Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[CH:5]=1.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:11]2[C:6]3[CH:5]=[C:4]([Cl:3])[S:19][C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:18][CH2:17]1
Reactant: O=Cc1ccccc1F
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Agent: Cl
Product: Fc1ccccc1CN1CCC(Nc2ncnc3sc(Cl)cc23)CC1

Procedure:
The title compound was prepared (65 mg, 37%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (160 mg, 0.47 mmol) and 2-fluorobenzaldehyde (58 mg, 0.47 mmol) by following the general procedure described for Preparation 11. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.37 (t, 1H), 7.25 (m, 1H), 7.13 (t, 1H), 7.07 (t, 1H), 6.97 (s, 1H), 4.85 (d, 1H), 4.16 (m, 1H), 3.63 (s, 2H), 2.92 (d, 2H), 2.29 (t, 2H), 2.08 (d, 2H), 1.61 (m, 2H); MS (ESI) m/z: Calculated for C18H19ClFN4S, 377.1; Observed: 377.2 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:11][C:10]=1[C:23]([OH:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](=[NH:37])[NH:35]O)=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.O1CCOCC1.CCOCC>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:11][C:10]=1[C:23]1[O:25][N:37]=[C:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)[N:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(Cc1ccc(F)cc1)NO
Reactant: Cn1c(N2CCOCC2)nc(C(=O)O)c(OCc2ccccc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(N2CCOCC2)nc(-c2nc(Cc3ccc(F)cc3)no2)c(OCc2ccccc2)c1=O
Temperature: 110 °C
Yield: 50 %

Procedure:
A mixture of 5-(benzyloxy)-1-methyl-2-morpholino-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (prepared according to the procedure in WO2004062613 (0.35 g, 1 mmol), 2-(4-fluorophenyl)-N-hydroxyacetimidamide (0.25, 1.5 mmol) HATU (0.76 g, 2 mmol), DIEA (0.35 mL) and DMAP (10 mg) in 1,4-dioxane (5 mL) was heated at 110° C. for 5 h. The mixture was cooled, diluted with Et2O (50 mL), washed with water (10 mL), sat. NaHCO3 (10 mL), brine (10 mL) then dried (Na2SO4), filtered and concentrated to give a brown residue. This residue was purified by flash chromatography on a silica gel column using 1:1 hexanes/EtOAc as eluant to afford the title compound (0.24 g, 50% yield) as a white solid. 1HNMR (500 MHz, CDCl3) δ: 7.42-7.39 (2H, m), 7.32 (2H, dd, J=8.4, 5.4 Hz), 7.28-7.25 (3H, m), 7.00 (2H, t, J=8.6 Hz), 5.28 (2H, s), 4.14 (2H, s), 3.84-3.82 (4H, m), 3.55 (3H, s), 3.24-3.22 (4H, m). HRMS (M+H) calcd for C25H25N5O4F: 478.1491. found: 478.5663.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[N:34]1([CH2:40][CH2:41]Cl)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: ClCCN1CCOCC1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCCN4CCOCC4)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 2-(morpholin-4-yl)ethyl chloride essentially as previously described. mp 175° C., NMR, IR, MS 572.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)[C:11]([N+:21]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][C:3]1=[O:24].[C:25]([C:27]1[O:31][C:30]([C:32](Cl)=[O:33])=[CH:29][CH:28]=1)#[N:26].C(C1OC(C(O)=O)=CC=1)#N>C(Cl)Cl>[CH3:20][CH:17]1[CH2:18][CH2:19][N:14]([C:12]2[C:11]([NH:21][C:32]([C:30]3[O:31][C:27]([C:25]#[N:26])=[CH:28][CH:29]=3)=[O:33])=[CH:10][CH:9]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:24])[CH2:4]3)[N:13]=2)[CH2:15][CH2:16]1
Reactant: CC1CCN(c2nc(N3CCN(C)C(=O)C3)ccc2[N+](=O)[O-])CC1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Agent: N#Cc1ccc(C(=O)O)o1
Solvent: ClCCl
Product: CC1CCN(c2nc(N3CCN(C)C(=O)C3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 51 %

