Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].CCN(CC)CC.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][O:4][C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: BrCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 653.5 %

Procedure:
2-Bromo-ethanol (6.3 g, 5.0 mmol), Et3N (10 mL, 72 mmol) and trityl chloride (14.6 g, 52.5 mmol) in anhydrous CH2Cl2 (50 mL) was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, 4:1) to give the title product (12 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([NH:19][C:20]3[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][C:34](=O)[C:35](O)=[O:36])[CH:28]=1>C(O)C>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][C:34]2[C:35](=[O:36])[N:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13](/[CH:12]=[CH:11]/[C:8]4[CH:9]=[N:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=4)[CH:14]=3)[C:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:26]=2)[CH:28]=1
Reactant: CC(=O)Nc1ccc(/C=C/c2cccc(Nc3ncccc3N)c2)cn1
Reactant: O=C(O)C(=O)Cc1cccnc1
Solvent: CCO
Product: CC(=O)Nc1ccc(/C=C/c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)cn1
Yield: 85.4 %

Procedure:
A suspension of 2-[3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]phenylamino]-3-aminopyridine (1.5 g) and 3-pyridylpyruvic acid (0.79 g) in ethanol (30 ml) was stirred under reflux for 8 hours. The cold reaction mixture was filtered and washed with ethanol to give 2-(3-pyridylmethyl)-3-oxo-4-[3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine as colorless crystals (1.76 g).
Reaction SMILES: CC[O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:5].[OH-].[Na+]>CO>[C:22]([O:21][C:19]([N:7]1[CH2:8][C@@H:9]([S:11][C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[CH2:10][C@H:6]1[C:4]([OH:5])=[O:3])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)[C@@H]1C[C@H](Sc2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](Sc2ccc(Br)cc2)C[C@H]1C(=O)O
Reaction time: 14 h
Yield: 107.7 %

Procedure:
(2S,4S)-4-(4-Bromo-phenylsulfanyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (Preparation 5, 120 mg, 0.30 mmol) was dissolved in MeOH (6 ml) and 2M sodium hydroxide was added (0.83 ml, 1.66 mmol). The solution was stirred for 14 h, concentrated and added to 0.5M HCl (50 ml). The aqueous was extracted with CH2Cl2 (50 ml) which was dried (magnesium sulphate) and concentrated. Flash column chromatography (eluting first with CH2Cl2 and then with 95% CH2Cl2/MeOH) gave the acid as a clear liquid (130 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:20]=1.Cl.N1C=CC=CC=1>C(OC(O)C)C>[CH3:15][N:13]([CH3:14])[CH:10]1[CH2:11][CH2:12][N:8]([C:6]([C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:3][CH:4]=2)=[O:7])[CH2:9]1
Reactant: CN(C)C1CCN(C(=O)c2ccc(N)cc2)C1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc(Nc3nc(-c4ccccc4)nc4ccccc34)cc2)C1
Temperature: 135 °C
Yield: 17.1 %

Procedure:
A mixture of 1-(4-aminobenzoyl)-3-dimethylamino-pyrrolidine (46 mg, 0.2 mmol), 4-chloro-2-phenylquinazoline (48 mg, 0.2 mmol) and pyridine hydrochloride (23 mg, 0.2 mmol) in ethoxyethanol is heated to 135° C. overnight, cooled to room temperature and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by reverse-phase semi-preparative HPLC1 to give the title product as a white powder (15 mg), identified by HPLC and mass spectral analyses. Retention Time, 2.69 min.; MS [438.2 m/e (M+H)]. 1Semi-preparative HPLC Conditions: A=0.02% TFA in water, B=0.02% TFA in acetonitrile, 10-95% B in 8 min., 34 mL/min, 50° C., 215 nm detection, Waters Xterra™ 20×50 mm column.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1.[Cl-].[NH4+]>C1COCC1.CCO.O.[Fe]>[Br:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1c(F)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(Br)cc(F)c1N
Temperature: 95 °C
Reaction time: 22 h
Yield: 99.9 %

