Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][C:26](CC)([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:34]C1C(C(O)=O)CCNC1.C(C1CCC(OC2C=C3C(=CC=2)C=C(C=O)C=C3)CC1)(C)(C)C.C(O)(=O)C.CO.C([BH3-])#N.[Na+]>>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]([OH:31])=[O:30])[CH:27]([CH3:34])[CH2:28]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1CNCCC1C(=O)O
Reactant: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Agent: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1CN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CCC1C(=O)O
Yield: 2 %

Procedure:
The compound was prepared in a manner similar as to that described for 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid using 3-Methyl-piperidine-4-carboxylic acid (0.154 g, 1.08 mmol), 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.3 g, 0.9 mmol) and Acetic acid (0.18 mL, 3.1 mmol) in Methanol (1.8 mL, 44 mmol) and sodium cyanoborohydride (84.101 mg, 1.3383 mmol) to give 6 mg 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-3-methyl-piperidine-4-carboxylic acid (2%). ESI-LCMS 438 (M+H). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.73-8.05 (m, 3H), 7.50-7.67 (m, 1H), 7.44 (s, 1H), 7.12-7.30 (m, 1H), 4.45 (br. s., 3H), 2.99-3.49 (m, 3H), 2.59-2.74 (m, 1H), 1.70-2.28 (m, 7H), 1.03-1.48 (m, 6H), 0.96 (d, J=6.8 Hz, 3H), 0.89 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.S(Cl)([Cl:19])=O.C1(C)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Cl:19])[CH:10]=2)=[N:6][CH:7]=1
Reactant: OCc1cccc(Oc2ncc(Br)cn2)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: ClCc1cccc(Oc2ncc(Br)cn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
(3-(5-Bromopyrimidin-2-yloxy)phenyl)methanol (0.790 g, 2.81 mmol) in dichloromethane (9 mL) was cooled to 0° C. and treated dropwise with thionyl chloride (0.215 mL, 2.95 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. Toluene (5 mL) was added and the mixture was concentrated to give the title compound (0.815 g, 97% yield) as a semi-solid. MS (APCI) M+1=299.0.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([CH3:21])[CH2:12][N:13]2[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]2)[CH:7]=[CH:8][CH:9]=1.I[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.O>CN(C)C=O>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([O:3][C:4]2[CH:5]=[C:6]([CH2:10][CH:11]([CH3:21])[CH2:12][N:13]3[CH2:14][CH:15]([CH3:20])[O:16][CH:17]([CH3:19])[CH2:18]3)[CH:7]=[CH:8][CH:9]=2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: CC(Cc1cccc(O)c1)CN1CC(C)OC(C)C1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Cc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1)CN1CC(C)OC(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
Dimethylformamide (5 ml) was added to 60% sodium hydride (0.12 g) under nitrogen stream, and a solution of 4-[3-(3-hydroxyphenyl)-2-methylpropyl]-2,6-dimethylmorpholine (0.48 g) in dimethylformamide (5 ml) was added thereto in 30 minutes, followed by stirring at room temperature for 2 hours. To the reaction mixture, p-iodonitrobenzene (0.97 g) and cuprous chloride (0.1 g) were added, and the resultant mixture was heated under reflux for 10 hours. Then, water (100 ml) was added to the reaction mixture, which was filtered through celite. The celite was washed with toluene (200 ml). The toluene layer and the toluene washing were combined together and shaken with 15% aqueous sodium hydroxide solution (30 ml). The toluene layer was separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 4-[3-(3-(4-nitrophenoxy)phenyl)-2-methylpropyl]-2,6-dimethylmorpholine (cis-isomer, 0.27 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2([NH2:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1.C(N(CC)CC)C>C(O)CCC>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2([NH2:14])[CH2:9][CH2:10][N:11]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:12][CH2:13]2)=[CH:15][CH:16]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NC1(Cc2ccc(Cl)cc2)CCNCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NC1(Cc2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 49.3 %