Procedure:
1-Methyl-4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-2-one (as prepared in previous step) (166 mg, 0.50 mmol) was converted to the corresponding amine according to the procedure in Example 55, step (c) and coupled with 5-cyano-furan-2-carbonyl chloride as prepared in Example 4, step (c) (obtained from 137 mg, 1.00 mmol of 5-cyano-furan-2-carboxylic acid as prepared in Example 1) in CH2Cl2 (2 mL) at 0° C. The product was isolated by flash chromatography on silica (20% EtOAc/hexane-10% MeOH/EtOAc) to obtain the title compound (108 mg, 51%). 1H-NMR (CDCl3; 400 MHz): δ 8.73 (br s, 1H), 8.44 (d, 1H, J=8.7 Hz), 7.24 (d, 1H, J=3.7 Hz), 7.22 (d, 1H, J=3.7 Hz), 6.32 (d, 1H, J=8.7 Hz), 4.16 (m, 2H), 3.84 (m, 2H), 3.46 (m, 2H), 3.20 (m, 2H), 3.04 (s, 3H), 2.84 (m, 2H), 1.8 (m, 2H), 1.4 (m, 1H), 1.32 (m, 2H), 1.04 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z): Calcd. for C22H26N6O3, 423.2 (M+H), found 423.1
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1.[F:13][C:14]1[CH:22]=[C:21]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>>[F:13][C:14]1[CH:22]=[C:21]([B:23]2[O:27][C:26]([CH3:28])([CH3:29])[C:25]([CH3:31])([CH3:30])[O:24]2)[CH:20]=[CH:19][C:15]=1[C:16]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[CH3:1])=[O:17]
Reactant: CC1(C)OB(c2ccc(C(=O)O)c(F)c2)OC1(C)C
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F

Procedure:
A 100 mL toluene/EtOH mixture of commercially available 4-carboxy-3-phenyl boronic acid and pinacol is stirred at 75-80° C. for 2 hours, then concentrated, slurried in toluene, concentrated, and dried in vacuo to give 2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid that is used without further purification. The title intermediate is prepared in a manner substantially analogous. General Procedure E using 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine and 2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid. The crude product is confirmed by NMR and MS (MS+) 417.5 (M+H)+ then used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1>>[CH3:19][C:20]1[C:24]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: Cc1noc(C)c1-c1cncc(N2CC3CC4CC2CN(C4)C3)c1

Procedure:
The title compound was prepared from the product of Example 65A and 3,5-dimethylisoxazol-4-ylboronic acid according to General Method B: LC-MS Method B (ESI+) m/z 325.0 (M+H)+, retention time 1.61 minutes.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1.CC(C)([O-])C.[Na+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:2]1([C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:14][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.5 %

Procedure:
An oven-dried test tube was charged with tris(dibenzylideneacetone) dipalladium (4.6 mg, 0.005 mmol) and bis(2-(diphenylphosphino)phenyl)ether [DPE-phos] (8.2 mg, 0.015 mmol), capped with a rubber septum, evacuated and refilled with argon. Benzophenone imine (190 mg, 1.05 mmol), 3-bromoanisole (187 mg, 1.0 mmol) and toluene (2 mL) were added via syringe. The resulting solution was stirred at rt for 5 minutes. The tube was opened and sodium tert-butoxide (135 mg, 1.4 mmol) was added. The tube was again capped with the septum, and additional toluene (2 mL) was added via syringe to wash the solid from the test tube wall into the solution. The solution was stirred at room temperature with a gentle argon purge for 5 minutes, then heated at 80° C. for 5 hours and 40 minutes. The reaction mixture was cooled to room temperature, washed with saturated aqueous sodium chloride (2 mL), and the organic layer was concentrated in vacuo. The product was isolated as a yellow oil (237 mg, 83%) by flash chromatography on silica gel using 10% ethyl acetate in hexanes as eluent.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].COC(OC)OC.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:19][CH2:20][CH2:21][CH2:22][OH:23])([O-:3])=[O:2]
Reactant: NCCCO
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: O=[N+]([O-])c1cccc(CNCCCO)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of m-nitrobenzaldehyde (94.23 mmol) and trimethylorthoformate (15.5 mL, 141 mmol) in MeOH (300 mL) is added dropwise 3-amino-1-propanol (7.21 mL, 94.23 mmol) at room temperature. The reaction is allowed to stir at room temperature for 5 hours followed by cooling to 0° C. in an ice bath. Sodium borohydride (3.56 g, 94.23 mmol) is added in two portions and when the bubbling stops the solvent is evaporated. The resulting residue is partitioned between ethyl acetate (75 mL) and water (75 mL). The aqueous layer is extracted twice with ethyl acetate (75 mL). The ethyl acetate extracts are collected and washed twice with Brine (50 mL), dried over MgSO4, filtered, and concentrated. Drying will give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:29]([O:38]C)=[CH:28][C:27]=2[CH3:40])[CH:19]=[CH:18][CH:17]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:8][C:6]1[C:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[C:26]3[CH:31]=[C:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:29]([OH:38])=[CH:28][C:27]=3[CH3:40])[CH:19]=[CH:18][CH:17]=2)=[C:2]([CH3:1])[CH:7]=1
Reactant: COc1cc(C)c(-c2cccc3cccc(-c4cc(-c5ccccc5)c(OC)cc4C)c23)cc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)c(-c2ccccc2)cc1-c1cccc2cccc(-c3cc(-c4ccccc4)c(O)cc3C)c12
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 1,8-bis(2′-methyl-4′-methoxy-5′-phenylphenyl)naphthalene, 6, (0.14 g, 0.28 mmol) in 10 mL of anhydrous CH2Cl2 at 0° C., BBr3 (1.67 mL, 1.67 mmol) was added dropwise and the mixture was stirred for sixteen hours at room temperature. The reaction was carefully quenched with isopropyl alcohol followed by addition of water, and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (CH2Cl2) afforded 0.12 g of 2 (0.25 mmol, 89%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:10]=1[Cl:11])=[O:5])C.[OH-].[Li+]>CO.O>[Cl:11][C:10]1[N:9]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(CCOCCOC)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOCCn1ncc(C(=O)O)c1Cl
Yield: 86 %

Procedure:
To a solution of 5-chloro-1-[2-(2-methoxyethoxy)-ethyl]-1H-pyrazole-4-carboxylic acid ethyl ester (3.43 g, 12.39 mmol) in methanol (12 mL) and water (12 mL) was added lithium hydroxide (415 mg, 17.3 mmol). The reaction mixture was stirred at reflux for 3 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was then acidified carefully with 6.0 N aqueous HCl. The resulting mixture was extracted with methylene chloride (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 5-chloro-1-[2-(2-methoxyethoxy)-ethyl]-1H-pyrazole-4-carboxylic acid as a white solid (2.65 g, 86%). Mass spectrum: m/z: 249.0 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3C(OC)=O)=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO>O1CCCC1.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCc4cc(C(C)(C)C)ccc43)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)CCC2NC(=O)Nc1cccc2[nH]ncc12
Reaction time: 0.5 h

Procedure:
Methyl 4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate (5.67 g, 14 mmol) in tetrahydrofuran (20 ml) was treated with A 5M solution of sodium hydroxide in methanol (8 ml, 40 mmol). After stirring for 30 minutes, the reaction mixture was diluted with water and filtered. The solid was air-dried and then treated with ethanolic HCl to provide the title compound as the hydrochloride salt. 1H NMR (DMSO-d6) δ 1.06 (t, 1.8H, EtOH), 1.27 (s, 9H), 1.75-1.88 (m, 1H), 2.40-2.48 (m, 1H), 2.76-2.88 (m, 1H), 2.90-3.01 (m, 1H), 3.44 (q, 1.2H, EtOH), 5.12 (m, 1H), 6.84 (br d, 1H), 7.05 (d, 1H), 7.20, (m, 1H), 7.26 (s, 2H), 7.31 (s, 1H), 7.69 (d, 1H), 8.10 (s, 1H), 8.70 (s, 1H); MS (ESI+): 349 (M+H)+; Elemental: Calculated for C21H24N4O.HCl.0.6EtOH.0.6H2O: C62.98, H7.09, N13.23; Found: C63.09, H6.97, N13.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH2:7]1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: COc1ccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 46.4 %

Procedure:
Example 22 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.028 g) and (4-methoxyphenyl)acetic acid (0.018 g) to give the title compound (0.02 g).
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.[C:8]([C:10]1[CH:18]=[CH:17]C(C(N)=O)=[CH:12][CH:11]=1)#[N:9].N([N+]([O-])=O)=O>C(O)(=O)C>[C:8]([C:10]1[CH:18]=[CH:17][C:6]([C:5]([OH:4])=[O:7])=[CH:12][CH:11]=1)#[N:9]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(C(N)=O)cc1
Agent: O=N[N+](=O)[O-]
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)O)cc1
Reaction time: 6 h
Yield: 94 %

Procedure:
Acetic acid (30 ml), acetic anhydride (70 ml), and p-cyanobenzamide (5 g) were mixed with stirring under cooling with ice, to thereby obtain a mixture. The mixture was allowed to react while dinitrogen trioxide gas was introduced thereto at 190 N ml/hour for six hours. The residual solvent was removed through distillation in vacuum, and water was added to the residue, to thereby form crystals. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 4.73 g of p-cyanobenzoic acid (yield 94%, based on p-cyanobenzamide). High performance liquid chromatographic analysis revealed that the p-cyanobenzoic acid obtained had a purity of 99% or more.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:25]([O:27][CH3:28])=[O:26])=[C:9]([CH3:24])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:29]([CH3:32])(=[O:31])=[O:30])[CH3:2].C1C(=O)N([Br:40])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:40][CH2:24][C:9]1[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[N:11][C:12]2[C:7]([C:8]=1[C:25]([O:27][CH3:28])=[O:26])=[CH:6][C:5]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=2
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1S(C)(=O)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CBr)c(C(=O)OC)c2cc1S(C)(=O)=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 7-(ethyloxy)-3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.92 g, 6.25 mmol), NBS (1.445 g, 8.12 mmol) and diphenylperoxyanhydride (0.151 g, 0.625 mmol) in carbon tetrachloride (30 mL) was heated to 100° C. and stirred overnight. The mixture was cooled to room temperature and the solvent was removed under reduced pressure to give methyl 3-(bromomethyl)-7-(ethyloxy)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 548.0 (M+H+).
Reaction SMILES: [CH:1](/[C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2)[CH:7]=[N:8][CH:9]=1)=[CH:2]\[CH3:3].[OH-].[Na+]>CO>[CH:1](/[C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:21])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)[CH:7]=[N:8][CH:9]=1)=[CH:2]\[CH3:3]
Reactant: C/C=C/c1cncc(-c2ccc(C(C)C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C=C/c1cncc(-c2ccc(C(C)C(=O)O)cc2)c1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a solution of 14c (38 mg, 0.13 mmol) in methanol (3 mL) was added 2N NaOH (0.1 mL, 0.2 mmol). The light yellow solution was stirred overnight, then concentrated. The residue was partitioned between pH 7 phosphate buffer and EtOAc. The organic phase was washed with brine, dried over MgSO4 and evaporated to provide 31 mg of the title compound as an oil.
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH:5]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:6][C:7]1[C:8]([CH2:16]Cl)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[NH:18][CH:5]1[C:4](=[O:3])[N:34]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:16][C:8]2[C:9]3[CH:10]=[N:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(Cc1ccc2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Reactant: CC(C)CN
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)CN1Cc2c(ccc3[nH]ncc23)CC(NC(=O)OCc2ccccc2)C1=O

Procedure:
In a manner similar to [9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamic acid benzyl ester, the title compound was prepared by treating 2-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionic acid methyl ester, hydrochloride with isobutylamine followed by treatment with acetic acid in refluxing toluene to give (9-Isobutyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamic acid benzyl ester in 91% yield. MS (ESI) 407 (M+H) ; Rf=1.58.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](S(C)=O)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH2:40][C:41]([CH3:44])([OH:43])[CH3:42])[N:25]=2)[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([CH2:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:1][C:2]4[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=4)[N:31]=3)=[CH:28][N:27]=[C:26]([NH:39][CH2:40][C:41]([OH:43])([CH3:42])[CH3:44])[N:25]=2)[CH2:21][CH2:22]1
Reactant: N#Cc1ccc(N)cc1
Reactant: CS(=O)c1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)CNc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(CC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
To a solution of 4-aminobenzonitrile (16.34 mg, 0.138 mmol) in THF (277 μl) cooled to −78° C. under nitrogen, LiHMDS (415 μl, 0.415 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 minutes. To the reaction mixture cooled back to −78° C., 1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol (5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for additional 1 hour. According to LC/MS, the reaction was complete. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (16 mg, 28%).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:32][CH2:31][C:6]2([N:10]([O:11]COC)[C:9](=[O:15])[C:8]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])=[C:7]2[O:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])[CH2:5][CH2:4]1.Br[Si](C)(C)C>ClCCl>[OH:11][N:10]1[C:6]2([CH2:31][CH2:32][N:3]([O:2][CH3:1])[CH2:4][CH2:5]2)[C:7]([O:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])=[C:8]([C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[C:9]1=[O:15]
Reactant: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(OCOC)C12CCN(OC)CC2
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(O)C12CCN(OC)CC2
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of carbonic acid ethyl ester 8-methoxy-1-methoxymethoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (compound P1 ii.7 obtained in analogy to preparation example 11, step 6) (1.0 g, 2.23 mmol) in bromotrimethylsilane (4.33 ml, 5.12 g, 33.44 mmol) under argon atmosphere was added 3 {acute over (Å)} molecular sieves (0.5 g) and the reaction mixture was stirred at 75° C. overnight. The mixture was diluted with dichloromethane, filtered, the filtrate evaporated, the residue triturated with cold diethyl ether, filtered and dried. The crude product was purified by chromatography on silica gel (gradient dichloromethane→dichloromethane/methanol 20:1→10:1). Yield: 580 mg of carbonic acid ethyl ester 1-hydroxy-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (compound P1ii.11) as a white solid, mp 154-155° C.