Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])=[CH:14][CH:13]=2)[CH:5]=1.C1COCC1.O.[OH-].[Li+].Cl>O>[F:26][C:19]1[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:27])=[O:2])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Temperature: 60 °C
Yield: 98.1 %

Procedure:
A solution of 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoic acid methyl ester (18.96 g, 50.92 mmol) in inhibitor free THF (100 mL) was treated with a near solution of lithium hydroxide monohydrate (8.4 g, 200.2 mmol) in water (100 mL) at room temperature and heated at 60° C. for 4 h. The reaction mixture was cooled, diluted with water, acidified with aq. 2N HCl and extracted with ethyl acetate. The organic layers were combined, washed with 1/1 water/brine, brine, dried (MgSO4), filtered and concentrated to give 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoic acid (17.89 g, 98.0%) as an off white solid. LC-MS (ES) calculated for C20H13F3O3, 358.32; found m/z 357 [M−H]−.
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Si](OS(C(F)(F)F)(=O)=O)([C:22](C)(C)[CH3:23])(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[CH:10]\[CH2:11][CH2:22][CH3:23])([CH3:7])[CH3:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Yield: 96 %

Procedure:
Compound 9t was synthesized by a procedure similar to that described for 9a using 3-chloropentaphenone (8k, 2.7 g, 0.014 mol), TBDMSOTf (3.5 mL, 15 mmol), and Et3N (3.1 mL) in CH2Cl2 (25 mL). After purification, 4.18 g (96%) of the title product was isolated as colorless oil: 1H NMR (CDCl3) δ 7.47-7.44 (m, 1H), 7.38-7.32 (m, 1H), 7.30-7.28 (m, 1H), 7.25-7.22 (m, 1H), 5.18 (t, 1H, J=7.2 Hz), 2.20 (q, 2H, J=7.5 Hz), 1.54-1.38 (m, 2H), 1.02 (s, 9H), 1.00-0.90 (m, 3H), −0.05 (s, 6H); 13C NMR (CDCl3) δ 148.0, 141.8, 133.9, 129.2, 127.6, 125.9, 123.9, 113.0, 28.3, 25.8, 22.8, 14.0, 0.0, −4.01. C17H27ClOSi.
Reaction SMILES: [Br:1][C:2]1[C:11]([Br:12])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:13]([OH:15])=[O:14].C(O)(=O)C.[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>O>[Br:1][C:2]1[C:11]([Br:12])=[C:10]([N+:20]([O-:22])=[O:21])[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1c(Br)c(Br)cc2c1OCCO2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Temperature: 37 °C
Yield: 83 %

Procedure:
A 20-mL round bottom flask was charged with 6,7-dibromo-2,3-dihydrobenzo[b][1,4]dio-xine-5-carboxylic acid (3.0 g, 0.61 mmol) and acetic acid (2 mL). The mixture was heated to 37° C., following by the addition of a solution of nitric acid (d=1.49, 1.0 mL), acetic acid (1.0 mL) and concentrated sulfuric acid (1.0 mL). After heating at 50° C. for 1 h, the mixture was poured in cold water while stirring. It was then filtered and the solid was washed with water to afforded the title compound (1.91 g, 83%). LCMS: ESI (3 minute run), m/z=382 [M+1]+; Retention time: 1.05 minute.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[C:12]([F:14])[C:9]([CH2:10][OH:11])=[C:8]([F:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[C@H:25]([CH2:32][CH3:33])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([F:15])[C:9]([CH2:10][O:11][C:29]([N:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][C@H:25]2[CH2:32][CH3:33])=[O:30])=[C:12]([F:14])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: CCCCOc1cc(F)c(CO)c(F)c1
Product: CCCCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(F)c1
Yield: 80 %

Procedure:
This compound was prepared from 4-butoxy-2,6-difluoro-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (454 mg; 80%); MS (ISP): 479.4 (M+Na)+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)([CH3:12])[CH3:11].[Br:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:30](Br)=[N:29][CH:28]=1>CC(O)C>[Br:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:30]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([CH:16]3[CH2:15][CH2:14][N:13]([CH:10]([CH3:12])[CH3:11])[CH2:18][CH2:17]3)=[CH:24][CH:23]=2)=[N:29][CH:28]=1
Reactant: CC(C)N1CCC(c2ccc(N)cc2)CC1
Reactant: Brc1ncc(Br)n2ccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)N1CCC(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1

Procedure:
N,N-Diisopropylethylamine (360 μL, 2.2 mmol) is added to a mixture of 4-(1-isopropylpiperidin-4-yl)phenylamine (220 mg, 1.0 mmol) and 5,8-dibromoimidazo[1,2-a]pyrazine (280 mg, 1.0 mmol) in iPrOH (5 mL) and heated at reflux for 48 h. The mixture is cooled and the solvent evaporated under reduced pressure to afford an orange-brown solid. This is partitioned between DCM (50 mL) and water (20 mL) and the layers are separated. The organic phase is washed with citric acid (10% aq., 3×25 mL). The combined washings are extracted with DCM (25 mL) and then made basic by addition of NaHCO3 (s). The mixture is extracted with DCM (3×25 mL) and the combined extracts dried over MgSO4 and evaporated. The material is used without further purification.
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[NH:21][C:1]1[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][CH2:3][C:2]2=1
Reactant: O=C1CCCc2ccccc21
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]c3c(c2c1)CCc1ccccc1-3

Procedure:
Following the procedure described in Example 4, using 3,4-dihydro-2H-naphthalen-1-one (2.90 g, 20 mmoL) and 4-methoxy-phenylhydrazine HCl salt as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:25](=[CH:26][CH:27]=5)[N:24]([CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])[CH:23]=[CH:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1>[C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:25](=[CH:26][CH:27]=5)[N:24]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:23]=[CH:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCCn1ccc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCn1ccc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 4-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-1H-indol-1-yl)butanoate (63 mg, 0.135 mmol) was dissolved in THF (1.3 mL) before lithium hydroxide, monohydrate (11 mg, 0.269 mmol) was added and stirred at ambient temperature for 3 h. The reaction mixture was concentrated, acidified with 2 N HCl, filtered, washed with water, and dried in a vacuum oven to give the title compound. MS (ESI) m/z: Calculated: 453.2; Observed: 453.8 (M++H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[C:30]([N:13]1[CH2:12][CH2:11][N:10]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:29])[CH:27]=[CH2:28])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:15][CH2:14]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCNCC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.3 %

Procedure:
Diisopropylethylamine (0.24 ml, 1.36 mmol) was added in one portion to a stirred solution of N-[4-(piperazine-1-sulfonyl)-phenyl]-acrylamide (0.1 g, 0.34 mmol) in THF (5 ml). The mixture was stirred at room temperature for 5 minutes before benzoyl chloride (0.05 ml, 0.44 mmol) was added drop wise and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The crude reaction mixture was concentrated under vacuum and the residue was purified by Prep HPLC to give the title compound (0.018 g, 13% yield) as a white powder.
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10](=O)[CH2:11][N:12]1[CH:16]=[CH:15][O:14][C:13]1=[NH:17].[OH-].[Na+]>O>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:17]=[C:13]2[N:12]([CH:11]=1)[CH:16]=[CH:15][O:14]2
Reactant: N=c1occn1CC(=O)c1ccc(F)cc1F
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc(-c2cn3ccoc3n2)c(F)c1
Temperature: 80 °C
Yield: 69.6 %

Procedure:
Polyphosphoric acid (124.4 g) was charged to a flask and heated to about 80° C. 1-(2,4-Difluorophenyl)-2-(2-iminooxazol-3(2H)-yl)ethanone hydrobromide salt (19.8 g, 62.0 mmol, Preparation #B.1 intermediate) was transferred to the flask in approximately 3 g portions over about 2 h. The thick solution was mixed and heated at about 80-90° C. for about 22 h. The reaction mixture was slowly transferred to a flask containing water (150 mL) and 30% aqueous NaOH (150 mL) that had been cooled to about 5-10° C. The pH of the resulting slurry was adjusted to about 5.4 by addition of 30% aqueous NaOH and the product was isolated by filtration. The wet cake was rinsed with warm water (3×150 mL) and dried under vacuum to give the title compound (9.5 g, 69%): MS m/z 221.1 (M+H)+ FIA (APCI)
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=2[CH:3]=1.[NH:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:12][C:6]1([CH3:13])[NH:5][C:4]2[CH:3]=[C:2]([C:17]3[CH:18]=[N:14][NH:15][CH:16]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)NC(=O)c2sc(-c3cn[nH]c3)cc2N1
Temperature: 120 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
A mixture of 6-bromo-2,2-dimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.125 g, 0.480 mmol), 4-pyrazoleboronic acid pinacol ester (0.279 g, 1.44 mmol), sodium carbonate (0.254 g, 2.40 mmol), 1,2-dimethoxyethane (2.4 mL) and water (1.2 mL) was purged with argon. Then, 1,1′-bis (diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.041 g, 0.050 mmol) was added to the mixture and the mixture was purged with argon again. The mixture was stirred at 120° C. for 4 h in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (50 mL). Extraction with ethyl acetate/THF (3:1, 2×50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure were carried out. The residue was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol). The fractions containing the desired product were collected. Some amount of starting material was recovered, reacted and purified with the above conditions again. The fractions containing the desired product were combined and concentrated in vacuo. This residue was further purified by column chromatography (Combiflash, 12 g silica gel, ethyl acetate to 90:10 ethyl acetate/methanol), then triturated with dichloromethane. The precipitate was collected by filtration to afford the title compound (0.0308 g, 26%) as a yellow solid:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[Li]CCCC.[CH3:14][C:15](=[O:36])[C@@H:16]1[C@:33]2([CH3:34])[C@H:19]([C@H:20]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C@@H:23]([CH2:24][C:25](=[O:35])[CH2:26][CH2:27]2)[CH2:22][CH2:21]3)[CH2:18][CH2:17]1.C(Cl)Cl>C1COCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C@@:25]1([OH:35])[CH2:26][CH2:27][C@@:28]2([CH3:29])[C@H:23]([CH2:22][CH2:21][C@@H:20]3[C@@H:30]2[CH2:31][CH2:32][C@@:33]2([CH3:34])[C@H:19]3[CH2:18][CH2:17][C@@H:16]2[C:15](=[O:36])[CH3:14])[CH2:24]1
Reactant: C#Cc1ccccn1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@](O)(C#Cc5ccccn5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-ethynylpyridine (270 mg, 2.6 mmol) in dry THF (15 mL) was treated with a n-BuLi (2.5 M in THF, 2.5 mmol, 1 mL) at −60° C. After stirring the mixture at −78° C. for 0.5 hr, a solution of 5β-pregnan-3,20-dione, cyclic 20-(1,2-ethanediyl acetal)170 mg, 047 mmol) in THF (15 mL) was added and the mixture was stirred at −78° C. for 1 hr. The cooling bath was removed and the mixture was quenched with NH4Cl solution (3 mL). The solvent was removed and the residue was then dissolved in acetone (25 mL). After adding 2N HCl (2 mL) the solution was stirred at rt for 15 min. Sat. NaHCO3 soln. was added to neutralize the acid. The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product (360 mg). This crude product was then dessolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave the unreacted ethynlpyridine as a first fraction. Further elution with the same solvent mixture yielded 3β-(2-pyridyl)ethynyl-3α-hydroxy-5β-pregnan-20-one (107 mg) as a colorless solid; mp 192-195° C.; TLC Rf (toluene:acetone 87:13)=0.21.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([CH3:16])[C:13](=S)[NH:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[NH3:18]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:12]=[C:13]([NH2:18])[C:14]([CH3:16])=[N:15]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC1=NC2(CCOc3ccc(Br)cc32)NC1=S
Reactant: N
Solvent: CO
Product: CC1=NC2(CCOc3ccc(Br)cc32)N=C1N
Temperature: 60 °C
Yield: 77 %

Procedure:
6-Bromo-4′-methylspiro[chroman-4,2′-imidazole]-5′(1′H)-thione (0.10 g, 0.32 mmol, Intermediate 3) was dissolved in MeOH (1 mL) and 7M ammonia in MeOH (4 mL, 28 mmol) was added. The solution was heated at 60° C. for 12 h in a sealed vial. The solution was evaporated in vacuo. The treatment with 7M ammonia was repeated in the same way one more time. Evaporation in vacuo gave the title compound (73 mg, 77% yield) which was used without further purification in the following step. 1H NMR (400 MHz, CDCl3) δ ppm 2.11 (m, 2 H), 2.35 (s, 3 H), 4.53 (m, 2 H), 4.98 (br s, 2 H), 6.66 (m, 1 H), 6.78 (d, 1 H), 7.22 (m, 1 H); MS (ES+) m/z 294 [M+H]+.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([N:15]1[CH2:22][C:21]([F:24])([F:23])[CH2:20][C@@:16]1([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:39][CH2:40][CH:41]([OH:48])[CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][CH3:45].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl>[F:23][C:21]1([F:24])[CH2:22][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[C:16]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=3)=[CH:28][CH:27]=2)([C:17]([NH:39][CH2:40][CH:41]([OH:48])[CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][CH3:45])=[O:19])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@]1(Cc1ccc(-c2ccc(F)cn2)cc1)C(=O)O
Reactant: CCC(C)(C)CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C)(C)CC(O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methylmorpholine (0.2 mL, 1.8 mmol) was added to a solution of 1-(tert-butoxycarbonyl)-4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]proline (175 mg, 0.40 mmol), 1-amino-4,4-dimethylhexan-2-ol (58 mg, 0.40 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (92 mg, 0.48 mmol), and hydroxybenzotriazole (65 mg, 0.48 mmol) in dichloromethane (40 mL). After stirring at ambient temperature overnight, the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated in vacuo to afford tert-butyl 4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]-2-{[(2-hydroxy-4,4-dimethylhexyl)amino]carbonyl}-pyrrolidine-1-carboxylate which was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Product: COC(=O)c1cccc2c1ccn2Cc1ccc([N+](=O)[O-])cc1

Procedure:
1-(4-Nitro-benzyl)-1H-indole-4-carboxylic acid methyl ester was prepared from 1H-indole-4-carboxylic acid methyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow powder: 1H NMR (DMSO-d6) δ 3.90 (s, 3H), 5.69 (s, 2H), 7.05(dd, J=3.1, 0.9 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.36 (d, J=8.9 Hz, 2H), 7.75 (td, J=7.6, 3.1 Hz, 3H), 8.18 (d, J=8.9 Hz, 2H); MS (ESI) m/z 311 (MH+), 309 ([M−H]−); Anal. calcd for C17H14N2O4: C, 65.80; H, 4.55; N, 9.03. Found: C, 65.81; H, 4.50; N, 8.98.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C.Cl[C:30]1[C:39]2[C:34](=[CH:35][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1>C(O)C>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:30]3[C:39]4[C:34](=[CH:35][C:36]([C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:12][CH2:13]1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: COc1ccccc1N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Solvent: CCO
Solvent: CC(=O)Cl
Product: COc1ccccc1N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.8 %

Procedure:
To 1.73 g (0.00498 n) of 1-[(p-aminophenyl)sulfonyl]-4-(o-methoxyphenyl)piperazine in absolute ethanol is added 0.35 ml acetyl chloride in 5 ml ethanol (source of hydrogen chloride). After stirring for 5 minutes, 1.15 g (0.00498 m) of 4-chloro-7-trifluoromethylquinoline is added. The reaction mixture is stirred at reflux for 3 hours and at room temperature overnight. The solvent is then removed in vacuo and the residue is extracted with methylene chloride/aqueous sodium bicarbonate. The organic layer is filtered through anhydrous sodium sulfate and taken to dryness and the product mixture is chromatographed on silica gel, once with 4% methanol: 96% methylene chloride as eluant, and a second time with methylene chloride as the eluant. Crystallization from methylene chloride/Skelly-solve® B hexanes gives 1.61 g (61%) of 1-(2-methoxyphenyl)-4-[[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl]sulfonyl]piperazine of melting point 146°-148° C.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][N:5]([CH3:29])[S:6]([N:9]1[CH:13]=[CH:12][C:11]([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[N:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])=[N:10]1)(=[O:8])=[O:7]>C1COCC1>[CH3:29][N:5]([CH3:4])[S:6]([N:9]1[CH:13]=[CH:12][C:11]([C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)([NH:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])[CH3:1])=[N:10]1)(=[O:8])=[O:7]
Reactant: C[Mg]Br
Reactant: CN(C)S(=O)(=O)n1ccc(C(=NS(=O)C(C)(C)C)c2cccc(Cl)c2)n1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccc(C(C)(NS(=O)C(C)(C)C)c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Methylmagnesium bromide (15.08 mL, 21.11 mmol) was added to a solution of 3-[(3-chloro-phenyl)-(2-methyl-propane-2-sulfinylimino)-methyl]-pyrazole-1-sulfonic acid dimethylamide (2.2 g, 5.28 mmol) in THF (25 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 2 hours, quenched with NH4Cl (aq. sat. solution) and the product was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield 3-[1-(3-chloro-phenyl)-1-(2-methyl-propane-2-sulfinylamino)-ethyl]-pyrazole-1-sulfonic acid dimethylamide (2.28 g, 99% yield) as a colourless oil which solidified upon standing.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[C:15]([CH3:22])[CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[C:15]([CH3:22])[CH:14]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: Cc1cc(F)ccc1B(O)O
Product: COC(=O)c1cc(-c2ccc(F)cc2C)oc1C
Yield: 84.2 %

Procedure:
An operation similar to that in Example 49 (2) was performed using methyl 5-bromo-2-methyl-3-furoate (4.4 g) and 4-fluoro-2-methylphenylboronic acid (3.7 g) to give the title compound (4.2 g, 85%) as a white crystal.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:17])=[O:16]
Reactant: COCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a stirred solution of 3-methoxy-propan-1-ol (300 g, 3.3 mol) in anhydrous CH2Cl2 (3 L) was added triethylamine (790 mL, 5.7 mol). The mixture was cooled to 0° C. and methanesulfonyl chloride (376 mL, 4.8 mol) in anhydrous CH2Cl2 (1 L) added dropwise. After stirring for 2 h at rt, the mixture was washed with water and brine, dried and evaporated to give the crude product as an oil (540 g, yield 96%) that was used in the next step without purification. 1H NMR (400 MHz, CDCl3): δ 3.40-3.37 (t, J=6.0 Hz, 2H), 2.55-2.52 (t, J=6.0 Hz, 2H), 2.40 (s, 3H), 2.06 (s, 3H), 1.08-1.02 (m, 2H).