Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:40])[CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:13][CH:12]=1.Cl>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([O:40][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:15][CH:16]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: COc1ccc(O)cc1
Agent: Cl
Product: COc1ccc(OC(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.13 (s, br, 1H), 7.72–6.70 (m, 12H), 5.08–4.97 (m, 1H), 3.72 (s, 3H), 3.66–3.50 (m, br, 2H), 3.03–2.82 (br, 2H), 2.80–2.54 (m, br, 4H), 2.53–2.17 (m, br, 2H), 2.08–1.78 (m, br, 6H), 1.65–1.38 (m, br, 2H) 1.25 (d, 6H, J=6.8 Hz). Anal. Calc. for C33H42Cl2N2O3.0.54CH2Cl2: C, 63.80; H, 6.88; N, 4.44. Found: C, 63.84; H, 7.18; N, 4.00. ESMS m/e: 549.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.Cl.[C:37](=[NH:42])(OCC)[CH3:38].C(N(CC)CC)C>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([C:37](=[NH:42])[CH3:38])[CH2:31][CH2:32]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:34][CH:35]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CC2CCNCC2)c2ccccc2C1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(=N)N1CCC(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
15 mg (0.029 mmol) of 4-(4-chlorobenzoyl)-1-(4-piperidinyl-methyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on trifluoroacetate was dissolved in 5 ml of ethanol. 120 mg (1.7 mmol) of ethyl acetimidate hydrochloride and 0.50 ml (3.6 mmol) of triethylamine were added to the obtained solution, and they were stirred at 80° C. for 2 days. The solvent was evaporated, and the obtained crude product was treated in the same manner as in Step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [OH-].[Na+].[Br:3]Br.[C:5]1([C:11]#[CH:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.C(COC)OC>[C:5]1([C:11]#[C:12][Br:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#Cc1ccccc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: BrC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of sodium hydroxide (31.4 g) in water (160 ml) was cooled to 6° C. and bromine (18 ml) was added dropwise, the temperature being kept below 20° C. Phenylacetylene (20 g) in dimethoxyethane (80 ml) was added over 15 minutes and the mixture was stirred at room temperature for 5 hours. Water (200 ml) was added, and the mixture was extracted with ether (4×60 ml), dried (MgSO4) and the solvents removed at room temperature to yield phenylbromoacetylene.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:36])[NH:17][C:18]([N:21]3[C:29]4[C:28]5[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:27]=5[CH2:26][CH2:25][C:24]=4[CH:23]=[N:22]3)([CH3:20])[CH3:19])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:36])[NH:17][C:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]5[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]5=4)[CH:23]=[N:22]3)([CH3:20])[CH3:19])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2c(c1)CCc1cnn(C(C)(C)NC(=O)OCC3c4ccccc4-c4ccccc43)c1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2c(ccc3cnn(C(C)(C)NC(=O)OCC4c5ccccc5-c5ccccc54)c32)c1
Temperature: 23 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
To a solution of the product from Step B (0.11 g, 0.23 mmol) in 1,4-dioxane (10 mL) was added DDQ (0.19 g, 0.8 mmol) and the solution stirred at 23° C. for 72 h. The solution was poured into aqueous NaHCO3 and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried (MgSO4) and concentrated to a residue, which was purified by chromatography (silica, 25% ethyl acetate in hexanes) to give an oil (0.1 g, 91%): 1H NMR (CDCl3) δ 8.5 (bs, 1H), 8.01 (s, 1H), 7.75 (d, J=6 Hz, 2H), 7.63 (d, J=12 Hz, 1H), 7.5 (bs, 1H), 7.4 (m, 3H), 7.3-7.2 (m, 5H), 5.2 (m, 1H), 5.0 (m, 1H), 4.75 (m, 1H), 4.4-4.3 (m, 2H), 4.1 (m, 1H), 3.93 (s, 3H), 1.21 (t, J=6 Hz, 3H); MS m/z 478 [M+H]+.
