Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]#[CH:8])(=[O:4])[CH:2]=[CH2:3].[C:9]1([N:15]=[N+:16]=[N-:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.O>[C:9]1([N:15]2[CH:8]=[C:7]([CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[N:17]=[N:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#CCOC(=O)C=C
Reactant: [N-]=[N+]=Nc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(=O)OCc1cn(-c2ccccc2)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
Propargyl acrylate (13.5 g, moles), phenyl azide (12.5 g, moles) and tetrakis(acetonitrile)copper (I) hexafluorophosphate (0.84 g, 2.3 mmoles) are dissolved in DMF (100 ml) and stirred at room temperature under nitrogen for 24 hours. The reaction mixture is poured in water and the product is extracted with ethyl acetate. The solvent is distilled under reduced pressure, and mixed with diethyl ether wherefrom the product crystallized as an off-white, crystalline solid (23 g; yield 89%; mp 55-56° C.). 1H NMR (CDCl3, δ ppm) 8.08 (s, 1H), 7.72 (d, 2H), 7.51 (t, 2H), 7.44 (q, qH), 6.48 (d, 1H), 6.17 (q, 1H), 5.88 (d, 1H), 5.50 (s, 2H). 13C NMR (CDCl3, δ ppm) 165.9, 143.4, 136.8, 131.5, 129.7, 128.8, 127.8, 122.1, 120.5, 57.5.
Reaction SMILES: [CH2:1]1[CH:4]2[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:3]2[C:2]1=[O:12].[OH:13]O.[Na]>C(O)(=O)C.O>[O:13]1[C:2](=[O:12])[CH2:1][CH:4]2[CH2:5][CH:6]3[C:11]([CH:10]=[CH:9][CH:8]=[CH:7]3)=[C:3]12
Reactant: O=C1CC2Cc3ccccc3C12
Reactant: OO
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2CC3C=CC=CC3=C2O1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A solution of 1,2a,7,7a-tetrahydro-2H-Cyclobut[a]inden-2-one (Example I4, 0.377 mg, 2.383 mmol) in acetic acid (5 mL) and water (0.5 mL) was cooled at 0° C. and hydrogen peroxide (30% in water, 0.810 mL, 7.14 mmol) was added. The solution as stirred for 3 h at 0° C. and the reaction mixture was poured into saturated solution of sodium hydrogenocarbonate. The solution was extracted with ethyl acetate and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (4/1) to give rac-Tetrahydroindeno[1,2-b]furan-2-one (Colourless oil, 383 mg, 92%), that solidified upon cooling (data match with litt data, CAS 4471-33-4). C11H10O2; MW: 174.20; LCMS (method A) RT 1.32 min; ES: 175 (60%, MH+), 129 (100%); IR: 1769 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.50 (1H, d), 7.25-7.39 (4H, m), 5.91 (1H, d), 3.28-3.45 (2H, m), 2.86-2.97 (2H, m), 2.41 (1H, dd) ppm.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.I[CH:31]([CH3:33])[CH3:32]>>[CH:31]([N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:9]=2[CH3:28])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:26])=[O:27])([CH3:33])[CH3:32]
Reactant: CC(C)I
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2C(C)C)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 2-iodo propane. 1H NMR (DMSO-d6) δ 7.91-7.88 (m, 1H), 7.63-7.53 (m, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.17-6.78 (m, 4H), 6.14 (s, 1H), 4.98 (s, 2H), 3.68 (sept., J=6.8 Hz, 1H), 2.43 (s, 3H), 1.34 (d, J=6.9 Hz, 3H), 1.02 (d, J=6.9 Hz, 3H); MS: ESI (negative): 397 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1.OO.[OH2:19].C(OCC)(=[O:22])C>C(O)(=O)C.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1)(=[O:22])=[O:19]
Reactant: O
Reactant: CCOC(C)=O
Reactant: OCc1ccc(Sc2ccccc2Br)cc1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(CO)cc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of {4-[(2-bromophenyl)thio]phenyl}methanol (Step 2, 5.0 g, 16.9 mmol) in acetic acid (32 mL) was added hydrogen peroxide (4.2 mL, 50.8 mmol) and the reaction stirred overnight at room temperature. Further hydrogen peroxide (4.2 mL, 50.8 mmol) and catalytic sodium tungstate were added and the reaction stirred overnight. Water and ethyl acetate were added and the aqueous layer extracted with ethyl acetate (×2). The combined organic layers were washed with sodium hydrogen carbonate and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 60% ethyl acetate/isohexane, to give {4-[(2-bromophenyl)sulfonyl]phenyl}methanol as a white solid (4.0 g, 80%). δH (400 MHz, d6 DMSO): 8.31 (1H, dd, J=1.5, 7.9 Hz), 7.85 (2H, d, J=8.3 Hz), 7.79 (1H, d, J=7.9 Hz), 7.70 (1H, t, J=7.6 Hz), 7.60 (1H, td, J=1.0, 7.7 Hz), 7.54 (2H, d, J=8.3 Hz), 5.42 (1H, t, J=5.7 Hz), 4.57 (2H, d, J=5.4 Hz); m/z (ES+) 327, 329 [MH+].
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[N:17]([CH3:18])[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:19])[N:6]([CH3:20])[CH2:5]1.N1C=CC=CC=1C1CNCCN1.C(N(CC)CC)C.[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>C1(C)C=CC=CC=1>[OH2:19].[CH3:18][N:17]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:19])[N:6]([CH3:20])[CH2:5][CH:4]1[CH2:3][CH2:2][N:49]1[CH2:50][CH2:51][N:46]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][N:40]=2)[CH2:47][CH2:48]1.[CH3:18][N:17]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:19])[N:6]([CH3:20])[CH2:5][CH:4]1[CH2:3][CH2:2][N:49]1[CH2:50][CH2:51][N:46]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][N:40]=2)[CH2:47][CH2:48]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CN1CC(CCCl)N(C)c2nc3ccccc3n2C1=O
Agent: c1ccc(C2CNCCN2)nc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1CC(CCN2CCN(c3ccccn3)CC2)N(C)c2nc3ccccc3n2C1=O
Product: O
Reaction time: 48 h
Yield: 103.7 %