Procedure:
A solution of 4-(4-chlorobenzyl)piperidin-4-yl amine hydrochloride (0.060 g, 0.2016 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.031 g, 0.2016 mmol) and triethylamine (0.140 ml, 1.0079 mmol) in n-butanol (2.0 ml) was heated to 100° C. for 24 hours. Concentration and purification by preparative silica TLC gave a white solid (0.034 g, 49%). LC-MS (LCT) m/z 342 [M+H+], Rt 3.25 min.
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NCCCCCCCC=O)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([NH:62][C:63]([C:65]3[CH:66]=[C:67]([S:71]([C:74]4[CH:75]=[C:76]5[C:81](=[C:82]([CH3:84])[CH:83]=4)[N:80]=[CH:79][C:78]([C:85]([NH2:87])=[O:86])=[C:77]5[NH:88][C:89]4[CH:94]=[CH:93][CH:92]=[C:91]([O:95][CH3:96])[CH:90]=4)(=[O:73])=[O:72])[CH:68]=[CH:69][CH:70]=3)=[O:64])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>>[CH3:96][O:95][C:91]1[CH:90]=[C:89]([NH:88][C:77]2[C:76]3[C:81](=[C:82]([CH3:84])[CH:83]=[C:74]([S:71]([C:67]4[CH:68]=[CH:69][CH:70]=[C:65]([C:63](=[O:64])[NH:62][C:59]5[CH:60]=[CH:61][C:56]([C:53]6[CH:54]=[CH:55][C:50]([CH2:49][CH2:48][CH2:47][CH:46]=[O:45])=[CH:51][CH:52]=6)=[CH:57][CH:58]=5)[CH:66]=4)(=[O:73])=[O:72])[CH:75]=3)[N:80]=[CH:79][C:78]=2[C:85]([NH2:87])=[O:86])[CH:94]=[CH:93][CH:92]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCCO)cc6)cc5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCC=O)cc6)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 112, using IBX in place of Dess-Martin reagent and Intermediate 90 as a substrate. ES/MS calcd. for C41H37N4O6S+ 713.2. Found m/z=713.3 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:10]([OH:12])=O)=O)(C)(C)C.[NH2:19][C@@H:20]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C@@H:21]([OH:27])[C@H:22]([CH:24]1[CH2:26][CH2:25]1)[OH:23]>>[NH2:8][CH:9]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:10]([NH:19][C@@H:20]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C@@H:21]([OH:27])[C@H:22]([CH:24]1[CH2:26][CH2:25]1)[OH:23])=[O:12]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)O
Product: NC(Cc1cccs1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described above, by the condensation of rac-α-(tert-butoxyformamido)-3-(thiophen-2-yl)propionic acid [Pol. J. Chem. 54(11-12), 2225 (1980)] and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol followed by acidic hydrolysis there was obtained (RS)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(thiophen-2-yl)propionamide, MS: 381 (M+H)+ as a colourless foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:23][CH2:22][C@@H:21]3[CH2:24][C@H:18]2[C:19](=[O:32])[N:20]3[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13]1=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:34].[OH-].[Li+].O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:23][CH2:22][C@@H:21]([NH:20][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:24][C@H:18]2[C:19]([OH:34])=[O:32])[C:13]1=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
A stirring solution of (1R,2S,5R)-tert-butyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate (108 g, 0.236 mol) in THF (1 L) was charged with lithium hydroxide monohydrate (21.74 g, 0.519 mol). Water (0.3 L) was added slowly, such that the temperature did not exceed 20° C. The reaction was stirred at room temperature overnight and the volatiles were removed in vacuo. The pH was adjusted to ˜4 through the addition of 1N HCl (450 mL) and NaH2PO4. The resultant white precipitates were collected by filtration and washed with water (2×1 L). The solid was dissolved in dichloromethane (1.5 L) and water (˜1 L). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in EtOAc (0.7 L) and the resultant solution was heated at reflux for 1 h. Solids separated after cooling to RT, and were collected via filtration. These solids were purified by recrystallization in isopropanol to afford the desired (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid as a white solid (104.5 g, 93% yield). LC/MS for primary peak: [M-tBu+H]+=420.2; [M-Boc+H]+=376.2; [M+H]+=476.2. 1H-NMR (400 MHz, d4-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.35 (m, 2H), 3.71 (m, 1H), 3.45-3.6 (m, 2H), 2.99 (m, 1H), 2.41 (m, 1H), 2.15 (m, 1H), 2.0 (m, 2H), 1.6-1.9 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1C1C=CC=CC=1.IC1C=C2C(=CC=1)C(=O)N[C:35](=O)[C:34]2=[CH:43][O:44][CH3:45].NCC1C=C(O)C=CC=1C1OC=CC=1>>[O:44]1[CH:43]=[CH:34][CH:35]=[C:45]1[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][C:6]=1[CH2:8][NH:9][CH:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[C:14](=[O:22])[NH:13][C:12]1=[O:23]
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Agent: NCc1cc(O)ccc1-c1ccco1
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1cc(O)ccc1-c1ccco1
Yield: 56 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (100 mg, 0.30 mmol) and 3-Aminomethyl-4-furan-2-yl-phenol (crude material from the previous reaction in 56% yield: MS (ESI): 485.1 (M−1)−1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21]CCC)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)cn1
Temperature: 40 °C
Yield: 88 %