Reaction SMILES: [O-]CC.[Na+].CCO[C:8]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)=[O:9].Cl.[C:20]([NH2:23])(=[NH:22])[CH3:21]>>[CH3:21][C:20]1[NH:23][C:8](=[O:9])[CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:22]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1nc(-c2ccccc2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a freshly prepared solution of sodium ethoxide (18 g of sodium metal was dissolved in 1 L of ethanol), was added ethyl benzoyl acetate (75 g, 0.39 mol) and the mixture was stirred at room temperature for 30 min. To this was added acetamidine hydrochloride (37 g, 0.39 mol) in portions and the mixture was refluxed for 24 h under nitrogen. The reaction mixture was cooled and excess ethanol was removed under vacuum. The residue was acidified to pH=4 with 1.5N HCl and the precipitate was filtered and dried under suction to afford 15 g (21%) of the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)=[O:20])=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)[OH:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=C(C(=O)c3ccc(OCCN4CCCC4)cc3)c3ccccc3CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C2=C(C(O)c3ccc(OCCN4CCCC4)cc3)c3ccccc3CC2)cc1
Temperature: 25 °C

Procedure:
850 mg (1.9 mmol) of [2-(4-methoxyphenyl)-3,4-dihydronaphth-1-yl][4-(1-pyrrolidinyl-2-ethoxy)phenyl] methanone was dissolved in 100 mL of THF and 160 mg (4 mmol) of LiAlH4 was added. The reaction mixture was stirred at room temperature and under a N2 atmosphere for eighteen hours. The reaction mixture was evaporated to dryness in vacuo. Fifty mL of water was carefully added to the residue and the reaction mixture was extracted twice with 100 mL of EtOAc. The EtOAc extracts were combind and washed with water, then the EtOAc layer was removed and dried by filteration through anhydrous Na2SO4 and evaporated to dryness in vacuo. This yielded 670 mg of the title compound as a white amorphous powder.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:22][O:23]/[N:24]=[C:25](/[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1)\[CH2:26]Br.Cl>CS(C)=O>[CH2:34]([C:31]1[CH:32]=[CH:33][C:28]([C:25](=[N:24][O:23][CH3:22])[CH2:26][O:1][C:2]2[CH:15]=[CH:14][C:5]([CH2:6][CH:7]3[S:11][C:10](=[O:12])[NH:9][C:8]3=[O:13])=[CH:4][CH:3]=2)=[N:29][CH:30]=1)[CH3:35]
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: CCc1ccc(/C(CBr)=N/OC)nc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1ccc(C(COc2ccc(CC3SC(=O)NC3=O)cc2)=NOC)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (210 mg, 0.941 mmol) in DMSO was added potassium tert-Butoxide (227 mg, 2.02 mmol) in a single portion. Stirred at RT for 15 minutes. Added a solution of (1Z)-2-bromo-1-(5-ethylpyridin-2-yl)ethanone O-methyloxime (242 mg, 0.941 mmol; Supplier=Kalexsyn; Lot=1003-TTP-186) in DMSO (2 ml). Added 1M HCl until pH of mixture was about 3. Extracted with EtOAc. The extract was washed with water, dried (Na2SO4), filtered and evaporated in vacuo to give an off-white foam. 278 mg. 1H-NMR (DMSO-d6): δ12.05 (brs, 1H), 8.47 (d, J=1.7 Hz, 1H), 7.77 (m, 1H), 7.70m, 1H), 7.14 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 5.17 (s, 2H), 4.87 (dd, J=8.9, 4.4 Hz, 1H), 4.01 (s, 3H), 3.30 (dd, J=14.2, 4.5 Hz, 1H), 3.06 (dd, J=14.1, 9.1 Hz, 1H), 2.64 (q, J=7.7 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H). HPLC: 3.103 min., 82area % and 3.379 min., 18 area % @254 nm; 3.109 min., 91area % and 3.379 min., 9area % @ 254 nm. MS (ESI−) for C20H21H3O4S m/z 400.3 (M+H)+;m/z 398.3 (M−H)−
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:28]([NH2:30])([CH3:29])[C:27](=[O:31])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:9]=2)[N:7]=1.[CH:32]1([CH:35]=O)[CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:28]([NH:30][CH2:35][CH:32]3[CH2:34][CH2:33]3)([CH3:29])[C:27](=[O:31])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:22])([F:21])[F:23])[N:9]=2)[N:7]=1
Reactant: O=CC1CC1