Procedure:
To 50 mL of toluene was added 5.0 g (0.0171 mol) of 2-(2-chloroethyl)-3,4-dihydro-1,4-dimethyl-1H-[1,3,5]triazepino[3,2-a]benzimidazol-5(2H)-one, 5.58 g (0.034 mol) of 2-(2-pyridyl)piperazine, and 3.4 g (0.034 mol) of triethylamine, and the entire reaction mixture heated to reflux. After 2 days, 1.5 g (0.009 mol) of 1-(2-pyridinyl)piperazine was added and reflux continued for 24 hours. The reaction mixture was washed with 2×50 mL of 1N NaOH, dried over Na2SO4, filtered and concentrated by rotary evaporation. The residue was subjected to preparative HPLC using silica gel as the stationary phase and eluting with 5% triethylamine in acetone. Like fraction were combined affording ~4.0 g (55%) of a glass.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4].[OH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]=2[OH:18])=[O:30])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
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: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Reaction time: 24 h

Procedure:
To a stirred solution of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester (150 mg, 0.62 mmol) and 1-hydroxy-naphthalene-2-carboxylic acid (90 mg, 0.75 mmol) in DMF (2 mL) were added HATU (285 mg, 0.75 mmol) and N,N-diisopropylethylamine (96 mg, 0.75 mmol). The mixture was stirred at room temp. for 24 h. The reaction mixture was then extracted with ethyl acetate and washed with water and brine. The organic layer was then dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C24H31N2O4 [(M+H)4] 411.0, obsd. 411.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2SC)[C:3]=1[CH3:23].O[O:25][S:26]([O-:28])=O.[K+].[CH2:30]1COCC1>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[S:26]([CH3:30])(=[O:28])=[O:25])[C:3]=1[CH3:23]
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C)cc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Agent: [K+]
Solvent: O
Product: Cc1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reaction time: 8 h