Procedure:
A solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxylate (see reference example 1) (10.2 g, 0.55 mmol) in THF (3 ml) and methanol (5 ml) was treated with 1N aqueous sodium hydroxide solution (2.7 ml) and was heated to 40° C. for 24 hours. The solvents were evaporated at reduced pressure, the residue treated with 1N acetic acid (2.7 ml) and the precipitate filtered, washed with water and air dried to give the title compound (0.17 g, 92%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.[S:9](Cl)([Cl:12])(=[O:11])=[O:10]>O1CCOCC1.C(#N)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:9]([Cl:12])(=[O:11])=[O:10])[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CN1CCN(S(=O)(=O)Cl)CC1
Temperature: 25 °C
Yield: 44 %

Procedure:
To a solution of N-methylpiperazine (1.48 mL, 13.3 mmol) in dioxane (6.7 mL) cooled to 0° C. was added 4N hydrochloric acid in dioxane (10 mL). The reaction was very exothermic, and the mixture was stirred until the reaction cooled to room temperature. The solvent was removed under reduced pressure and chased with ether (2×). The solid obtained was taken up in acetonitrile (7 mL) and sulfuryl chloride (3.53 mL, 3.3 equiv) was added. The mixture was warmed at relux for 24 hours and the product removed by filtration and washed with 1:1 acetonitrile/ether (100 mL). This crude material was recrystallized from hot methanol and acetonitrile to afford 4-methylpiperazin-1-ylsulfonyl chloride (1.36 g, 44%) as a white crystalline solid.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[O:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(Cl)Cl.O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[O:18])=[CH:14][CH:15]=2)[CH:5]=[CH:4]1
Reactant: COc1ccc(Cc2ccc(NC(=O)Nc3ccc(C)cc3)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)Nc2ccc(Cc3ccc(=O)[nH]c3)cc2)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension of N-(4-(6-methoxy-pyridin-3-ylmethyl)-phenyl)-N′-(4-methyl-phenyl)-urea (Example 95; 0.28 g, 0.81 mmol) and trimethylsilyl-jodide (0.6 ml) in chloroform (10 ml) is stirred for 16 h at 60° C. Then CH2Cl2 (4 ml), water (10 ml) and saturated NaHCO3 solution (5 ml) is added and the suspension stirred vigorously. Filtration, washing with CH2Cl2 and water followed by column chromatography (SiO2; AcOEt/MeOH 9:1→4:1 MeOH) yields the title compound: 1H-NMR (DMSO-d6): 11.4 (s, HN), 8.52 (s, HN), 8.47 (s, HN), 7.33 (d, 2H), 7.29 (d, 2H), 7.25 (dd, 1H), 7.16 (s, 1H), 7.07 (d, 2H), 7.04 (d, 2H), 6.24 (d, 1H), 3.58 (s, 2H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:39])=[C:35](F)[CH:36]=3)[C:31](=[O:40])[N:30]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:29]2=[O:49])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:39])=[C:35]([N:11]4[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]4)[CH:36]=3)[C:31](=[O:40])[N:30]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:29]2=[O:49])=[CH:26][CH:27]=1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccc(F)cc2)C1
Yield: 79.7 %

Procedure:
Using General Method 4, the reaction of 3-t-butoxycarbonylamino-pyrrolidine (0.28 g, 1.5 mmol), triethylamine (0.2 mL, 1.5 mmol), and 1-(4-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B-1, 0.2 g, 0.5 mmol) provided 0.225 g of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][OH:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH2:21](Br)[C:22]#[CH:23]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:23][C:22]#[CH:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: C#CCBr
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCO
Product: C#CCOCCn1c(COCC)nc2cnc3ccccc3c21
Yield: 101 %

Procedure:
Using the general method of Example 1 Part A 2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethanol (1.39 g, 5.123 mmol) was reacted with propargyl bromide (80% in toluene, 1.7 mL, 15.37 mmol) to provide 1.6 g of 2-(ethoxymethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[N:7]=1)=O)C.[BH4-].[Na+]>CCO>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:7]=[C:6]([CH2:4][OH:3])[S:10][N:9]=2)=[CH:12][CH:13]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1nc(-c2ccc(OCc3ccccc3)cc2)ns1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1nc(-c2ccc(OCc3ccccc3)cc2)ns1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
To a solution of 3-(4-benzyloxyphenyl)-[1,2,4]thiadiazole-5-carboxylic acid ethyl ester (0.20 g, 0.59 mmol) in EtOH (20 ml) was added sodium borohydride (0.44 g, 1.17 mmol) portion wise and the resulting reaction mixture was stirred at room temperature for 2 h. After the completion of the reaction (TLC monitoring), the reaction mass was cooled to 0° C., quenched it with 5 ml of water and concentrated under vacuum. Added 75 ml water and extracted with ethyl acetate (3×30 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 30% EtOAc-Hexane) to get the desired product (0.052 g, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][C:3]=1[C:4](OC)=[O:5].CC1C=C(Br)C(S(C)(=O)=O)=CC=1C(OC)=O.[Cl-].C([Zn+])(C)C.[NH2:40][C:41]([NH2:43])=[NH:42]>CO.[Cu]I>[NH2:42][C:41]([NH2:43])=[N:40][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]([CH:12]([CH3:14])[CH3:13])=[CH:11][C:2]=1[CH3:1]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(C(C)C)cc1C
Agent: [Cu]I
Agent: CC(C)[Zn+]
Agent: COC(=O)c1cc(S(C)(=O)=O)c(Br)cc1C
Solvent: CO
Product: Cc1cc(C(C)C)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reaction time: 5 h

