as described in Preparation 14 (B3)] in 20 ml of dimethylformamide and the mixture was stirred at room temperature for 3 hours. 0.81 g (0.0041 mole) of O-(2,4-dinitrophenyl)hydroxylamine was then added, and the mixture was stirred at room temperature for 6 hours. At the end of this time, the solvent was distilled from the reaction mixture under reduced pressure. The residue was washed, in turn, with water and with ethanol. The solid produced was extracted with chloroform, and the solvent was stripped from the extract, to give 0.62 g of ethyl 1-amino-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (XV) as an ocherous powder.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].Cl.ClC1C=C(NC2C3C(=CC(OC4CCNCC4)=C(OC)C=3)N=CN=2)C=CC=1F>>[ClH:1].[Br:28][C:29]1[CH:30]=[C:31]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH:15]4[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: COc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC1CCNCC1
Agent: Cl
Product: COc1cc2c(Nc3cccc(Br)c3)ncnc2cc1OC1CCNCC1

Procedure:
tert-Butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate was coupled with 3-bromoaniline using an analogous process to that described in Example 21 (preparation of starting materials) for the preparation of N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride, to give N-(3-bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride; 1H NMR Spectrum: (DMSO d6): 1.8-2.1 (m, 2H), 2.1-2.3 (m, 2H), 3.0-3.35 (m, 4H), 4.05 (s, 3H), 4.88 (m, 1H), 7.38-7.52 (m, 2H), 7.6 (s, 1H), 7.8 (d, 1H), 8.05 (s, 1H), 8.5 (s, 1H), 8.87 (s, 1H), 9.2 (bs, 2H), 11.7 (s, 1H); Mass Spectrum: (M+H)+ 431.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[OH-].[K+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[CH:28]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1)=[CH2:29]>C(O)C>[CH:28]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)=[CH2:29]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: OCc1ccc(O)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=Cc1ccc(COc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A mixture of 4-hydroxybenzyl alcohol (56.7 g, 0.459 molar), 85% potassium hydroxide (32.4 g, 0.459 molar) and 2,6-di-tert-butyl-p-cresol (1 g) in ethanol (600 ml) was stirred at room temperature for 30 minutes. To this mixture was added 4-vinylbenzylchloride (70.5 g, 0.459 molar) very rapidly and it was then heated to 80° C. for 6 hours and stirred at ambient temperature overnight. The mixture was cooled, filtered and the solvent reduced to 300 ml by placing on a rotary evaporator. The solution was then placed in the freezer overnight. The next day the product was filtered to give a white solid. This material was recrystallized from methanol/dichloromethane (2/1) to give a white solid: m.p. of 110°-111.5° C. Yield of 77%. Analysis calculated for C16H16O2 : C, 79.97, H, 6.71. Found: C, 79.31, H, 6.69. 1H NMR (CDCl3) δ 2.55 (broad s, 1H, OH), 4.5 (s, 2H, CH2OH), 5.08 (s, 2H, ArCH2OAr), 5.25+5.75 (AB quartet, 2H, CH2 =), 6.8 (m, 1H, CH=), 6.8-7.6 (m, 8H, ArH's).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].[Br:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[C:26](F)[C:25]([F:32])=[C:24]([F:33])[CH:23]=1>C1COCC1>[Br:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[Cl:13])[C:25]([F:32])=[C:24]([F:33])[CH:23]=1
Reactant: O=C(O)c1c(Br)cc(F)c(F)c1F
Reactant: Nc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
To a solution of i-Pr2NH (5.83 mL, 41.2 mmol) in THF (16 mL) at 0° C. was added n-BuLi (16.4 mL, 41.1 mmol, 2.5 M solution in hexanes). After stirring for 15 minutes, the reaction mixture was cooled to −78° C. 2-Chloroaniline (2.89 mL, 27.5 mmol) was added. After vigorous stirring for 10 minutes, a solution of 6-bromo-2,3,4-trifluorobenzoic acid (3.51 g, 13.8 mmol) in THF (4 mL) was added. The reaction mixture was warmed to room temperature and stirred for 2 hours at room temperature. The reaction mixture was concentrated, treated with 10% aqueous HCl (15 mL) until the aqueous phase was acidic, and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that was triturated three times with boiling CH2Cl2 to afford the desired product (3.18 g, 64%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([SH:32])=[N:30][CH:31]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:32][C:29]2[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][N:30]=2)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:23])([F:24])[CH2:19]1)=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCC(F)(F)C1