Procedure:
To a solution of 4-bromo-2-fluoro-6-nitroaniline (0.5 g, 2.1 mmol) in THF (4.6 mL), EtOH (4.6 mL) and H2O (1.5 mL) was added iron powder (0.6 g, 10.6 mmol) and ammonium chloride (0.17 g, 3.2 mmol). The resulting mixture was stirred at 95° C. for 22 hours. The mixture was cooled to room temperature and filtered through diatomaceous earth. The solid was washed with EtOH until no further color came through the filter. The filtrate was concentrated and the residue was dissolved in EtOAc, washed with H2O and brine, dried over Na2SO4, filtered and concentrated to give the title compound (0.43 g, 99%) as a brown, waxy solid.
Reaction SMILES: COC([C:5]1([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:9]([CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][O:7][C:6]1=[O:25])=O.[Cl-].[Li+]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:35][O:34][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:5]1[CH:9]([CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][O:7][C:6]1=[O:25])=[O:33]
Reactant: CCCCC/C=C/C(Sc1ccccc1)C1COC(=O)C1(CCCCCCC(=O)OC)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCC/C=C/C(Sc1ccccc1)C1COC(=O)C1CCCCCCC(=O)OC
Yield: 41.4 %

Procedure:
166 mg (0.33 mmol) of 3-methoxycarbonyl-3-(6-methoxycarbonylhexyl)-4-(1-phenylthio-trans-2-octenyl)-oxolane-2-one was dissolved in 4 ml of hexamethylphosphoric triamide in an argon atmosphere followed by stirring. 70 mg (1.65 mmol) of lithium chloride was then added to the solution and the mixture was stirred at a temperature of 100° C. for 5 hours. The resulting mixture was then worked up in the same manner as described in Example 5 to obtain 61 mg (41% yield) of 3-(6-methoxycarbonylhexyl)-4-(1-phenylthio-trans-2-octenyl)oxolane-2-one.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([S:15]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH2:28][OH:29])=[CH:23][CH:24]=3)[CH2:19]2)(=[O:17])=[O:16])=[C:10]([CH3:30])[CH:9]=1>C(Cl)Cl>[CH3:1][S:2]([O:29][CH2:28][C:22]1[CH:21]=[C:20]2[C:25]([CH2:26][CH2:27][N:18]([S:15]([C:11]3[C:12]([CH3:14])=[CH:13][C:8]([O:7][CH3:6])=[CH:9][C:10]=3[CH3:30])(=[O:16])=[O:17])[CH2:19]2)=[CH:24][CH:23]=1)(=[O:4])=[O:3]
Reactant: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(CO)cc3C2)c(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(COS(C)(=O)=O)cc3C2)c(C)c1
Reaction time: 1 h

Procedure:
MsCl (3.32 mmol, 1.5 equiv.) was added at 0° C. to a solution of (2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)methanol (2.22 mmol, 1 equiv.) and TEA (2.5 equiv.) in DCM (16 ml), and the mixture was stirred for 1 h. The reaction mixture was diluted with DCM, extracted with sat. sodium hydrogen carbonate solution, water and sat. NaCl solution and dried over Na2SO4. The solvent was removed in vacuo and the crude product was purified by column chromatography (silica gel).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:6]=1)(=O)=O.[F:31][C:32]1[CH:33]=[C:34]([OH:39])[CH:35]=[CH:36][C:37]=1[F:38]>>[F:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][C:37]=1[F:38])[O:39][C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:6]=1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(N2CCCC2)n1
Reactant: Oc1ccc(F)c(F)c1
Product: Fc1ccc(Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c(N3CCCC3)n2)cc1F

Procedure:
2-(Methylsulfonyl)-4-(N-pyrrolidinyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (24 mg, 0.05 mmol) was treated with 3,4-difluorophenol by the same general procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 70/30 hexanes/ethyl acetate) afforded the title compound. HPLC/MS: m/e=534 (M++1); Rt=4.39 min. 1H-NMR 500 MHz (CDCl3): δ 1.80 (bs, 4H), 3.2 (bs, 4H), 6.85-7.28 (m, 10H).
Reaction SMILES: N1C=CC(C=O)=CC=1.Cl.[CH:10]1[CH:14]=[C:13]([CH:15]([C:22]2[NH:26][CH:25]=[CH:24][CH:23]=2)C2C=CN=CC=2)[NH:12][CH:11]=1.B(F)(F)F.Cl.C1COCC1>CO.N1C=CC=C1>[CH:24]1[CH:23]=[C:22]([CH2:15][C:13]2[NH:12][CH:11]=[CH:10][CH:14]=2)[NH:26][CH:25]=1
Reactant: c1c[nH]c(C(c2ccncc2)c2ccc[nH]2)c1
Agent: Cl
Agent: FB(F)F
Agent: O=Cc1ccncc1
Solvent: C1CCOC1
Solvent: c1cc[nH]c1
Solvent: CO
Product: c1c[nH]c(Cc2ccc[nH]2)c1