Procedure:
A solution of 1.4 g of methyl 2-methyl-4-isopropyl-5-methylsulfonylbenzoate [obtainable by reacting methyl 2-methyl-4-bromo-5-methylsulfonylbenzoate with isopropylzinc chloride in the presence of Pd(II) 1,1'-bis(diphenylphosphine)ferrocene chloride and CuI] and 1.5 g of guanidine in 50 ml of methanol is boiled for five hours and the solvent is then removed. The residue is treated with water and the remaining crystalline crop is filtered off with suction and treated with dil. sodium hydroxide solution. The solid residue is filtered off and recrystallized from ethanol, and N-diaminomethylene-2-methyl-4-isopropyl-5-methylsulfonylbenzamide is obtained, m.p. 220°-223°.
Reaction SMILES: C([Li])CCC.[C:6]([CH:8]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9]1)#[N:7].[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>CCCCCC.O1CCCC1>[C:6]([C:8]1([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9]1)#[N:7]
Reactant: O=C1CCCCC1
Reactant: N#CC1Cc2ccccc21
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CC1(C2(O)CCCCC2)Cc2ccccc21
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Whilst maintaining the temperature at -78° C., 69 ml of 1.6M butyllithium in n-hexane are added to a solution of 12.9 g of 1-cyanobenzocyclobutane in 200 ml of tetrahydrofuran. After stirring for half an hour at that temperature, 15.5 ml of cyclohexanone are added and the reaction mixture is brought back to room temperature. After stirring for 3 hours at room temperature, the reaction mixture is hydrolysed at -10° C. with water. After extraction with diethyl ether, the organic phase is washed with brine, dried over MgSO4 and concentrated in vacuo. The crystalline residue is recrystallised from isopropyl ether to yield 12.32 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)(=[O:13])[CH2:10][CH2:11][CH3:12].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCC(=O)O
Reactant: Nc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc(O)cc1

Procedure:
4-aminophenol (550 mg; 5 mmol) is added to a solution of butyric acid (1.4 mL; 15 mmol) in DCM (20 mL) at room temperature and stirred vigorously. To this solution DCC (2.48 g; 12 mmol) is added followed by DMAP (24 mg) and the contents stirred overnight at room temperature. The reaction mixture is then filtered and washed with DCM. The filtrate is concentrated and redissolved in methanol, added with 10% aqueous sodium bicarbonate solution and stirred vigorously until diacylated byproduct disappeared (as detected by LC-MS) to yield 4-butyramidophenol as the only product. The product was used for further transformation without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][C:27]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: COc1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-5-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c7) the title compound is obtained as yellow solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]([C:30](OCC)=[O:31])[N:19]([CH3:29])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28]>>[CH:1]1([NH:7][C:30]([C:18]2[N:19]([CH3:29])[C:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:16]([C:10]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=3[Cl:8])[N:17]=2)=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2Cl)n1C
Reactant: NC1CCCCC1
Product: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1Cl

Procedure:
Using essentially the same procedure as Example 30, Step E, but using cyclohexylamine (1 mL), ethyl 4,5-di-(2,4-dichlorophenyl)-1-methylimidazole-2-carboxylate (10 mg, 0.022 mmol) from Example 30, Step D was converted to the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][C:16]3=[CH2:21])([CH3:14])[C:12](=[O:22])[CH2:11][CH2:10]4)[C@H:7]([CH3:23])[CH2:6][C:5]=2[CH:4]=1.[BH4-].[Na+]>>[OH:22][C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([C:16](=[CH2:21])[CH2:15][C@:13]12[CH3:14])[C@@H:18]1[C:5](=[CH:4][C:3](=[O:2])[CH2:20][CH2:19]1)[CH2:6][C@H:7]3[CH3:23]
Reactant: C=C1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2[C@H](C)Cc3cc(OC)ccc3[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Product: C=C1C[C@]2(C)[C@@H](O)CC[C@H]2[C@H]2[C@H]1[C@H]1CCC(=O)C=C1C[C@H]2C

Procedure:
3-Methoxy-7α-methyl-11-methyleneestr-1,3,5(10)-trien-17-one (A-11) was subjected to sodium borohydride reduction of the 17-ketone function, Birch reduction with lithium/NH3(1), and acid hydrolysis and rearrangement to the title compound. Experimental details are as follows: