Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].Br[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([CH3:14])[C:10]([O:12][CH3:13])=[O:11].C(=O)=O.CO.CC#N>CN(C=O)C>[C:3]([CH:2]([C:1]#[N:5])[C:9]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:4]
Reactant: N#CCC#N
Reactant: COC(=O)C(C)(Br)c1ccccn1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC#N
Product: COC(=O)C(C)(c1ccccn1)C(C#N)C#N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A DMF (7 mL) solution of malononitrile (0.413 g, 6.24 mmol) was added to a suspension of NaH (0.252 g, 6.30 mmol, 60%) in DMF (9 mL) cooled to 0° C. After 10 minutes a DMF (7 mL) solution of the intermediate from Step B (1.438 g, 5.89 mmol) was added. The reaction solution was then stirred overnight at room temperature. The solution was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR (400 MHz, CHCl3-d): δ 8.59 (d, J=4.8 Hz, 1H); 7.79 (td, J=7.7, 1.8 Hz, 1H); 7.50 (d, J=8.0 Hz, 1H); 7.32 (dd, J=7.6, 4.8 Hz, 1H); 5.25 (s, 1H); 3.77 (s, 3H); 2.01 (s, 3H). m/z=230.2 (M+H). The racemic material was resolved on a Berger SFC II preparative instrument using a ChiralCel IA-H, 250×30 mm I.D. column and a SFC CO2/Methanol/MeCN eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([NH:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:13][C:14]1[C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[C:17]([CH3:31])[O:16][N:15]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([N:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:18]3[C:14]([CH3:13])=[N:15][O:16][C:17]=3[CH3:31])=[CH:26][CH:25]=2)(=[O:28])=[O:29])=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CNc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
N-(4-chlorophenyl)-4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-isobutylbenzenesulfonamide was prepared in an array format. 4-chloro-N-isobutylaniline (1.493 mg, 0.099 mmol) was pre-weighed into a 2 mL vial, and 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (30 mg, 0.099 mmol) then added, followed by 4-DMAP (approx 2 mg). Pyridine (0.3 mL) was added last. The reaction solution was capped and stood at RT for 3 days. After this time the reaction was not complete and the reaction were warmed to 80° C. for 2 hours. The pyridine was removed to almost dryness. DMSO (1 mL) was added to the residues which were then purified by mass directed autoPrep on a Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required products.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=3.[C:24]1([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C1O[CH2:59][CH2:58]OCCOCCOCCOCCOC1>ClC1C=CC=CC=1Cl.[Cu]>[C:31]1([N:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][C:10]([N:6]([C:59]2[CH:58]=[CH:12][CH:7]=[CH:8][CH:9]=2)[C:5]2[CH:13]=[CH:14][CH:2]=[CH:3][CH:4]=2)=[CH:9][CH:8]=4)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(c1ccccc1)n1c2ccc(I)cc2c2cc(I)ccc21
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: O=C(c1ccccc1)n1c2ccc(N(c3ccccc3)c3ccccc3)cc2c2cc(N(c3ccccc3)c3ccccc3)ccc21

Procedure:
A mixture of 3,6-diiodo-9-benzoyl-9H-carbazole (5.7 mmol), diphenylamine (1.86 g, 11 mmol, available from Aldrich), powdered potassium carbonate (6.35 g, 46 mmol), copper powder (1.46 g, 23 mmol), and 18-crown-6 (0.4 g, available from Aldrich) is refluxed in o-dichlorobenzene (30 ml) under nitrogen for 24 hours. The copper and inorganic salts are filtered off and the solvent is removed by distillation. The product is recrystallized, washed with methanol, filtered, and dried.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[H-].[Na+].[C:12]([C:16]1[N:20]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]2[CH:28]=[CH:29][C:30]([S:32](Cl)(=[O:34])=[O:33])=[CH:31][C:18]=2[N:17]=1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([C:16]1[N:20]([CH2:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:19]2[CH:28]=[CH:29][C:30]([S:32]([N:1]3[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]3)(=[O:33])=[O:34])=[CH:31][C:18]=2[N:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)c1cc[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1
Yield: 26.8 %

Procedure:
Following the same procedure in Example 29, using methyl 1H-pyrrole-3-carboxylate (0.16 g, 1.3 mmol) (see following step B for preparation), sodium hydride (0.18 g, 60%, 4.5 mmol) and 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (0.48 g, 1.3 mmol) in THF (10 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 0.16 g (27%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.46-1.54 (m, 4 H), 1.56 (s, 9 H), 2.15-2.32 (m, 1 H), 3.25-3.37 (m, 2 H), 3.79 (s, 3 H), 3.93-4.03 (m, 2 H), 4.22 (d, J=7.42 Hz, 2 H), 6.62 (dd, J=3.32, 1.56 Hz, 1 H), 7.15 (dd, J=3.32, 2.34 Hz, 1 H), 7.42 (d, J=8.79 Hz, 1 H), 7.74-7.81 (m, 2 H), 8.33 (d, J=1.37 Hz, 1 H); MS (ESI) (M+H)+=459.8; Anal. Calcd for C23H29N3O5S+0.10 EtOAc+0.30H2O (474.98): C, 59.43; H, 6.45; N, 8.85. Found: C, 59.34; H, 6.60; N, 8.84.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[OH:43][C@H:44]1[C@H:49]([OH:50])[C@@H:48]([OH:51])[CH:47](O)[O:46][C@@H:45]1[C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54]>>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][C@@H:47]3[O:46][C@H:45]([C:53]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[O:54])[C@@H:44]([OH:43])[C@H:49]([OH:50])[C@H:48]3[OH:51])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)O[C@@H]2O[C@H](C(=O)OCc3ccccc3)[C@@H](O)[C@H](O)[C@H]2O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with (2S,3S,4S,5R)-benzyl 3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate (prepared according to the procedure reported in Bowkett et al. Tetrahedron 2007, 63, 7596-7605) to give (2S,3S,4S,5R,6S)-benzyl 6-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([C:33]2[CH:38]=[CH:37]C=CC=2)(=[N:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])=[CH:21][CH:20]=1>>[CH2:31]([O:30][C:28]([N:27]=[S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH:33]1[CH2:38][CH2:37]1)=[O:26])=[O:29])[CH3:32]
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CCOC(=O)N=S(=O)(c1ccccc1)c1ccc(N)cc1
Product: CCOC(=O)N=S(=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1)C1CC1
Yield: 43 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (155 mg, 0.57 mmol) with (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-phenyl-sulfoximide (159 mg, 0.52 mmol) according to procedure 5c, the desired product is obtained in 43% yield (120 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.Cl.Cl.[CH2:19]([N:26]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[N:28]=[CH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>COCCO.O>[CH2:19]([N:26]1[C:34]2[CH2:33][CH2:32][N:31]([C:2]3[NH:11][C:10](=[O:12])[C:9]4[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=4)[N:3]=3)[CH2:30][C:29]=2[N:28]=[CH:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Reactant: c1ccc(Cn2cnc3c2CCNC3)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Solvent: O
Product: COc1cc2nc(N3CCc4c(ncn4Cc4ccccc4)C3)[nH]c(=O)c2cc1OC
Temperature: 120 °C
Reaction time: 6 h
Yield: 29.9 %

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1 (wherein R is methyl and Z is —C(O)—, 296 mg, 1.24 mmol), 1-benzyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine dihydrochloride 15a (440 mg, 1.54 mmol)) and diisopropylethylamine (1.2 g, 9.26 mmol) in 2-methoxyethanol (10 mL) was stirred at 120° C. for 6 hours. The reaction mixture was concentrated in vacuo to give an oil residue, which was diluted with water. The white precipitate that formed was collected by filtration to give 155 mg of 2-(1-benzyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-6,7-dimethoxy-3H-quinazolin-4-one 501, [M+H]+=418.
Reaction SMILES: C(OC(=O)[N:7]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:32])[CH2:10][CH2:9]1)(C)(C)C.[ClH:45].O1CCOCC1>O1CCOCC1>[ClH:45].[CH2:30]([NH:29][C:27]([NH:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[CH:18][C:17](=[O:32])[N:16]2[CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH:7][CH2:33][C:34]2[CH:43]=[CH:42][C:37]3[O:38][CH2:39][CH2:40][O:41][C:36]=3[CH:35]=2)[CH2:9][CH2:10]1)=[O:28])[CH3:31]
Reactant: CCNC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 55 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(3-ethylureido)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature for 3 hours. The resulting solid was filtered to give 26 mg of 1-ethyl-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)quinolin-2(1H)-on-5-yl)urea hydrochloride as a yellow solid.
Reaction SMILES: O[CH:2](CN1CCOCC1)CN1CCCC2NC(C=O)=C(C)C=2C1=O.F[C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])/[C:29]/2=[CH:36]\[C:37]1[NH:46][C:45]2[CH2:44][CH2:43][CH2:42][N:41]([CH2:47][C@H:48]([OH:56])[CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[C:40](=[O:57])[C:39]=2[C:38]=1[CH3:58].CC1C=CC=C2C=1CC(=O)N2.N1CCCCC1>C(O)C>[OH:56][C@H:48]([CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1)[CH2:47][N:41]1[CH2:42][CH2:43][CH2:44][C:45]2[NH:46][C:37](/[CH:36]=[C:29]3\[C:30](=[O:35])[NH:31][C:32]4[C:28]\3=[C:27]([CH3:2])[CH:26]=[CH:34][CH:33]=4)=[C:38]([CH3:58])[C:39]=2[C:40]1=[O:57]
Reactant: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CCC2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CC(O)CN1CCOCC1)CCC2
Agent: Cc1cccc2c1CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc2c1/C(=C/c1[nH]c3c(c1C)C(=O)N(C[C@H](O)CN1CCOCC1)CCC3)C(=O)N2
Temperature: 45 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 53f (30 mg, 0.09 mmol) and 4-methyl-1,3-dihydro-indol-2-one (12 mg, 0.08 mmol) were dissolved in 156 μl of ethanol, and added with 4.4 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at 45° C. for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the title compound (R,Z)-5-(2-hydroxy-3-morpholinopropyl)-3-methyl-2-((4-methyl-2-oxoindolin-3-ylidene)methyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 76(12 mg, yield 30%) as a orange solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1.[CH3:31][NH:32][CH3:33].O>CCO>[CH3:31][N:32]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1)[CH3:33]
Reactant: CNC
Reactant: O=C1CC(c2cccc(-c3nc(CCl)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Solvent: O
Solvent: CCO
Product: CN(C)Cc1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[3-(4-chloromethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 78a) (125 mg) and KI (5 mg) in a 5.6M solution of dimethylamine in EtOH (1.5 mL) was stirred at 20° C. for 16 h. H2O (20 mL) was added and the precipitate was collected by filtration and purified by chromatography on silica gel using MeOH as eluent. The product was stirred with 20% aqueous MeOH (10 mL) the pH of the mixture being set to 11 by addition of 1N NaOH solution, and the solid was isolated by filtration to give the title compound (50 mg) as yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:29]=[CH:28][CH:27]=[CH:26][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:29]=[CH:28][CH:27]=[CH:26][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:31][C:32]#[N:33])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(O)ccc3c2)o1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCC#N)ccc3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A mixture of 6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthol (1.29 g, 3.37 mmol), prepared in the previous step, bromoacetonitrile (282 μL, 4.05 mmol) and of potassium carbonate (2.33g, 16.8 mmol) in 100 mL of DMF was stir under nitrogen overnight at room temperature. The reaction was diluted with ethyl acetate, extracted three times with water, dried (MgSO4), filtered and the solvent was removed under reduced pressure to give ({6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (1.12 g, 79%) as a white solid, mp 127-127° C. Elemental Analysis for C27H22N2O3 Calc'd: C, 76.76; H, 5.25; N, 6.63. Found: C, 76.53; H, 5.22; N, 6.59.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C@H:49]([C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CC#N>[F:68][C:65]1[CH:64]=[CH:63][C:62]([C@@H:49]([NH:48][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([N:11]3[CH:15]=[CH:14][CH:13]=[N:12]3)=[N:5][CH:6]=2)=[O:10])[C:50]2[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=2)=[CH:67][CH:66]=1
Reactant: CCOP(C)(=O)c1ccc([C@H](N)c2ccc(F)cc2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.7 %

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (5.15 g, 25 mmol) and Et3N (6.9 g, 68 mmol) in MeCN (100 ml) was added HATU (9.5 g, 25 mmol). The mixture was stirred for 5 min at room temperature and then compound 18-e (7 g, 23 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. Then it was concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (petroleum ether:ethyl acetate=2/1) to provide the product, 18-f, (8.1 g, 65.7%).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:31])[C:26]=1[C:27]([F:30])([F:29])[F:28])=O)(=O)OC.O.[NH2:33][NH2:34]>>[CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4]1[C:3]2=[N:33][N:34]=[C:20]([C:22]2[CH:23]=[N:24][N:25]([CH3:31])[C:26]=2[C:27]([F:30])([F:29])[F:28])[CH:19]=1
Reactant: COP(=O)(CC(=O)c1cnn(C)c1C(F)(F)F)OC
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: NN
Solvent: O
Product: Cn1ncc(-c2cc3c(nn2)[C@@]2(C)CC[C@@H]3C2(C)C)c1C(F)(F)F

Procedure:
yellow oil. MS (ESI): 337.0 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(1-Methyl-5-trifluoromethyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1>[Pd].CCO.CCOC(C)=O>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(N)cn1
Reaction time: 16 h