Procedure:
The earliest one-flask synthesis entailed reaction of 4-pyridine carboxaldehyde with 2.1 molar equiv of pyrrole in methanol acidified with gaseous HCl, whereupon the corresponding 5-(4-pyridyl)dipyrromethane precipitated as the hydrochloride salt.2 In most applications such precipitation is not possible, in which case all excess of pyrrole is employed to suppress the continued reaction leading to linear and cyclic oligomers. A number of reports in the early-mid 1990s described methods where the aldehyde (0.04–0.5 M) was treated with excess pyrrole (2.1–40 molar equiv) in an acidified organic solvent: BF3-etherate/CH2Cl2,3 acetic acid/DMF4 or THF,5 SnCl4/CH2Cl2,6 p-toluenesulfonic acid/MeOH7,8 or toluene,9 or aq. HCl/THF.10 Workup typically entailed several steps including column chromatography, though Hammel et al. employed flash chromatography followed by Kugelrohr distillation.3 In 1994, we reported a method that employed the reaction of the aldehyde (0.34 M) dissolved in neat pyrrole (˜14 M) with no other solvent, relying on column chromatography for purification (“1994 procedure”).11 Catalysis was achieved at room temperature with TFA or BF3.O(Et)2, or in some cases12 upon heating without added acid. The reaction proceeded in a few minutes at room temperature and afforded the dipyrromethane in yields of ˜40–60%, but the use of chromatography for purification limited the scale.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13](=[O:18])[NH:14][CH:15]3[CH2:17][CH2:16]3)[CH:10]=[CH:9][C:8]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([OH:22])=O.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH2:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH:30][C:20]([C:3]1[CH:4]=[N:5][N:6]([C:7]2[CH:12]=[C:11]([C:13](=[O:18])[NH:14][CH:15]3[CH2:17][CH2:16]3)[CH:10]=[CH:9][C:8]=2[CH3:19])[C:2]=1[NH2:1])=[O:22]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)O)c1N
Reactant: CC1CCCCC1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)NC2CCCCC2C)c1N
Yield: 68.7 %

Procedure:
A solution of 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (21 mg), 2-methylcyclohexylamine (10 mg), EDCI (28 mg) and HOBt (12 mg) in DMF (0.75 ml) was reacted at room temperature for 24 h. Water (4 ml) was added and the solution was extracted with ethyl acetate (3 mL ×2). The organic phase was then washed with water (3 mL), dried over Na2SO4 and evaporated. The residue was purified by preparative TLC plate to give the desired product 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (2-methylcyclohexyl)-amide (19 mg, 70%). HPLC (4 minute gradient) tR 2.34 min; MS m/z 396.31 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Li+].[CH3:13][CH:14]([N-]C(C)C)C.BrCCO[Si](C(C)(C)C)(C)C.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:14][CH2:13][O:10][C:9]2=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CC(C)[N-]C(C)C
Agent: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OCCC1c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 18.8 %

Procedure:
4-Bromophenylacetic acid (1.00 g, 4.65 mmol) was dissolved in 45 mls of dry THF and chilled to −78° C. To this was added LDA (9.30 mls, 18.6 mmol, 2M in THF/heptane), resulting in a dark color, and this mixture was stirred at −78° C. for 20 minutes. (2-bromoethoxy)(tert-butyl)dimethylsilane (1.20 mls, 5.58 mmol) was then added via syringe, and then the cooling bath was removed to allowed the reaction to warm to room temperature. Upon warming, the mixture became an amber color. Once at room temperature, 50 mls of 1N aqueous HCl were then added and the mixture was vigorously stirred for 16 hours, then extracted with EtOAc (2×), extracts washed with 2M aqueous sodium carbonate, dried over sodium sulfate and concentrated to an orange oil. Flash 40 Biotage (40M cartridge, 3:1 Hexane:EtOAc) afforded 211 mgs (19%) of 3-(4-bromophenyl)dihydrofuran-2(3H)-one as an orange oil.
Reaction SMILES: [CH2:1]([C:7]1[O:11][C:10]([CH3:12])=[C:9]([C:13]([O:15]CC)=[O:14])[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>[OH-].[Na+]>[CH2:1]([C:7]1[O:11][C:10]([CH3:12])=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc(C(=O)OCC)c(C)o1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCc1cc(C(=O)O)c(C)o1