Procedure:
The 4-chloro-5,7-difluoro-3-methyl-2-(5-methyl-2-(methylthio)phenyl)quinoline (160 mg, 0.46 mmol) was slurried in a mixture of THF (3.4 mL) and water (1.1 mL). Oxone™ (700 mg, 1.1 mmol) was added and the mixture was stirred vigorously overnight. The reaction mixture was then poured into water (25 mL) and stirred for 10 min. The mixture was then filtered and washed with water. The ppt. was dissolved in EtOAc (50 mL) and dried over magnesium sulfate. The filtrate was cond to give crude 4-chloro-5,7-difluoro-3-methyl-2-(5-methyl-2-(methylsulfonyl)phenyl)-quinoline. Mass Spectrum (ESI) m/e=382.0 (M+1).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][CH:20]([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[S:18])=[CH:12][CH:11]=1>ClCCl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:2](=[O:8])[C:3](=[O:5])[N:19]([CH:20]([CH3:25])[C:21]([CH3:23])([CH3:22])[CH3:24])[C:17]2=[S:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(NC(=S)Nc1ccc(Br)cc1)C(C)(C)C
Solvent: ClCCl
Product: CC(N1C(=O)C(=O)N(c2ccc(Br)cc2)C1=S)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Ethyl chlorooxoacetate (0.496 mL, 4.44 mmol) was added to a stirring solution of the above thiourea (0.70 g, 2.22 mmol) in dichloromethane (15 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.647 g (79%) of 1-(4-bromo-phenyl)-2-thioxo-3-(1,2,2-trimethyl-propyl)-imidazolidine-4,5-dione as a yellow solid: mp 207.1–207.9° C.; 1H NMR (DMSO-d6): δ 7.74 (d, 1H), 7.32 (d, 2H), 4.81 (q, 1H), 1.48 (d, 3H), 0.99 (s, 9H); IR (KBr): 3500, 2970, 2230, 1770, 1500 cm−1; MS (m/z) 368 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:33]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH:30][S:40]([N:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)(=[O:42])=[O:41])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)N1CCCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)CC(NS(=O)(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of the product from Example AI ([S-(R*,R*)]-2-(2-amino-4-methyl-pentanoylamino)-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (220 mg, 0.50 mmol), homopiperidinesulfonyl chloride (110 mg, 0.55 mmol, prepared by the method of Von Geldem, et al., J. Med. Chem., 1996;39:968-981), N,N-diisopropylethylamine (129 mg, 1.00 mmol), and DMAP (20 mg) in DMF (1 mL) is stirred at room temperature for 72 hours, diluted with ethyl acetate, and washed with water, 1N HCl, saturated NaHCO3 solution and brine, dried over anhydrous sodium sulfate, and concentrated. The oily residue thus obtained was purified via flash chromatography (30% EtOAc/hexane) followed by preparative TLC (2 elutions, 30% EtOAc/Hexane) to afford 39 mg of a clear colorless oil which is dissolved in 0.5 mL CHCl3, diluted with 4 mL hexane, and maintained at 3° C. until crystallization occurred. The crystals are collected and weigh 10.1 mg (3%), mp=123-124° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=C(C=O)[C:17]=3[CH:23]=2)[C:3]1=[O:24].[CH:25]([SH:28])([SH:27])[CH3:26].B(F)(F)F.[CH3:33][CH2:34]OCC>C(Cl)Cl>[S:27]1[CH2:34][CH2:33][S:28][CH:25]1[C:26]1[C:17]2[CH:23]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[N:2]([CH3:1])[C:3]3=[O:24])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1
Reactant: CCOCC
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Reactant: CC(S)S
Agent: FB(F)F
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C4SCCS4)c3c2)c1=O
Yield: 46.3 %

Procedure:
To a mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (0.300 g, 0.850 mmol) and methylene chloride is added ethanedithiol (0.0940 g, 1.00 mmol) and boron trifluoride-etherate (0.200 ml). The resultant mixture is stirred overnight at room temperature and partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to a yellow solid which is stirred in hot methylcyclohexane and filtered to afford the title compound as a light yellow solid (0.170 g, 46.3%, mp 227-232° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.FC(F)(F)C1C=C(C(F)(F)F)C=CC=1CN1C2C(=CC(C=C3S[C:50]([N:52]4[CH2:57][CH2:56][NH:55][C@@H:54]([C:58](NC)=[O:59])[CH2:53]4)=NC3=O)=CC=2)C=N1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:55]5[CH2:56][CH2:57][N:52]([CH3:50])[CH2:53][C@@H:54]5[CH2:58][OH:59])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC(=O)[C@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)[C@@H](CO)C1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R) (4-Methyl-piperazin-2-yl)-methanol following General Procedure C.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:29])([CH3:28])[C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].C1COCC1.[OH-].[Na+]>CO>[OH:27][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:16]1([CH3:28])[CH3:29]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 65.6 %

Procedure:
3β-Hydroxy-4,4-dimethylchola-5,7-dien-24-oic acid methyl ester (120 mg) is saponified in a mixture of 15 ml of methanol, 15 ml of THF and 0.7 ml of 1M sodium hydroxide at 50° C. After aqueous work-up and crystallisation from methanol, the title compound (76 mg) is isolated. Melting point: 210-213° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:12][CH2:13]Cl)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O.[NH2:16][NH2:17].[Cl-].[NH4+]>>[NH2:16][N:17]1[CH2:13][CH2:12][N:4]([C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: NN
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(N)CC1

Procedure:
Under an inert atmosphere at ambient temperature, 15.3 g of the product of Step A and 80 ml of hydrazine hydrate were mixed together and then 150 ml of a saturated aqueous solution of ammonium chloride were added. Extraction was done with methylene chloride and the organic phase was washed with an aqueous solution of ammonium chloride, dried, and the solvent was eliminated under reduced pressure. After chromatography on silica (eluent:methylene chloride - methanol, 100/7) 5 g of the expected product were obtained.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[CH:20][C:3]=1[CH2:4][N:5]1[C@H:9]([C:10]([CH3:18])([CH3:17])[O:11][SiH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][C:6]1=[O:19].[CH2:30]([O:37][C:38]1[C:43](B(O)O)=[CH:42][CH:41]=[CH:40][N:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:30]([O:37][C:38]1[C:43]([C:2]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[CH:20][C:3]=2[CH2:4][N:5]2[C@H:9]([C:10]([CH3:18])([CH3:17])[O:11][SiH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][C:6]2=[O:19])=[CH:42][CH:41]=[CH:40][N:39]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: OB(O)c1cccnc1OCc1ccccc1
Reactant: COc1cc(CN2C(=O)CC[C@H]2C(C)(C)O[SiH2]C(C)(C)C)c(Br)cc1C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(CN2C(=O)CC[C@H]2C(C)(C)O[SiH2]C(C)(C)C)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Yield: 75 %

Procedure:
step 2—A sealed tube containing 104 (141 mg, 0.29 mmol), 2-benzyloxy-pyridin-3-yl boronic acid (100 mg, 0.44 mmol), Na2CO3 (92 mg, 0.87 mmol) and Pd(PPh3)4 (33 mg, 0.029 mmol) in a mixture of MeOH (1.5 mL) and DCM (0.5 mL) was irradiated in a microwave synthesizer at 100° C. for 30 min. The reaction mixture was diluted with DCM, filtered through a pad of CELITE and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 40% EtOAc/hexanes to afford 128 mg (75%) of (S)-1-[2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one (106).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.Cl.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[N:23]1[C:31]2[C:26](=[CH:27][C:28]([NH2:32])=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>C(O)=O>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[N:23]1[C:31]2[C:26](=[CH:27][C:28]([NH:32][CH:1]=[O:3])=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(N3CCc4cc(N)ccc43)c2cc1OC
Agent: Cl
Solvent: O=CO
Product: COc1cc2ncnc(N3CCc4cc(NC=O)ccc43)c2cc1OC
Temperature: 5 °C

Procedure:
Formic acid (42 μL) was added to acetic anhydride (88 μL) while stirring at 5° C. and the mixture was allowed to stir at 20° C. for 1 hour before adding 1-(6,7-dimethoxy-quinazolin-4-yl)-2,3-dihydro-1H-indol-5-ylamine (102 mg, 0.316 mmol; freebase from Example 83). The mixture was stirred at 20° C. for 1.5 hours, quenched with H2O (5 mL), stirred 30 min. and diluted with CHCl3 (15 mL). The organic phase was separated and washed with saturated aqueous NaHCO3, dried over Na2 SO4(s), filtered and concentrated in vacuo. Flash chromatography on silica (4% MeOH/CH2Cl2) afforded 66 mg of product. (M.P. 239°-244° C. (dec); LC-MS: 351 (MH+); anal. RP18-HPLC RT: 2.92 min.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[F:11])[CH:5]=[O:6]
Reactant: Oc1ccc(F)cc1F
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 105 °C
Yield: 68 %

Procedure:
A suspension of 3-bromo-4-fluorobenzaldehyde (500 mg, 2.46 mmol), 2,4-difluorophenol (0.353 mL, 3.69 mmol) and cesium carbonate (1204 mg, 3.69 mmol) in dimethylsulfoxide (24 mL) was heated at 105° C. overnight. The reaction mixture was partitioned between ethyl acetate (200 mL) and 50% saturated aqueous sodium chloride (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×75 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2.5-100% ethyl acetate in heptanes) to afford the title compound (524 mg, 68% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 104.7 %

Procedure:
To 4-bromo-1-ethyl-2-nitrobenzene (20.0 g, 87 mmol) in 1,2-dimethoxyethane (150 ml) is added, at room temperature, 4-chlorophenylboronic acid (14.98 g, 96 mmol) and tetrakis-(triphenylphosphine)palladium(0) (2.0 g, 1.74 mmol) and nitrogen gas is bubbled through the mixture. After stirring for 10 minutes at 20° C., a solution of sodium carbonate (73.8 g, 0.696 mol) in water (350 ml) is added and mixture is refluxed for 16 hours. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth, washing with ethyl acetate (200 ml). The mixture is poured into a separating funnel and the two phases are separated. The aqueous phase is extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 4′-chloro-4-ethyl-3-nitrobiphenyl (23.84 g) as a brown oil used without further purification in the next step.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH2:3][OH:4].Cl[C:9]1[N:14]2[N:15]=[CH:16][N:17]=[C:13]2[N:12]=[CH:11][CH:10]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[N:15]1[N:14]2[C:9]([N:1]3[CH2:7][CH2:6][CH2:5][C@@H:2]3[CH2:3][OH:4])=[CH:10][CH:11]=[N:12][C:13]2=[N:17][CH:16]=1
Reactant: Clc1ccnc2ncnn12
Reactant: OC[C@H]1CCCN1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@H]1CCCN1c1ccnc2ncnn12

Procedure:
1 g of commercially available (D)-prolinol, 1.5 g of 7-chloro-[1,2,4]triazolo-[1,5-a]pyrimidine and 2.6 g of N-ethyldiisopropylamine are heated at 130° C. in a microwave for 3 h in 60 ml of 1-butanol. The butanol is subsequently removed in vacuo, the residue is taken up in ethyl acetate, mixed with water, adjusted to pH 12 using 1 N NaOH solution, phases are separated, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel, giving 1.7 g of ((R)-1-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylpyrrolidin-2-yl)methanol as beige crystals;