Procedure:
Palladium on carbon (200 mg) was added to a solution of N,N-dimethyl-5-nitropyridin-2-amine (1.29 g, 7.75 mmol) in EtOH (40 mL) and EtOAc (40 mL). The resulting mixture was stirred for 16 h under a H2 atmosphere, filtered and concentrated in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:12][CH3:13])[CH:6]=[N:7]2.C(OC(=O)[NH:23][CH:24]1[CH2:27][NH:26][CH2:25]1)C1C=CC=CC=1>>[CH3:13][O:12][C:5]1[CH:6]=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([N:26]1[CH2:27][CH:24]([NH2:23])[CH2:25]1)[CH:11]=[CH:10][CH:9]=2
Reactant: COc1cnc2cccc(Br)c2c1
Reactant: O=C(NC1CNC1)OCc1ccccc1
Product: COc1cnc2cccc(N3CC(N)C3)c2c1

Procedure:
Starting from 5-bromo-3-methoxyquinoline (WO 2007/107965) and azetidin-3-yl-carbamic acid benzyl ester (commercial) the title compound was prepared according to procedure L followed by procedure G and was isolated as a pale yellow solid (122 mg, 63% over two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][OH:9].C(OC([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=O)(C)(C)C.C(N(CC)CC)C.Cl>C(O)C.O1CCOCC1>[ClH:1].[N:17]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:8][OH:9])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: OCc1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: OCc1cnccc1N1CCNCC1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-3-hydroxymethylpyridine (J. Med. Chem., 49 (13), 2832-2840 (2002))(143 mg, 1 mmol), 1-(tert-butoxycarbonyl)piperazine (186 mg, 1 mmol) and triethylamine (1 mL, 7 mmol) were dissolved in ethanol(3 mL), and the mixture was stirred overnight in a threaded test tube at 130° C. The solvent was evaporated and work-up according to a conventional method gave a crude product. The obtained crude product was dissolved in a dioxane solution (5 mL) containing 4 N hydrogen chloride, and the mixture was stirred for 2 hrs. The solvent was evaporated to give the title compound, which was used for the synthesis of C-22 and C-37.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([CH3:49])[CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][C:15]([C:19]3[CH:20]=[CH:21][C:22]4[NH:23][C:24]5[C:29]([C:30]=4[CH:31]=3)=[CH:28][C:27]([C:32]3[CH:33]=[CH:34][C:35]4[N:36]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:37]6[C:42]([C:43]=4[CH:44]=3)=[CH:41][CH:40]=[CH:39][CH:38]=6)=[CH:26][CH:25]=5)=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[CH2:50](Br)[CH:51]=[CH2:52]>CS(C)=O>[CH3:3][CH:4]([CH3:49])[CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][C:15]([C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH2:52][CH:51]=[CH2:50])[C:24]5[C:29]([C:30]=4[CH:31]=3)=[CH:28][C:27]([C:32]3[CH:33]=[CH:34][C:35]4[N:36]([CH2:45][CH:46]([CH3:48])[CH3:47])[C:37]6[C:42]([C:43]=4[CH:44]=3)=[CH:41][CH:40]=[CH:39][CH:38]=6)=[CH:26][CH:25]=5)=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: C=CCBr
Reactant: CC(C)Cn1c2ccccc2c2cc(-c3ccc4[nH]c5ccc(-c6ccc7c(c6)c6ccccc6n7CC(C)C)cc5c4c3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCn1c2ccc(-c3ccc4c(c3)c3ccccc3n4CC(C)C)cc2c2cc(-c3ccc4c(c3)c3ccccc3n4CC(C)C)ccc21
Reaction time: 3 h
Yield: 50.1 %

Procedure:
A mixture of NaOH (0.1 g, 2.58 mmol) and 7 (0.26 g, 0.43 mmol) in DMSO (20 ml) was stirred at room temperature for 10 minutes before allylbromide (0.26 g, 2.13 mmol) was added in one portion. The mixture was stirred for another 3 hours before quenching with water followed by extraction with methylene chloride. The organic extracts were combined, washed with water and dried over MgSO4. Upon evaporating off the solvent, the crude product was purified by column chromatography on silica gel using hexane/methylene chloride 4:1 (v/v) as the eluent to yield 8 (0.14 g, 49%) as a white powder. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.52-8.44 (m, 4H), 8.21-8.19 (d, 2H), 7.87-7.84 (m, 4H), 7.52-7.42 (m, 8H), 7.27-7.25 (m, 2H), 6.15-6.02 (m, 1H), 5.28-5.12 (m, 2H), 5.02-5.01 (d, 2H), 4.16-4.14 (d, 4H), 2.50-2.40 (m, 2H), 1.04-1.03 (d, 12H).