Reactant: CC1(N)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1(NCC2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the intermediate from Step B (20 mg, 0.045 mmol) in MeOH (45.2 μl) and DCM (45.2 μl) was added cyclopropanecarbaldehyde (3.17 mg, 0.045 mmol) followed by sodium triacetoxyborohydride (28.7 mg, 0.136 mmol). The reaction was stirred for 3 h at room temperature and was quenched with aqueous NaHCO3. The solution was extracted with EtOAc. The organic layer was dried (sodium sulfate), concentrated in vacuo and purified by silica gel column chromatography to afford the title product as a white solid. 1H NMR (500 MHz, CHCl3-d): δ 9.20 (s, 1H); 8.77 (d, J=8.07 Hz, 1H); 8.56 (dd, J=4.53, 1.58 Hz, 1H); 7.13 (dd, J=8.08, 4.50 Hz, 1H); 5.55 (s, 2H); 4.95-4.88 (m, 3H); 2.88-2.74 (m, 2H); 2.27 (dd, J=11.46, 6.00 Hz, 1H); 2.20-1.94 (m, 1H); 1.54 (s, 3H); 0.87-0.80 (m, 1H); 0.48-0.37 (m, 2H); 0.05-0.00 (m, 2H). m/z=497.1 (M+H).
Reaction SMILES: [O-:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].[Na+].Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[O:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]3)=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: ClCCN1CCOCC1
Reactant: O=S(=O)([O-])c1ccc2ccc([O-])cc2c1
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2ccc(OCCN3CCOCC3)cc2c1
Yield: 44.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 26B, sodium 7-oxidonaphthalene-2-sulfonate (Pfaltz and Bauer, 200 mg, 0.75 mmol) and 4-(2-chloroethyl)morpholine (223 g, 1.49 mmol) were converted to the title compound (113 mg, 45%). 1H NMR (DMSO-d6) δ 9.90 (br s, 1H), 8.10 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.58 (dd, J=8.1, 1.3 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.24 (dd, J=8.7, 2.3 Hz, 1H), 4.48 (br s, 2H), 3.99 (br s, 2H), 3.65 (br s, 4H), 3.26 (br s, 4H); MS (ESI+) m/z 336.3 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]3)[CH:12]=2)[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3].[CH2:26](I)[CH3:27].C(N(CC)CC)C>CN(C)C=O>[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:26][CH3:27])[CH:16]([CH3:20])[CH2:15]3)[CH:12]=2)[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C)C3)cc21
Reactant: CCI
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CC1C
Yield: 48.1 %

Procedure:
A solution of 1.00 g of 1-ethyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid hydrochloride, 1.29 g of ethyl iodide and 1.09 g of triethylamine in 20 ml of N,N-dimethylformamide was heated at 70° to 80° C. for 1.5 hours. The solvent of the reaction mixture was evaporated and the residue was acidified with 50% aqueous acetic acid. The solution was neutralized with 20% aqueous sodium hydroxide and the precipitate was filtered. The precipitate was chromatographed on silica gel using chloroform-methanol (9:1) as eluent to give 0.47 g of the title compound as colorless crystalls, which was recrystallized from a mixture of chloroform and methanol as colorless needles, M.p. 203°-205° C.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.C1(C)C=CC=CC=1.O1CCCC1.[F:21][C:22]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](=[O:56])[C@@H:31]([NH:37][C:38](=[O:55])[C@H:39]([NH2:54])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH2:48][O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:42][CH:41]=1)[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34].C(N(CC)C(C)C)(C)C>O1CCCC1.O>[F:21][C:22]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](=[O:56])[C@@H:31]([N:37]1[C:38](=[O:55])[C@@H:39]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH2:48][O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:44][CH:45]=2)[NH:54][C:2]1=[O:1])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)C[C@H](NC(=O)[C@H](N)c1ccc(OCCOC(C)(C)C)cc1)C(=O)Nc1ccc(I)cc1F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)C[C@@H](C(=O)Nc1ccc(I)cc1F)N1C(=O)N[C@H](c2ccc(OCCOC(C)(C)C)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 135.7 %

Procedure:
To a solution of diphosgene (41 μL, 0.34 mmol) in 1:1 v/v toluene/tetrahydrofuran (18 mL total) at −35° C. under an atmosphere of dry argon was added a solution of (S)-2-{(R)-2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetylamino}4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-amide (300 mg, 0.49 mmol) and N,N-diisopropylethylamine (260 μL, 1.47 mmol) in tetrahydrofuran (9 mL) dropwise with stirring over 10 minutes. After an additional 45 minutes ice was added and the reaction mixture stirred vigorously and warmed to ambient temperature. The reaction mixture was poured into water, extracted with ethyl acetate (twice) and the combined organic layers washed sequentially with water (twice), 0.1 M aqueous hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and brine, then dried over sodium sulfate, filtered and concentrated in vacuo to give (S)-2-{(R)-4-[4-(2-tert-butoxyethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}4,4-dimethylpentanoic acid (2-fluoro-4-iodo-phenyl)-amide as yellow sticky solid (295 mg, 95%) which was used in the subsequent step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: BrCCCCBr
Reactant: N#Cc1ccc2[nH]ccc2c1
Product: N#Cc1ccc2c(ccn2CCCCBr)c1

Procedure:
The procedure is as for Example 39 using as substrate 1H-indole-5-carbonitrile and 1,4-dibromobutane.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@H:5]([CH3:18])[CH2:4][N:3]1[C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22].[CH2:28]([CH2:30][NH2:31])[OH:29].[Cl-].[NH4+]>CN1CCCC1=O>[CH3:1][C@H:2]1[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:31][CH2:30][CH2:28][OH:29])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@H:5]([CH3:18])[CH2:4][N:3]1[C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:22])[F:23]
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(F)cc1
Reactant: NCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(NCCO)cc1
Temperature: 120 °C
Yield: 37.6 %

Procedure:
To a solution of (R)-[(2S,5R)-2-methyl-5-methyl-5-methyl-4-(4-fluorophenylsulphonyl)-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (Example 6, 350 mg, 0.85 mmol) in 1-methyl-2-pyrrolidone (2 ml) was added ethanolamine (114 mg, 1.87 mmol) and the mixture heated at 120° C. for 24 hours. The mixture was cooled to ambient temperature, poured onto saturated ammonium chloride solution (30 ml), the mixture extracted with diethyl ether (2×30 ml), the combined ether extracts washed with brine, dried and evaporated. The residue was chromatographed on silica with EtOAc as eluent to give the title compound as a solid (143 mg, 0.32 mmol). NMR: 0.95 (d, 3H), 1.55 (d, 3H), 1.6 (s, 3H), 3.1 (m, 2H), 3.3 (dt, 2H), 3.4 (d, 1H), 3.8 (dt, 2H), 4.2 (s, 1H), 4.6 (m, 2H), 6.6 (d, 2H), 7.5 (d, 2H); m/z 411.
Reaction SMILES: [CH2:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)[CH2:2][CH3:3].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[CH2:12]([O:11][C:9]([C:7]1[CH:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([Br:14])=[CH:16][CH:17]=2)[N:6]=1)=[O:10])[CH3:13]
Reactant: CCCc1cc(C(=O)OCC)[nH]n1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OCC)nn1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 3-n-propylpyrazole-5-carboxylate (8.0 g, 43.0 mmol), 4-bromobenzyl bromide (11.0 g, 43.0 mmol) and potassium carbonate (5.9 g, 43.0 mmol) were dissolved in DMF (433 mL, 5590 mmol). The resulting suspension was stirred at room temperature over approximately 48 hours. The material was concentrated, then diluted with aqueous NaHCO3 and diethyl ether. The aqueous layer was further extracted with diethyl ether. The combined organics were dried over MgSO4, filtered and concentrated. The residue was purified using flash chromatography (1st 40:1 hexanes/EtOAc; 2nd 5:1 hexanes/EtOAc). The two isomers were separated and analyzed by NMR and NOE: 1-(4-bromobenzyl)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (5.7 g) and 2-(4-bromobenzyl)-5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH:3]1[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH2:18](O)[CH2:19][OH:20].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:18]1[CH2:19][O:20][C:5]2([CH2:6][CH2:7][CH:2]([CH3:1])[CH:3]([S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:10])=[O:11])[CH2:4]2)[O:8]1
Reactant: CC1CCC(=O)CC1S(=O)(=O)c1ccccc1
Reactant: OCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1CCC2(CC1S(=O)(=O)c1ccccc1)OCCO2
Yield: 97 %

Procedure:
To a solution of 2.45 g of 4-methyl-3-(phenylsulfonyl)-cyclohexan-1-one in 40 ml of benzene, were added 0.7 ml of 1,2-ethanediol and 0.2 g of anhydrous paratoluenesulfonic acid. The resulting mixture was heated under reflux for 4 hours. After the reaction, a 2M aqueous sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate three times. The combined organic layers were washed with saturated saline, and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was recrystallized from ethyl ether, whereby 1,1-(ethylenedioxy)-4-methyl-3-(phenylsulfonyl)-cyclohexane was obtained in the form of white crystals. Yield: 97%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15](=O)[CH2:16][CH3:17])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>>[CH2:16]([C:15]1[N:14]=[C:9]2[C:8](=[C:5]3[C:6]=1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4]3)[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH3:17]
Reactant: CCC(=O)Nc1ccccc1-c1ccc(F)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc2ccccc2c2ccc(F)cc12

Procedure:
The title compound was prepared from N-(4′-fluoro-1,1′-biphenyl-2-yl)propanamide (5.00 g, 20.6 mmol) and phosphorous oxychloride (9.6 mL, 103 mmol), according to the procedure and in the same manner as described in Example 36, Step b to yield, after purification by re-crystallization from a mixture of ethyl acetate-hexane, 6-ethyl-8-fluorophenanthridine as a white solid (1.43 g, 31%, m.p. 105-106° C.;
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:41][CH2:40][C:35]2([O:39][CH2:38][CH2:37][O:36]2)[CH2:34][CH2:33]1)[C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])=[O:16].[CH3:42][C:43]1([CH3:50])[CH2:48][CH2:47][C:46](=[O:49])[CH2:45][CH2:44]1>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:46]2([OH:49])[CH2:47][CH2:48][C:43]([CH3:50])([CH3:42])[CH2:44][CH2:45]2)=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:41][CH2:40][C:35]2([O:39][CH2:38][CH2:37][O:36]2)[CH2:34][CH2:33]1)[C:23]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]1)=[O:24])=[O:16]
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Reactant: CC1(C)CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1sc(C2(O)CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (5.75 g, 56.8 mmol) and dry THF (58 mL) were added to a dry 500 mL 3 neck round bottom flask under nitrogen. The solution was cooled to −40° C. and nBuLi (39 mL, 47.4 mmol) was added slowly while keeping the internal temperature at −40° C. After 15 min, a suspension of 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbo-nyl)-amino]-thiophene-2-carboxylic acid methyl ester (10.0 g, 23.7 mmol) in THF (70 mL) was added dropwise while maintaining the internal temperature at −40° C. After 30 min at −40° C., 4,4-dimethyl-cyclohexanone (5.88 g, 47.7 mmol) was added in one portion and stirred at −40° C. for 30 min. The reaction mixture was quenched with saturated NH4Cl, partitioned and the aqueous phase extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, filtered and evaporated to obtain crude 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(1-hydroxy-4,4-dimethyl-cyclohexyl)-thiophene-2-carboxylic acid methyl ester (14.4 g) which was used for the next step without any purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[NH:6][C:5]2=[O:23].[CH3:24][C:25](OC(C)=O)=[O:26]>N1C=CC=CC=1>[C:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[NH:6][C:5]2=[O:23])(=[O:26])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2cc1O
Solvent: c1ccncc1
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2cc1OC(C)=O
Temperature: 105 °C
Reaction time: 2 h

Procedure:
A mixture of 6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (2.3 g, 7.34 mmol), Ac2O (40 mL) and pyridine (4 mL) were heated at 105° C. for 3.5 h. The reaction mixture was allowed to cool and poured into ice-water (ca. 300 mL) and the resulting slurry was stirred for 2 h. The solid was collected by filtration and washed with water, EtOH and Et2O and dried under high vacuum to give 7-methoxy-2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate. (2.6 g, 7.31 mmol, 99%). HPLC retention time 6.24 min.