Procedure:
Saponification of 0.5 g of the ester was accomplished by refluxing 12 hours in 10 ml of 25% aqueous sodium hydroxide. Acidification precipitated the crude acid, which was purified by sublimation to give 5-hexyl-2-methyl-3-furoic acid, mp 59°-60° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[N:19]([CH3:20])[NH:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25].[ClH:29]>C(Cl)(Cl)Cl.N#N.CCOCC>[ClH:29].[CH2:22]([NH:26][C:27]([N:18]1[C:17](=[O:21])[CH2:16][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[N:19]1[CH3:20])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: COc1ccc(C2CC(=O)NN2C)cc1OC1CCCC1
Reactant: CCCCN=C=O
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCCNC(=O)N1C(=O)CC(c2ccc(OC)c(OC3CCCC3)c2)N1C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (2.06 mmol, 0.600 g) is dissolved in dry chloroform (10 mL) in a N2 atmosphere. To this is added dropwise at room temperature butyl isocyanate (5.15 mmol; 0.583 mL) neat. The sample is heated to reflux for 4 hours at which time TLC shows no starting material. The sample is evaporated to yield a clear oil which is dissolved in ether. To this solution is added ethanolic HCl and the sample is stirred for 15 minutes and evaporated in vacuo to afford a solid which is recrystallized from chloroform and hexane to give the title compound as a white solid (0.495 mg; 56%) m.p.: 115°-122° C. (dec) 1H NMR (DMSO-d6, 400 MHz) δ8.3 (s, 1H); 7.91 (t, 3H, J=5.7 Hz); 6.95 (d, 1H, J=1.3 Hz); 6.89 (d, 1H, J=8.3 Hz); 6.81 (dd, 1H, J=8.3, 1.6 Hz); 4.68 (m, 1H); 4.35 (d, 1H, J=5.6 Hz); 3.69 (s, 3H); 3.15 (m, 2H); 2.73 (s, 3H); 1.84 (m, 2H); 1.68 (m, 3H); 1.54 (m, 2H); 1.40 (m, 2H); 1.23 (m, 3H); 0.85 (t, 2H, J=7.3 Hz). IR (KBr, cm-1) 1760
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1>O1CCOCC1>[CH3:3][O:4][CH2:5][CH2:6][O:7][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: COCCO
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCCOc1ccc(S(=O)(=O)Nc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspention of NaH (2.2 mmol, 55-65% in oil) in dry dioxane (6 mL) was added 2-methoxyethanol (158 μl, 2 mmol). The mixture was stirred 1 h at room temperature. A solution of 4-fluoro-N-(4-methylphenyl)benzenesulfonamide (265.3 mg, 1 mmol) in dry dioxane (2 mL) was added. The resulting mixture was heated 24 h at 100° C. Solvents were evaporated. NH4Cl saturated solution in water (5 mL) was added and the desired product was extracted with three portions of ethyl acetate (3×5 mL). Combined organic phases were dried over magnesium sulfate before filtering and removal of solvent. The desired product, e.g. 4-(2-methoxyethoxy)-N-(4-methylphenyl)benzenesulfonamide was obtained as a colorless oil, in 77% purity by HPLC (MaxPlot detection between 230 and 400 nm). This intermediate was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[N+:13]([O-])=O.[H][H]>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[NH2:13]
Reactant: COc1ccc([Si](C)(C)C)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc([Si](C)(C)C)cc1N
Yield: 60.2 %