Reactant: Sc1ccc(Cl)cn1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(Cl)cn2)C[C@H]1C(=O)N1CCC(F)(F)C1

Procedure:
The title compound was prepared in analogy to example 68/69 step 8 using (1R,2R,4R)-2-(3,3-Difluoro-pyrrolidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (example 186 step 3) and 5-chloropyridine-2-thiol. Yellow solid (83%). MS (EI): 419.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:13][Mg]Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH:10]2[CH2:11][CH2:12]2)([OH:9])[CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(c1ccnc(Cl)n1)C1CC1
Reactant: C[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)(c1ccnc(Cl)n1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of (2-chloropyrimidin-4-yl)(cyclopropyl)methanone (175 mg, 0.958 mmol) in THF (3 mL) at −78° C. under a nitrogen atmosphere was added methyl magnesium chloride (3.0 M in diethyl ether, 0.380 mL, 1.15 mmol) dropwise. The solution was warmed to room temperature and stirred for an additional 30 min. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness to afford 1-(2-chloropyrimidin-4-yl)-1-cyclopropylethanol (115 mg, 0.579 mmol, 60% yield). MS ESI: [M+H]+ m/z 199.1. 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J=5.2, 1H), 7.43 (d, J=5.2, 1H), 3.43 (s, 1H), 1.52 (s, 3H), 1.26 (m, 1H), 0.60 (m, 1H), 0.50 (m, 1H), 0.40 (m, 1H), 0.30 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:14]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[S:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]([CH3:43])[CH:15]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:14]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]3[S:31][N:30]=[CH:29][N:28]=3)(=[O:24])=[O:25])=[CH:20][CH:21]=2)[N:16]([CH3:43])[CH:15]=1
Reactant: COc1ccc(B(O)O)c(Cl)c1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: COc1ccc(-c2cn(C)c3cc(S(=O)(=O)Nc4ncns4)ccc23)c(Cl)c1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (2-chloro-4-methoxyphenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(2-chloro-4-methoxyphenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.82 (s, 3 H) 3.92 (s, 3 H) 6.96-7.04 (m, 1 H) 7.17 (d, J=2.63 Hz, 1 H) 7.42 (d, J=8.59 Hz, 1 H) 7.45-7.53 (m, 2 H) 7.71 (s, 1 H) 7.93 (s, 1 H) 8.19 (s, 1 H). m/z (ESI) 434.0 (M+H)+.
Reaction SMILES: CN(C)C[CH2:4][CH:5]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.C([Li])CCC.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29]CCl>CCOCC.CCCCCC>[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:4][CH:5]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2
Reactant: CN(C)CCC1Sc2ccccc2Sc2ccccc21
Reactant: CN(C)CCCCl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)CCCC1Sc2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.10 g 11H-dibenzo(b,e)-1,4-dithiepin (of example 14, reference given) in 50 ml of ether was stirred and treated dropwise with 10 ml of 15% n-butyllithium solution in hexane for 15 minutes in a nitrogen atmosphere. The mixture was stirred for another 30 minutes at room temperature. It was then treated dropwise with 10 ml of 3-dimethylaminopropyl chloride, the mixture stirred for 4 hours and washed with water. The basic product was then extracted with dilute hydrochloric acid, the acid layer made alkaline with aqueous ammonia and the base extracted with ether. Processing of the extract yielded 3.7 g for oily base which was chromatographed on a column of 200 g neutral of aluminium oxide (activity II). A small amount of less polar impurities was initially eluted with benzene which then eluted 2.89 g of a homogeneous oily base which was converted by neutralization with oxalic acid to the hydrogen oxalate, m.p. 181°-182° C. (ethanol).