Procedure:
The above trimethyl-silane (760 mg, 3.4 mmol) was dissolved in 25 mL of EtOH. To this was added 10% Pd/C (128 mg). The reaction was stirred for 12 h under a 1 atm balloon of hydrogen gas. The reaction was then filtered through diatomaceous earth and concentrated in vacuo to provide 400 mg (60%) of 2-methoxy-5-trimethylsilanyl-phenylamine as an amber oil which was used without further purification.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:44]([NH:46][S:47]([CH:50]4[CH2:52][CH2:51]4)(=[O:49])=[O:48])=[O:45])=[CH:16][C:17]=3[N:18]3[CH2:24][CH:23]([C:25]([N:27]4[CH2:34][C:33]56[CH2:35][NH:36][CH2:37][C:29]5([CH2:30][O:31][CH2:32]6)[CH2:28]4)=[O:26])[CH2:22][C:21]4[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:20]=4[C:19]=23)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C=O>CO>[CH:5]1([C:11]2[C:12]3[CH:13]=[CH:14][C:15]([C:44]([NH:46][S:47]([CH:50]4[CH2:52][CH2:51]4)(=[O:48])=[O:49])=[O:45])=[CH:16][C:17]=3[N:18]3[CH2:24][CH:23]([C:25]([N:27]4[CH2:34][C:33]56[CH2:35][N:36]([CH3:1])[CH2:37][C:29]5([CH2:30][O:31][CH2:32]6)[CH2:28]4)=[O:26])[CH2:22][C:21]4[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:20]=4[C:19]=23)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc2c(c1)CC(C(=O)N1CC34CNCC3(COC4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CC(C(=O)N1CC34COCC3(CN(C)C4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A 1M solution of sodium cyanoborohydride in THE (0.16 mL, 0.16 mmol) was added to a solution of 13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-(3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-ylcarbonyl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxamide (Example 24A) (11 mg, 0.016 mmol) and formaldehyde (37 wt. % in water) (0.01 mL, 0.1 mmol) in MeOH (1 mL) and the mixture was stirred at rt for 16 h. The reaction was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC (H2O-MeOH with 0.1% TFA buffer) to yield 13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-((10-methyl-3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-yl)carbonyl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxamide (12 mg, 0.013 mmol, 82% yield) as a yellow solid. LCMS: m/e 687 (M+H)+. LCMS retention time: 2.47 min. (Column: Phenomenex-Luna 3.0×50 mm S10. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=4 mL/min).
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH2:13]([C:15]1[C:22]([O:23][CH3:24])=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[O:25][CH3:26])[CH3:14].[CH3:27][S:28][CH2:29][S:30]([CH3:32])=[O:31].C(Cl)Cl>CO.O1CCCC1>[CH2:13]([C:15]1[C:22]([O:23][CH3:24])=[CH:21][C:18](/[CH:19]=[C:29](\[S:28][CH3:27])/[S:30]([CH3:32])=[O:31])=[CH:17][C:16]=1[O:25][CH3:26])[CH3:14]
Reactant: CCc1c(OC)cc(C=O)cc1OC
Reactant: CSCS(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1c(OC)cc(/C=C(\SC)S(C)=O)cc1OC
Yield: 68.8 %

Procedure:
130 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol (Triton B) were added to a solution of 126.5 g (651.2 mmol) of 4-ethyl-3,5-dimethoxy-benzaldehyde and 80.89 g (651.2 mmol) of methyl methylthiomethyl sulphoxide in 300 ml of tetrahydrofuran and the mixture was heated at reflux for 5 hours. After the addition of 300 ml of methylene chloride the mixture was extracted with 200 ml of 0.5M sulphuric acid. The organic phase was dried (MgSO4), filtered and evaporated. Chromatography of the resulting residue (silica gel, ethyl acetate/hexane 1:1) yielded 134.6 g (69%) of (E)-2-ethyl-5-(2-methylsulphanyl-2-methylsulphinyl-vinyl)-1,3-dimethoxybenzene as a colorless oil, which gave colorless crystals of m.p. 82-83° by crystallization from hexane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[F-].[Cs+].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>CN(C=O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1ccc(-c2ncoc2-c2ccncc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: c1ccc2nc(COc3ccc(-c4ncoc4-c4ccncc4)cc3)ccc2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
To a solution of compound 4-(5-(pyridin-4-yl)oxazol-4-yl)phenol (90 mg, 0.38 mmol) in 1 mL of dry DMF was added CsF (115 mg, 0.76 mmol). After stirring for 0.5 h, 2-(chloromethyl)quinoline (67 mg, 0.38 mmol) was added and the reaction was heated at 80° C. for 48 h. Upon removal of DMF under vacuum, the residue was purified by PTLC (1:2 hexane/EtOAc) to give 29 mg (20%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ: 5.47 (s, 2H), 7.11 (m, 2H), 7.56 (m, 5H), 7.70 (d, 1H), 7.78 (t, 1H), 7.86 (d, 1H), 8.01 (s, 1H), 8.12 (d, 1H), 8.26 (d, 1H), 8.57 (d, (2H). MS m/z: 380 [M+1]+.